Comprehensive Physiology || Catecholaminergic Brain Stem Regulatory Systems

C H A P T E R 3

Catecholaminergic brain stem regulatory systems

Department of Histology, University of Lund, A N D E R S B J o R K L U N D ~ Lurid, Sweden

Department of Neurology, University of Lund, O L L E L I N D V A L L 1 Lund, Sweden

C H A P T E R C O N T E N T S

Catecholaminergic Cell Groups Noradrenergic cell groups

Locus coeruleus-subcoeruleus complex Lateral tegmental cell system Dorsal medullary cell group

Mesencephalic neuron system Diencephalic cell groups

Dopaminergic cell groups

Phylogenetic Perspective Comparative aspects of brain stem catecholaminergic

Catecholaminergic projections to forebrain

Dorsal tegmental bundle Central tegmental tract Periventricular system Nigrostriatal pathway Medial forebrain bundle

cell groups

Catecholaminergic Fiber Tracts

Dopaminergic fiber trajectories Noradrenergic fiber trajectories

Dopaminergic Projection Systems Mesotelencephalic system

Mesostriatal system Mesolimbocortical system

Diencephalic projections of mesencephalic dopaminergic

Descending projections from mesencephalic dopaminergic

Projections of diencephalic cell groups

cell groups

cell groups

Diencephalospinal system Periventricular system Incertohypothalamic system Tuberohypophysial system

Mesotelencephalic Dopaminergic Neurons and Organization of Striatal and Limbic Forebrain Circuitry

General organizational features Transmitter characteristics

Functional Aspects of Mesotelencephalic Dopamine System Dopamine-deficiency syndrome Simplified scheme for dopaminergic regulation of striatal

output functions Level-setting action Gating action Response selection and activation of motor responses

Dopaminergic modulation of neurotransmission in substantia nigra through dendrites of nigral neurons

I

Dendritic dopamine appears to tonically inhibit activity of

Dendritic dopamine may modulate y-aminobutyric

Dendritic dopamine can activate pars reticulata

dopaminergic cells

acid release

efferent neurons Noradrenergic Projection Systems

Locus coeruleus system General organizational features Forebrain projection Cerebellar projection Brain stem projection Spinal cord projection

Forebrain projection Brain stem projection Spinal cord projection

Lateral tegmental and dorsal medullary systems

Noradrenergic Systems Viewed as Components of Brain Stem

Functional Aspects of Brain Stem Noradrenergic Systems Reticular Formation

Neuromodulatory actions Arousal and attention Descending effects on locomotion Blood flow, stress, and epileptic seizures

Regenerative Responses and Functional Recovery After Brain Injury

Regeneration after axotomy Collateral sprouting after deafferentation Compensatory hyperactivity Reinnervation and recovery of function by grafted

catecholaminergic neurons Summary

Catecholamine neurons can operate in both synaptic and

Catecholamines function a t both axonal and dendritic terminals Catecholamine release depends on neuronal activity and local

neurohumoral manners

transmitter interactions

THE STUDY OF THE CENTRAL catecholamine (CA) neuron systems has played an important role both in unraveling the chemical coding of the central regulatory systems and in reaching deeper insights into the organization and function of the brain stem reticular core. Historically the CAs gained special interest

.55

156 HANDBOOK OF PHYSIOLOGY - T H E NERVOUS SYSTEM IV

partly because of observations (in 1950s and early 1960s) that they occur within neurons of the brain stem reticular formation. The CA neurons thus provided unique opportunities to study an identified subset of neurons within the brain stem reticular core. The availability of selective neuroanatomical tracing methods for monoamine neurons (e.g., aldehyde fluorescence histochemistry and immunocytochemical and autoradiographic methods) and the parallel development of a range of pharmacological tools for selective functional manipulation of these neurons provided unique opportunities to study the role of monoaminergic neurotransmission in central nervous functions. In several respects therefore the monoaminergic neurons became useful as models in studies of brain stem regulatory mechanisms. This has had a profound impact on our understanding of how the brain regulates its own behavioral and neurological performance.

Moruzzi and Magoun’s (367) demonstration of the reticular activating system in 1949 emphasized the lower brain stem’s influence on the activity of the cerebral cortex. However, prior to the discovery of the monoaminergic systems (74), only indirect anatomical connections between the brain stem and the cortical mantle were known. The Golgi impregnation studies of Scheibel and Scheibel (464a) and the anterograde degeneration studies of Nauta and Kuypers (380) emphasized that the diencephalon, especially the midline and intralaminar thalamic nuclei, was the main relay station for ascending control from the brain stem. The assertions made by Dahlstrom and Fuxe (102, 103) and Anden et al. (9-13) that long ascending projections of CA-containing neurons from the lower brain stem reached wide areas of the telencephalon therefore remained highly controversial throughout the 1960s. Their claim was mainly based on the disappearance of monoamine-containing terminals after lesioning and their failure to demonstrate any monoamine- containing cell bodies in the telencephalon. In contrast, silver stains for anterograde degeneration, which were the most sensitive axonal tracing methods available at that time, did not demonstrate any degenerating axons or terminals in the neocortex, striatum, or hippocampus after lesions of the medial forebrain bundle (MFB) (218, 219, 358). Moreover, the time course of disappearance of the monoamines from the forebrain after lesions of the brain stem or the MFB was more protracted than could be expected from the time course of axonal degeneration then known. Heller and Moore (219) summarized this dilemma:

If the proposal that the effect of lesions on monoamines in all areas of the brain is a direct result of section and degeneration of monoamine-producing neurons is ac- cepted, it would have two consequences. I t would require an extension of current concepts of the connections of the medial forebrain bundle to include projections to the striatum, the hippocampus and all regions of the neocor-

tex, and it would impugn the validity of all techniques which have been used to date to study the connections of the medial forebrain bundle.

Moore and Heller (219,351) proposed that the metabolism of monoamine neurons within the forebrain was at least partly controlled transsynaptically from the brain stem.

As Bloom (57) pointed out, the main weakness of the fluorescence histochemical evidence at the time was the inability of the original Falck-Hillarp form- aldehyde method to demonstrate the proposed axonal pathways in their entirety. Thus firm anatomical evidence for the postulated direct monoaminergic connections to the forebrain was not obtained until the introduction of the glyoxylic acid-Vibratome method in 1974, which permitted direct microscopic tracing of norepinephrine (NE) and dopamine (DA) axons from their origins in cell bodies of the lower brain stem to their telencephalic terminal areas (296, 297) and the application of the new anterograde and retrograde anatomical tracing methods for studies of monoaminergic systems (250, 281, 378, 428, 467-469).

The discovery of monoaminergic neurons was thus not just a matter of adding chemical tags to known projection systems in the CNS. It meant revealing previously unknown projection principles of specific sets of brain stem neurons. It is probably no exagger- ation to state that the discovery of the central monoamine systems and their organizational principles has had a fundamental impact not only on the development of new concepts of the intrinsic regulatory systems of the brain but also as a starting point for the emergence of a new “chemical” neuroanatomy. The monoaminergic neurons are unconventional in several ways. Although there are relatively few of them, they innervate large areas of the neuraxis, partly in a widely collateralized fashion and partly in a highly organized manner. They exhibit remarkable regenerative and plastic properties (49c) and their axons degenerate slowly after axotomy, sometimes very slowly; for example, the anterograde degeneration process of locus coeruleus axons to the cortex takes 2-3 wk (293). This phenomenon probably explains why monoamine axons are difficult to stain with silver degeneration methods. In addition the synaptic features of monoaminergic neurons are at least partly unconventional. In some areas the terminals may possess mostly nonjunctional synaptic connections (see ref. 26), and part of their action may occur via second messengers (163a,

We approach the CA-containing neuron systems from an anatomical viewpoint. We focus on the long ascending and descending projections and the diencephalic DA neurons, as well as their interconnections with the functional circuitries of the brain, as we know them primarily from studies of the rat. In addition we touch on some current concepts of the function of the noradrenergic and dopaminergic systems. Admittedly

356,357,474-476).

CHAPTER 3: CATECHOLAMINERGIC SYSTEMS 157

we deal with only a few facets of this fascinating topic. It is impossible for us to cover the whole field, and more extensive reviews of the functional and behavioral role of the central CA systems are available (see refs. 125, 163a, 325, 330, 330a, 348, 444).

CATECHOLAMINERGIC CELL GROUPS

Catecholamine-containing neurons are found in the brain stem (from medulla oblongata up to diencephalon), olfactory bulb, and retina. Dahlstrom and Fuxe (102) originally described 12 different CA cell groups, which they designated A1-A12. To these were added the A13 cell group in the rostra1 zona incerta (46,173), the A14 cell group in the anterior periventricular hypothalamus and the preoptic region (46), the A15 cell group of periglomerular cells in the olfactory bulb (208, 227), and the dopaminergic amacrine cells in the retina (135,322). The latter two systems are not dealt with here (see refs. 135, 208 for review of these systems).

The noradrenergic neurons of the brain are primarily located in the medulla oblongata and pons. They can be divided into three major cell systems (102, 299, 357): 2 ) the locus coeruleus-subcoeruleus complex; 2) the lateral tegmental cell system (which has a medullary and a pontine part); and 3) the dorsal medullary cell group. Figures 1 (levels 1-8) and 2 give an overview of the distribution of the noradrenergic perikarya in the rat brain. In their dopamine P-hydroxylase (DBH) immunofluorescence study of the rat, Swanson and Hartman (507) counted -4,700 noradrenergic (i.e., DBH-positive) neurons on each side of the brain stem. Combining their data with data reported in the histofluorescence study of Nygren and Olson (393), it appears that -45%-50% of the noradrenergic neurons are in the locus coeruleus, -10%-15% are in the subcoeruleus, -30% are in the lateral tegmental cell system, and -10% are in the dorsal medullary cell group. This means that -70%-75% of the noradrenergic neurons in the brain are located in the pons and -25%-30% are in the medulla oblongata.

The DA-containing neurons are principally located in the mesencephalon and diencephalon (Fig. 1, levels 9-16). There is no good evidence for DA cell bodies in the pons or medulla oblongata, although the presence of such neurons cannot be entirely excluded. The vast majority of the DA neurons are found in the mesencephalic DA cell system (A8-A10), a system that comprises the neurons of origin for the extensive mesotelencephalic DA projection system. There are -15,000-20,000 neurons on each side of this system in the rat (12, 207, 215, 502). In studies of tyrosine hydroxylase-stained material, Swanson (502) reported that -9,000 DA neurons are located outside the substantia nigra proper (i.e., in areas corresponding to A10 cell group) (Fig. 3). Although a sharp border

line between the substantia nigra and the A10 cell group is difficult to draw, -50% of the mesencephalic DA neurons are located in each area.

Figure 1 (levels 13-16) shows the diencephalic DA cell system (A10-A14). There are far fewer of these neurons, which give rise to extensive intradiencephalic projections and to the descending diencephalospinal pathway, than there are mesencephalic DA cells. From Lichtensteiger’s (292) data (adjusted for double counts with Abercrombie’s formula) one can estimate that the tuberal A12 cell group, which is the source of the tuberoinfundibular and tuberohypophysial DA projections, comprises -500 cells on each side. The number of cells in the remaining diencephalic groups may be of the same order of magnitude. Thus the entire diencephalic DA cell population probably amounts to 4 0 % of the mesencephalic population. Tyrosine hydroxylase immunohistochemistry reveals considerably larger numbers of putative dopaminergic neurons in the diencephalon (77b, 230a). In particular, Hokfelt et al. (230a) have described an additional tyrosine hydroxylase-positive cell system in the preoptic and retrochiasmatic areas (including the bed nucleus of the stria terminalis and supraoptic nucleus) that is not demonstrable with DA histofluorescence. The DA cell distribution given in Figure 1 should therefore be viewed as a conservative assessment of established DA neurons.

In summary, the central CA cell system comprises -50,000 neurons in the rat (excluding dendritic cells of olfactory bulb and retina), with -25,000 on each side, out of which -80% contain DA and -20% contain NE. Approximately 5% of the CA neurons are found in the medulla oblongata, -15% in the pons, -70%-75% in the mesencephalon, and -5%-10% in the diencephalon. Whereas the DA neurons outnum- ber the NE neurons by about fourfold, the total DA content of the rat CNS is only -50% larger than the NE content, i.e., -1.25 pg of DA and 0.75 pg of NE. This means that in its entire extent (cell body and axonal and dendritic processes), the average NE neuron should contain -2-3 times as much transmitter as the average DA neuron. Using these figures, the total steady-state content per neuron is estimated to be -30 pg for the average DA neuron and -75 pg for the average NE neuron. However, since the average turnover rate of DA is about twice that of NE in whole brain (95), the average production rate of DA and NE per neuron is similar. Based on an average half-life of 2 h for brain DA and 4 h for brain NE (95, 245, 391), the average production rate of the transmitter is on the order of 10 pg/h for each neuron type. This can be compared with the average total content of NE in peripheral sympathetic neurons in the rat, which Dahlstrom (101) estimated to be -250 pg. Neverthe- less, since the turnover of peripheral NE is considerably slower than that of central CA [half-life -10-15 h (9511, the transmitter production rates of the average

158 HANDBOOK OF PHYSIOLOGY - THE NERVOUS SYSTEM IV

A

n 1

n P

FIG. 1. Distribution of catecholamine (CA)- containing cell bodies in rat brain (coronal sec-

CSC, commissure of superior colliculus; DLF, dorsal longitudinal fasciculus; dm, dorsomedial hypothalamic n.; drn, dorsal raphe n.; F, fornix; FLM, f. longitudinalis medialis; FMT, f. mam- millothalamicus; FR, f. retroflexus; G VII, genu of facial nerve; gp, globus pallidus; HI and HP, tegmental fields of Forel; ha, anterior hypothalamic area; hl, lateral hypothalamic area; hp, posterior hypothalamic area; IC, internal capsule; ioc, inferior olivary complex; ip, interpeduncular n.; Ic, locus coeruleus; LM, lemniscus medialis; MCP, middle cerebellar peduncle; me

forebrain bundle; MLF, medial longitudinal f.; 2 6 P

V, mesencephalic trigeminal n.; MFB, medial

N 111, oculomotor nerve; N VII, facial nerve; n V, principal trigeminal n.; n VII, facial n.; n X, dorsal motor n. of vagus; n XII, hypoglossal n.; ns V, spinal trigeminal n.; nst, n. of solitary tract; nvm, medial vestibular n.; nvp, posterior vestibular n.; OC, optic chiasm; OT, optic tract or olfactory tubercle; P, pyramidal tract; PC, posterior commissure; pm, posterior mammillary n.; pv, periventricular hypothalamic n.; r, n. ruber; rl, lateral reticular n.; sc, suprachias- matic n.; SCP, superior cerebellar peduncle; SM, stria medullaris; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; SOC, superior olivary complex; TS V, spinal tract of trigeminal nerve; V, trigeminal nerve; V 111, 3 P

3rd ventricle; V IV, 4th ventricle; vm, ventromedial n.; vta, ventral tegmental area; vtn, ventral tegmental or ventral thalamic n.; and ZI, zona incerta. [Adapted from Bjorklund and No- bin (46), Dahlstrom and Fuxe (102), Palkovits and Jacobowitz (403), and Swanson and Hart- man (507).]

1 P

tions). ar, Arcuate nucleus; CC, crus cerebri; 5 P

n P 1s P

P

TSP

nP

7

.*: ) SCP

4 P a peripheral and central NE neurons are probably similar.

Both the noradrenergic and dopaminergic neurons are highly collateralized. The average peripheral sympathetic axon in the rat probably gives rise to a terminal network of -20 cm (101). The dimensions of central CA neurons appear to be similar. The estimates made by Andin et al. (12) and Moore and Bloom (357) show that in the rat, each nigrostriatal DA neuron terminal arbor has an average total length of -30 cm and contains -250,000 terminal boutons; each

locus coeruleus neuron has a terminal length (within cerebral cortex alone) of -30 cm and contains - 100,000 terminal boutons.' However, the dimensions of the different central CA neuron systems vary

I The estimates of Anden et al. (12) for the nigrostriatal system (axons 50-70 cm long and 500,000 varicosities) were based on an estimate of 3,500 DA neurons in the substantia nigra. The actual cell number in the rat seems to be at least twice as high; the figures in this section are thus based on an estimate of 7,000 DA neurons on each side.


B

9 13

10 14

widely. If the nigrostriatal and locus coeruleus neurons thalamic arcuate nucleus) is restricted to the median are taken as examples of highly ramified systems, the eminence and the neurointermediate lobe of the pi- tuberohypophysial DA neurons can be considered tuitary. This region contains -2-3 ng of DA (41,42), short-axoned neurons that ramify within much more or -2-3 pg/neuron. Assuming that the DA content restricted territories. Thus the projection of the per unit axon is similar in the different projection -1,000 neurons in the A12 cell group (within hypo- systems, one can estimate that the total axonal length


+* I I 0:

I

I

I I I

I I

\ I d

I FIG. 2. Distribution of noradrenergic neurons (0) in locus coeruleus of rat; sections are transverse

to longitudinal axis of brain stem. Level 1 is most rostra1 and level 6 most caudal. dtn, Dorsal tegmental n.; and Vm, mesencephalic trigeminal n. [Adapted from Grzanna and Molliver (ZOl).]

of the short-axoned neurons of the tuberohypophysial system is 10-fold shorter than the richly collateralized nigrostriatal projection, i.e., on the order of a few centimeters in the rat.

Noradrenergic Cell Groups

Figure 2 shows, the rat locus coeruleus is a compact structure composed exclusively, or almost exclusively, of NE neurons (102,201,501). It contains 1,400-1,600 cells (114, 501) and is usually divided into a dorsal part composed of densely packed fusiform cells and a ventral part containing somewhat larger multipolar neurons. There are -200 of these larger ventral neurons on each side of the locus coeruleus (501), and they are structurally similar to the NE neurons in the

LOCUS COERULEUS-SUBCOERULEUS COMPLEX. AS

subcoeruleus area. In fact, the multipolar neurons in the ventral locus coeruleus are topographically contin- uous with the more ventrally located subcoeruleus cells and have similar projection patterns. This makes a sharp distinction between the locus coeruleus and nucleus subcoeruleus difficult (see ref. 8). According to Nygren and Olson (393), the subcoeruleus contains -200 NE neurons on each side.

The NE neurons of the locus coeruleus complex also extend rostrally in the dorsolateral part of the central gray (Fig. 2, levels 1 and 2) and dorsolaterally along the medial aspect of the superior cerebellar peduncle into the roof of the fourth ventricle [Fig. 2, level 6; A4 cell group of Dahlstrom and Fuxe (102)l. The A4 cell group is particularly prominent in primates and humans (61, 109).

The locus coeruleus-subcoeruleus complex in the

C

I I , ,

I

I

'\ *-

TM B

D

, ,

FIG. 3. Distribution of dopaminergic neurons in A10 cell group and medial substantia nigra, as revealed by tyrosine hydroxylase immunohistochemistry. A is most rostral and H most caudal. AOB, basal n. of accessory optic tract; bp, brachium pontis; CL, central linear n.; cp, cerebral peduncle; dbc, decussation of brachium conjunctivum; EW, Edinger-Westphal n.; fr, f. retroflexus; IF, interfascicular n.; IPC, central interpeduncular n.; IPF, interpeduncular fossa; IPI, posterior interpeduncular n., inner division; IPO, posterior interpeduncular n., outer division; IPP, paramedian interpeduncular n.; ml, medial lemniscus; mlf, medial longitudinal f.; MM, medial mammillary n.; mp, mammillary peduncle; mt, mammillothalamic tract; PHA, posterior hypothalamic area; PV,, posterior periventricular n.; RL, rostral linear n.; RN, red n.; RR, retrorubral n.; SN,, substantia nigra, pars compacta; SN,, suhstantia nigra, pars reticulata; SUM,, supramammillary region, pars lateralis; SUM,,,, supramammillary region, pars medialis; TM, tuberomammillary n.; VTA, ventral tegmental area; vtd, ventral tegmental decussation; ZI, zona incerta; 111, oculomotor n.; IIIn, oculomotor nerve; and IIIr, oculomotor root fibers. [From Swanson (502).]

161


cat is more loosely arranged and has a more intricate topography than in the rat (81, 249, 288, 319). The locus coeruleus proper, which corresponds to the dorsal compact part of the locus coeruleus in the rat, is located in the periventricular gray and the adjoining tegmentum, extending -3 mm along the mesencephalic root of the trigeminal nerve. More-scattered NE neurons extend ventrolaterally from the locus coeruleus proper in the nucleus subcoeruleus and dorsoventrally in the medial and lateral parabrachial nuclei and the Kolliker-Fuse nucleus. Catecholamin- ergic neurons, probably corresponding to the A4 cell group, are also found in the white matter separating the vestibular and intracerebellar nuclei (422). Ac- cording to Wiklund et al. (556), the entire locus coeruleus complex in the cat contains -9,000 noradrenergic neurons on each side, out of which -5,300 are located in the locus coeruleus proper. Both the locus coeruleus and subcoeruleus contain a significant number of serotonergic cell bodies in the cat (288).

LATERAL TEGMENTAL CELL SYSTEM. Lateral tegmental cells are located in the ventrolateral tegmentum and extend from the caudal pole of the medulla oblongata to the level of the motor nucleus of the trigeminal nerve in the pons (53, 102, 403, 507,556). On the basis of its ontogenetic development and topography (470), this disseminated cell system can be divided into medullary [groups A1 and A3 of Dahlstrom and Fuxe (102)] and pontine parts (groups A5 and A7).

The cells in the medullary part extend, both in rat and cat, from the pyramidal decussation up to the level of the rostral part of the inferior olivary nucleus. They are mainly scattered around the lateral reticular nucleus, but in the rat some cell bodies are also found within this nucleus (53, 102, 556); these NE cells form the A1 cell group. Hokfelt et al. (225) reported that most of the medullary phenylethanolam- ine N - methyltransferase (PNMT) - immunoreactive (i.e., most probably epinephrine-producing) neurons are located in the rostral part of the A1 cell group. These presumably adrenergic neurons, designated group C1, appear to project to the diencephalon and perhaps also to the intermediolateral column of the spinal cord (86, 225).

Cells from the A5 cell group lie in the pontine part of the lateral tegmental cell system and are distributed from the rostral portion of the facial nucleus up to the trigeminal motor nucleus. Caudally, they are caudal and medial to the outgoing fibers of the facial nerve, close to the superior olivary complex. Further rostrally, these cells extend into the area between the ventrolateral border of the superior cerebellar peduncle and the lateral lemniscus, forming the A7 cell group. The border between the A7 cell group and the subcoeruleus cell group is not well defined. The topography of the lateral tegmental neurons is similar in the rat (102, 507) and cat (53, 556).

DORSAL MEDULLARY CELL GROUP. Dorsal medullary cells, the A2 cell group, occur in both the rat and cat in the posterior aspect of the nucleus of the solitary tract and in the commissural nucleus (53, 102, 507, 556). This cell group also contains putative epinephrine-producing neurons, as revealed by PNMT immunohistochemistry (225). These adrenergic cells, which are primarily located in the rostralmost part of the dorsal medullary cell group, are designated group C2; like the C1 neurons they probably project to the diencep halon.

Dopaminergic Cell Groups MESENCEPHALIC NEURON SYSTEM. The mesencephalic DA neurons form an extensive and fairly con- tinuous cell system in the ventral tegmentum (Fig. 1, levels 9-12, and Fig. 3). A distinction is usually made between the nigral (A9) and nonnigral (A8 and AlO) DA neurons, although there is no clearly definable boundary between them. The nigral neurons are mainly confined to the pars compacta and pars lateralis of the substantia nigra in the rat. Some scattered DA neurons are also found in the pars reticulata. The nonnigral DA neurons, which Nauta et al. (381) referred to as “outlying neurons” of the substantia nigra, are predominantly found rostromedial, medial, and caudal to the substantia nigra proper and extend from the supramammillary region rostrally to the decussation of the superior cerebellar peduncle caudally. Figure 3 gives the topographical distribution of the nonnigral DA neurons according to Swanson’s (502) mapping with tyrosine hydroxylase immunohistochemistry in the rat. The medial neurons (group A10) are largely confined to the ventral tegmental area (VTA). On the basis of cytoarchitecture, Phillipson (423) distinguished four subgroups of neurons in the VTA: the nucleus paranigralis, nucleus parabrachialis pigmentosus, nucleus linearis caudalis, and nucleus parafascicularis. However, since the arrangement of the DA projections from the VTA does not seem to follow this subdivision, the VTA group is usually regarded as a single entity (see refs. 146, 502). The DA neurons of the A8 cell group, which are located in the ventrolateral tegmentum caudal to the substantia nigra proper [ retrorubral nucleus (502); level H in Fig. 31, project to the striatum like the substantia nigra neurons (381, 525). These cells can therefore be regarded as a caudal extension of the nigral DA cell group.

DIENCEPHALIC CELL GROUPS. The diencephalic DA neurons are usually divided into four topographical subgroups (levels 13-16 in Fig. 1). The best known subgroup is the tuberal cell group (A12), which seems to project exclusively to the neurohypophysial complex (median eminence and neural lobe) and the pars intermedia of the pituitary [see TUBEROHYPOPHYSIAL SYSTEM, p. 187; (41, 42, 45, 168, 170, 171, 292, 483a)l.


These cells are located in the arcuate nucleus and the adjacent part of the periventricular nucleus, dorsal to the arcuate nucleus.

The caudal diencephalic cell group (Al l ) comprises larger, angular or fusiform cell bodies distributed in the periventricular gray matter of the caudal thalamus and the posterior and dorsal hypothalamus (46, 102). Some A l l cell bodies are also found scattered along the mesencephalic periaqueductal gray. There is no clear caudal boundary between the A l l cell group and the dorsal A10 cell group of the mesencephalic raphe region. The A l l cell group gives rise to the DA innervation of the spinal cord (see DIENCEPHALOSPINAL SYSTEM, p. 185), but it is likely that it also projects locally in the diencephalon [see PERIVENTRICULAR SYSTEM, p. 186; (297)l.

The dorsal hypothalamic cell group (A13) comprises small, rounded cell bodies, most of which are found clustered in the medial part of the zona incerta, just ventromedial to the mammillothalamic tract (46,173). These neurons, as well as the neurons of the rostral periventricular cell group (A14), are likely the cells of origin for.the incertohypothalamic DA projection system (see ref. 44). The periventricular cells of the A14 cell group are scattered in the periventricular hypothalamic region, from the anterior commissure back to the rostral border of the median eminence.

PHYLOGENETIC PERSPECTIVE

Broadly speaking, the brain stem CA neurons can be divided into five principal projection systems: 1 ) a pontine noradrenergic system with widespread ascending and descending projections to all parts of the neuraxis; 2) a medullary noradrenergic (and in rats a t least, partly adrenergic) system with primarily ascending projections to the diencephalic and limbic areas; 3) a mesencephalic dopaminergic system that mainly innervates striatal, limbic, and cortical areas; 4 ) a periventricular, predominantly dopaminergic system with short diencephalic and long descending projections; and 5 ) a system of short diencephalic dopaminergic neurons that innervate circumscribed hypothalamic and hypophysial areas.

These organizational features appear to be similar in all mammalian species, from the opossum (97, 118) to primates (21, 150, 151, 181, 234, 240, 514) and humans (389, 421, 429). In a wider comparative perspective, however, the CA systems vary considerably.

Comparative Aspects of Brain Stem Catecholaminergic Cell Groups

The monoaminergic neuron systems appear to be phylogenetically old. Thus both CA- and serotonin- containing neurons occur in the brains of all vertebrate classes, even in the phylogenetically oldest forms, such as cyclostome and teleost fishes. This

trend is, however, very different for the serotonin and CA neurons. Even in anamniotic vertebrates, fishes, and amphibians, a serotonergic system develops in the raphe region of the lower brain stem (i.e., medulla, pons, and mesencephalon) that is topographically very similar to that found in mammals (22, 60, 410, 413a, 414). Thus the serotonergic raphe system is a remark- ably constant feature of all vertebrate forms. By contrast the CA cell groups of the lower brain stem are rudimentary or absent in lower vertebrates. Moving from fish and amphibians to reptiles, birds, and mammals there is a dramatic increase in the size of both the mesencephalic and rhombencephalic CA neuron systems. The anamniotic vertebrates nevertheless exhibit whole-brain CA concentrations (0.4-0.6 pg/g) similar to those of mammals (0.4-1.1 pg/g; Table 1). This is because the phylogenetically oldest vertebrate forms possess an elaborate diencephalic CA neuron system, which in reptiles, birds, and mammals is gradually replaced by the mesencephalic and rhombencephalic systems. This general phylogenetic trend is summarized in Figure 4.

The mesencephalic CA neuron system in the anamniotic vertebrates (cyclostomes, teleosts, and amphibians) is limited to a small number of cells located near the midline, at the border between the mesencephalon and diencephalon (22,60, 167,410,414, 416, 516, 563). These cells are often referred to as the nucleus tuberis (Fig. 5A, B ) . In reptiles (25, 409, 417) and birds (127,175,520) the mesencephalic cell group is considerably larger, with a mediolateral extension reminiscent of that seen in mammals. From the cells’

TABLE 1. Whole-Brain Catecholamine Concentrations in Some Vertebrates

Concentration, p g / g

NE E DA Total Species Ref.

Fish Lamprey Dogfish

(cyclostome) - (elasmobranch)

Goldfish (teleost)

Frog (Ram pipiens) Frog ( R a m

Amphibian

temporaria) Reptile

Turtle Tortoise Lizard

Bird Pigeon

Mammal Rat Cat Dog Pig Sheeu

22 0.03 0.57 0.6 0.22 0.28 0.5

0.30 0.06 0.4

0.21 1.07 0.29 1.6 22 0.24 0.84 0.36 1.4 254

1.56 * 1.51 3.1 413 1.31 0.61 0.97 2.9 254 0.79 0.15 0.9 22

0.28 0.37 0.7

0.49 0.60 1.1 0.22 0.28 0.5 0.16 0.19 0.4 0.14 0.22 0.4 0.25 0.30 0.6

254a

36a

NE, norepinephrine; E, epinephrine; DA, dopamine. * Not analyzed.


Cyclostomes Teleosts Amphibians Reptiles Birds Rodents Man

Pontine NA neurons 0 (el

Mesencephal ic DA neurons

Diencephalic DA neurons

Diencephalic NA (+A) neurons

FIG. 4. Relative development of pontine, mesencephalic, and diencephalic CA neuron systems in 7 vertebrate classes. Values are crude estimates of number of cell bodies, as extracted from various studies. a, Ref. 521; b, ref. 520; c, ref. 501; d, ref. 341; e, ref. 22; 1, ref. 502; g , ref. 537; i, ref. 414; j , ref. 418; k , refs. 60, 410. NA, norephinephrine; DA, dopamine; and A, epinephrine.

topography, as well as from lesions and tracing studies with horseradish peroxidase (36, 412, 413), it seems that the cell group can be dissociated into a lateral part, corresponding to the mammalian substantia nigra, and a medial part, corresponding to the mammalian A10 cell group (Fig. 5C, D). Progressing from fish and amphibians to reptiles, birds, and mammals, the total number of mesencephalic CA neurons increases dramatically, from just a few in the cyclostomes and teleosts to a few 10s in frogs, a few 100s in reptiles, -30,000-40,000 in the rat, and -800,000 in humans (Fig. 4).

Apparently there is no rhombencephalic CA neuron system in the lamprey [Fig. 4; (22)]. There are few catecholaminergic neurons in teleosts and amphibians, both in the pontine isthmus and scattered throughout the medulla oblongata [Fig. 5A, B; (413a, 414,519, 563)]. The pontine CA neurons are clustered in an area similar to the locus coeruleus in higher vertebrates, and according to the lesion experiments of Tohyama et al. (520a), these pontine cells appear to project to the cerebellum and spinal cord, but not to the telencephalon. A fully developed locus coeruleus cell group with established projections to the telencephalon occurs in reptiles [Fig. 5C; (413, 417, 418)] and is further increased in birds [Fig. 50; (127, 520)]. Tohyama et al. (520) found -300 CA neurons on each side of the locus coeruleus in the parakeet, compared with -1,500 on each side in the rat (501), -9,000 on each side in the cat (556), and -15,000-20,000 cells on each side in humans [Fig. 4; (537)]. Thus, as in the mesencephalic system, the number of rhombence-

phalic CA neurons increases dramatically in higher vertebrate forms.

The diencephalic CA neuron system is most abun- dantly developed in fish and amphibians and is pro- gressively less developed in reptiles, birds, and mammals (Figs. 4 and 5). Parent et al. (413a) estimated that the diencephalic CA neurons are approximately three times as numerous in fish and approximately two times as numerous in frogs as they are in mammals. This means that several thousand CA neurons should exist in lower vertebrate forms. In submam- malian species these neurons are peculiar in that many of them are located within or just underneath the ventricular ependyma and possess a bulbous apical aminergic dendritic process projecting into the cere- brospinal fluid (CSF) and a basal axon innervating diverse diencephalic, tectal, and telencephalic areas. In addition to these bipolar CSF-contacting CA neurons, which seem to have no correlate in mammals, in fish, amphibians, reptiles, and birds there are more deeply located scattered cells similar to those found in mammals.

There are some interesting differences in amine content among the diencephalic neurons in different species. In the primitive cyclostome fish (e.g., lamprey), as in more advanced mammals, the diencephalic system appears to be exclusively dopaminergic (22). In teleosts and amphibians it comprises both dopaminergic and noradrenergic neurons (167, 433), whereas in reptiles and birds the diencephalic neurons seem to be exclusively noradrenergic (22, 39, 142). In amphibians and phylogenetically older reptile radia-


C

CEPHALIC PATHWAV

ISTHMO- -cm1icAL

PATH WAY COERULEO CMITICAL PATHWAY

c

,CC€RULEO- CORTICAL PATHWAY

FIG. 5. Major CA projection systems in 5 classes of vertebrates (A, fish; B, amphibian; C, turtle; D, chicken; E , rat). ACC, anterior cingulate cortex; AS, n. accumbens septi; CER, cerebellum; DC, dorsal cortex; LPO, paraolfactory lobe; LS, lateral septa1 n.; NPT, n. posterior tuberis; PA, Palleo- striatum augmentatum; PFC, prefrontal cortex; PVO, paraventricular organ; S, septum; STR, striatum; TECT, tectum. [Adaped from Parent et al. (414), Parent (413, 413a), Dube and Parent (127), and Lindvall and Bjorklund (297).]

tions (e.g., tortoise), it seems likely that epinephrine also occurs in the diencephalic neurons, either together with NE or in separate cells. In fact, epinephrine is the predominant CA in the hypothalamus of the frog and tortoise (see Table 3).

Catecholarninergic Projections to Forebrain

The fundamental differences in the distribution of CA neurons in different vertebrate classes seem to be consistent with a shift in the CA-containing regulatory system during phylogenetic development from a dien-

cephalic, largely CSF-contacting system closely associated with the neuroendocrine apparatus, to a brain stem system closely associated with the mesencephalic, pontine, and medullary reticular formations.

Fluorescence histochemical studies have shown that the telencephalon receives CA innervations, even in those lower vertebrate species in which the mesencephalic and rhombencephalic CA cell groups are rudimentary or absent. Table 2 shows that the combined CA concentration (NE, epinephrine, and DA) in the forebrain of goldfish and frogs (0.9-1.0 ng/mg of tissue) is similar to that in birds and rodents (0.9-1.5


ng/mg of tissue), although the total amine content (nanograms per forebrain) is -100 times lower.

The telencephalic CA innervation in fish is probably derived exclusively from the diencephalic, largely CSF-contacting, neuronal system (Fig. 5A, B). In the lamprey this diencephalic forebrain projection is predominantly dopaminergic (22), whereas in the goldfish the biochemical data suggest it is -80% noradrenergic (22, ,254). According to Baumgarten (22), the diencephalic DA neurons in the lamprey project not only to hypothalamic areas and the neurohypophysis, but also to the optic tectum and the ventral part of the telencephalon (corpus striatum and preoptic nucleus in particular). There also seems to be a sparse projection to the deep periventricular zone of the dorsal and lateral pallium. According to Tohyama (519) and To- hyama et al. (521), the rudimentary locus coeruleus and medullary cell groups in teleosts and frogs give rise to cerebellar and descending projections, whereas the noradrenergic innervation of the tectum and the forebrain is entirely a function of the diencephalic neuronal system. From lesion experiments, Tohyama (519) suggested that the diencephalic cell group in fish (but not frogs) contributes to the innervation of the cerebellum. Thus the diencephalic NE neurons in

teleosts and frogs appear to provide a widespread projection system to tectal and forebrain areas, as well as to the neurohypophysis [Fig. 5A, B ; (24, 167, 414, 433, 516)]. Interestingly, in amphibians part of this system probably produces epinephrine (Tables 2 and 3).

The CA innervation of the telencephalon in fish and amphibians is confined to the ventral portions corresponding to the striatum, accumbens, septal, and preoptic areas of higher vertebrates (22,60, 413). The appearance of a distinct innervation of the dorsal pallium (which is a simply organized cerebral cortex), as seen in reptiles and birds, is apparently correlated with the emergence of a coeruleocortical (or isthmo- cortical) NE pathway as we know it from mammals. Such a projection has been well established in the turtle [Fig. 5C; (418)] and in birds [Fig. 50; (127,520)] and is further elaborated in mammals (Fig. 5E) . As in mammals, the locus coeruleus appears to be the prime source of CA innervation of the avian cerebellum (370, 519).

The mesotelencephalic DA projection may be present in a rudimentary form in frogs (60, 413), and it is definitely established in reptiles (25, 408, 412) and birds (36, 127, 413a). In frogs (Fig. 5B) the DA inner-

TABLE 2. Forebrain Catecholamine Content and Brain Stem Catecholamine Cell Numbers in Some Vertebrates

Norepinephrine Epinephrine Dopamine Total Pontine Mesen- Forebrain Norepi- cephalic

Content, Concn, Content, Concn, Content, Concn, Content, Concn, Wt, g nephrine Dopamine ng n g / w ng n g / w ng ng/mg ng ng/mg Neurons Neurons

Species

Teleost fisWb

Amphibian".b

Reptileb

Birdg

Mammal'

Goldfish 7-20 0.8-1.0 <0.5 <0.08 1.5 0.2 10-20 1.0 0.01-0.02 10' 10"

Frog 3-5 0.2 7-10 0.3-0.5 5 0.3 15-20 0.9 0.02 lod 10-loze

Tortoise 100 0.9 35 0.3 140 1.2 275 2.4 0.1 10-10~~ 10-lo3'

Pigeon 240 0.2 40 0.04 670 0.6 1,000 0.9 1.1 lozh

Rat 340 0.4 1,100 1.1 1,500 1.5 1.0 lo3' 10' "Baumgarten (22). Juorio (254). Estimated from Parent et al. [sunfish (414)]. Tohyama et al. (521). Estimated

Tohyama et from Parent (410) and Braak (60). al. [parakeet (520)]. A. Bjorklund, unpublished observations. Swanson (501). ' Swanson (502).

Estimated from Parent and Poitras [turtle (418)l. Juorio and Vogt (254a).

TABLE 3. Hypothalamic Catecholamine Content in Some Vertebrate Species Norepinephrine Epinephrine Dopamine Total

Ref. Hypothalamic Content, Concn, Content, Concn, Content, Concn, Content, Concn, Wt, g Species

ng w/mg ng n g / w ng w/mg ng n g / w

Teleost fish

Amphibian

Reptile

Bird

Mammal

Goldfish 2.5 1.3 0.5 0.2 3.5 1.8 6.5 3.3 0.002 254

Frog 1.5 1.2 5 4.8 1.5 1.2 8 7.2 0.001 254

Tortoise 20 2.7 30 4.1 10 1.3 60 8.1 0.01 254

Pigeon 50 1.5 13 0.4 5 0.2 70 2.1 0.03 254a

Rat 100 1.1 30 0.4 130 1.5 0.1 41


vation seems to be confined primarily to the septa1 and accumbens regions of the ventral forebrain, whereas the striatum is only poorly innervated (60, 411, 516). Thus the mesencephalic DA projection in frogs may correspond mainly to the mesolimbic pathway in mammals. Both the mesolimbic and nigrostriatal pathways appear to be developed in reptiles and birds [Fig. 5C, D); (412, 413a)], but a well-developed mesocortical DA system has been established only in mammals (Fig. 5E).

The phylogenetic development of the ascending CA projections from the reticular formation evidently follows the general development of the forebrain. In particular the appearance of the mesotelencephalic DA system seems to follow closely the phylogenetic development of the limbic and striatal regions of the ventral telencephalon (see ref. 529). In fact, the establishment of the mesolimbic and the nigrostriatal dopaminergic control systems may signify the establishment of functional limbic and striatal forebrain systems in the various vertebrate forms. Likewise the establishment of the coeruleocortical noradrenergic system may reflect the general development of the ascending control systems from the brain stem reticular core in different vertebrate forms.

Observations on amphetamine-induced stereotypy are of interest in this context. It is known that amphetamine-induced stereotypic behavior is elicited via an action on the mesotelencephalic DA system, probably mainly on its nigrostriatal component (263, 439). On these grounds it is notable that amphetamine- induced stereotypic behaviors have been demonstrated in precisely those classes of vertebrates that possess a well-developed nigrostriatal DA system (e.g., reptiles, birds, and mammals), whereas in those species in which the mesotelencephalic system is rudimentary (e.g., fish and frogs), this response is absent (14, 438). This points to a similar functional role for mesotelencephalic DA neurons in striatal functions in all vertebrate forms. Andersen et al. (14) pointed out that activation of the DA system by amphetamine has fewer functional consequences in the tortoise, in that the depression of other elements of behavior during stereotypy, as observed in mammals, does not occur in the tortoise. They noted that blockade of the DA receptors with neuroleptics did not produce catalepsy or any sign of sedation in the nonmammalian vertebrates; this might be viewed as a functional correlate of the poorly developed mesocortical DA system in this species.

CATECHOLAMINERGIC FIBER TRACTS

The CA axons from pontine and medullary cell groups in the lower brain stem of the rat are confined to two major fiber systems. One system, comprising both ascending and descending axons, forms a catecholaminergic component of the central tegmental

tract (see refs. 69, 380, 560). In the dorsomedial part of this tract, the ascending CA fibers are densely aggregated and typically arranged in fascicles. These aggregated fascicles form the dorsal tegmental bundle, first described by Ungerstedt (525). The second major fiber tract is the dorsal periventricular system, which is formed by ascending and probably also descending axons running within the dorsal longitudinal fasciculus of Schutz in its extension through the medulla oblongata, pons, mesencephalon, and diencephalon. In the ventromedial tegmentum of the rostral mesencephalon, axons of mesencephalic, pontine, and medullary origin assemble to form three additional ascending CA fiber systems: the ventral periventricular system, the nigrostriatal pathway, and the MFB.

In the following description, which is based mainly on our own observations in tissue treated with glyoxylic acid (297), each of the different axonal systems is covered in more detail. We describe the descending fiber pathways within the spinal cord in connection with the other projection systems in following sections (see DIENCEPHALOSPINAL SYSTEM, p. 185, and SPINAL CORD PROJECTION, p. 204 and p. 206).

Dorsal Tegmental Bundle

The dorsal tegmental bundle seems to originate exclusively in the locus coeruleus proper and constitutes the most important ascending projection route for locus coeruleus neurons (250, 297, 319, 320, 396, 428,473, 525). It emerges from the locus coeruleus in a rostroventral direction and then turns rostrally to ascend lateral to the medial longitudinal fasciculus (Fig. 6). Some fibers immediately leave the bundle and cross the midline medial and ventral to the locus coeruleus (250, 297, 395, 428, 507, 525). These axons then join the contralateral dorsal tegmental bundle (250). The dorsal tegmental bundle initially lies between the medial longitudinal fasciculus and the superior cerebellar peduncle; further rostrally, in the caudal mesencephalon, it lies ventral to the root of the trochlear nerve and passes through the most dorsal part of the decussation of the superior cerebellar peduncles.

Along its course through the mesencephalon, the dorsal tegmental bundle gives off fibers in several directions. Within and just rostral to the decussation of the superior cerebellar peduncles, some fibers turn rostroventrally along the so-called tegmental radiations (Fig. 6) to reach the VTA and the MFB along the dorsal and ventral aspects of the medial lemniscus. Other fibers leave the bundle laterally toward the dorsal tegmental regions and the geniculate bodies. One branch issues dorsally toward the inferior colliculus; somewhat further rostrally, another branch deviates from the lateral part of the dorsal tegmental bundle in a rostrodorsal direction toward the superior colliculus (297, 507).

At the mesodiencephalic junction, the main bundle


FIG. 6. Ascending CA fiber system of dorsal tegmental bundle (DTB), originating in locus coeruleus (LC), and its projections in diencephalon. Medial part of MFB and cells in medial part of pars compacta of substantia nigra (SNC) are also included. Figure is composite of slightly different sagittal planes. am, Anteromedial n.; av, anteroventral n.; DPS, dorsal periventricular system; DSCP, decussation of superior cerebellar peduncles; G VII, genu of facial nerve; lh, lateral habenular n.; MB, medullary CA bundle; ML, medial lemniscus; ret, reticular n.; SOD, supraoptic decussations; and TR, tegmental CA radiations. [From Lindvall and Bjorklund (297).]

bends ventrally and somewhat laterally, passing between the fasciculus retroflexus and the medial lemniscus and just lateral to the mammillothalamic tract. Along its course through the middle hypothalamus the dorsal tegmental bundle gradually merges with the MFB system of ascending CA fibers (Fig. 6). When passing ventral to the posterior commissure, the bundle sends fibers dorsally to cross the midline in the commissure (250, 297, 428, 525). These fibers join the contralateral dorsal tegmental bundle or run out into the contralateral pretectal region (250,304). One component leaves the bundle dorsolaterally along the surface of the fasciculus retroflexus and enters medial and midline thalamic regions, and another bends laterally and fans out on the dorsal surface of the medial lemniscus into the ventrobasal thalamic complex (297, 507). More rostrally, another branch deviates along the mammillothalamic tract and reaches the anterior thalamic nuclei (250, 297, 507). At the level of the subthalamic nucleus, shortly before the bundle joins

the MFB, some dorsal bundle fibers bend laterally and somewhat dorsally and run intermingled with fibers of the nigrostriatal DA system into the internal capsule or along its medial surface (239, 250, 297, 453, 520a). The dorsal bundle fibers in the internal capsule either take a rostroventral course toward the CA fiber systems in the supraoptic decussations and the ansa lenticularis (297) or penetrate the caudate nucleus and the corpus callosum, innervating the cerebral cortex and the amygdaloid-piriform lobe (137, 239, 250, 297, 453, 520a). (The further course of the dorsal bundle fibers within the MFB system is described in Medial Forebrain Bundle, p. 171.)

Central Tegmental Tract

In the early neuroanatomical literature, based on studies performed with the Falck-Hillarp formalde- hyde method in conjunction with lesions, the CA fiber systems running in the pontine and mesencephalic


tegmentum were subdivided into a dorsal bundle (originating in locus coeruleus) and a ventral bundle (originating in other pontine and medullary groups) (173, 174, 396, 525). This is not, however, a clear-cut distinction, and with newer and more sensitive fluorescence histochemical and immunohistochemical techniques, the so-called dorsal and ventral bundles are seen to be partly intermingled subcomponents of a fiber system running in the central tegmental tract.

The medullary portion of the central tegmental tract comprises both ascending and descending CA fibers (11, 297, 319, 320, 396, 428, 453, 525). The descending fibers originate in the locus coeruleus- subcoeruleus complex and in pontine CA cell groups A5 and A7 and are the path of the CA innervation to the spinal cord (see SPINAL CORD PROJECTION, p. 204 and p. 206). In addition it is conceivable that at least some of the diencephalospinal DA axons descend here. The ascending CA axons in the medullary portion of the central tegmental tract originate in groups A1 and A2 (11, 173,297,525).

Most of the central tegmental tract fibers in the medulla oblongata are aggregated into a compact bundle situated just ventrolateral to the hypoglossal nucleus and ventral to the dorsal vagal nucleus. More

rostrally this bundle passes between the root fibers of the facial nerve and just ventral to the genu of the facial nerve (Fig. 7). At the level of the locus coeruleus, most of the fibers with a medullary origin deviate slightly ventrally into the central tegmental tract, immediately ventrolateral to the dorsal tegmental bundle. Here, ascending CA axons from the A5 and A7 cell groups and from the locus coeruleus-subcoeruleus complex join the system. Some of these axons join the bundle of CA fibers of medullary origin, while others ascend as a loosely arranged system distributed over practically the entire tegmentum ventrolateral to the dorsal tegmental bundle.

The pontine and medullary CA fibers in the central tegmental tract ascend through and ventral to the decussation of the superior cerebellar peduncles (Fig. 7). Their course through the tegmental radiations in the rostral mesencephalon is quite complex (see ref. 297). The fiber system in the tegmental radiations is rather widely dispersed, although many of the axons converge on the MFB as it is formed at the mesodiencephalic junction. Some axons, however, follow a separate, more dorsal route running through and partly lateral to the medial lemniscus to ascend into the zona incerta and the Hz field of Fore1 (Fig. 7). In the rostral

FIG. 7. Ascending and descending CA fiber systems in central tegmental tract (CTT) and its caudal extension, the medullary CA bundle (MB). Rostrally, part of nigrostriatal pathway is represented in its extension through internal capsule (CI) and globus pallidus. Figure is composite of different sagittal planes. Note that mesencephalic and pontine parts of drawing illustrate plane situated -0.5 mm more medial than rest. AC, anterior commissure; CC, CNS cerebri; G VII, genu of facial nerve; ML, medial lemniscus; NCP, n. caudatus-putamen; NSP, nigrostriatal pathway; OT, optic tract; SC, n. subcoeruleus; SNC, substantia nigra, pars compacta; so, supraoptic n.; SOD, supraoptic decussations; ST, stria terminalis; and TUB, olfactory tubercle. [From Lindvall and Bjorklund (297).]

170 HANDBOOK OF PHYSIOLOGY - THE NERVOUS

mesencephalon and caudal diencephalon, axons deviate laterally and run around or through the crus cerebri toward the deep inner surface of the optic tract into the supraoptic decussations; further rostrally, some of the central tegmental tract axons take a ventrolateral course through the internal capsule toward the ansa lenticularis and the supraoptic decussations.

Periventricular System

The dorsal portion of the periventricular CA fiber system forms an ascending and probably also descending adrenergic fiber component of the dorsal longitudinal fasciculus of Schutz and can be traced along the periventricular and periaqueductal gray from the medulla oblongata up to the rostral diencephalon (Fig.

SYSTEM IV

8). The ventral portion of the system runs along the periventricular region of the hypothalamus. The relative contribution of the different CA cell groups to the periventricular system is not known in detail. It has been shown that fibers originate both in the DA neurons located within the fiber system itself and in the pontine and medullary NE cell groups. Since the diencephalic portions of the systems are believed to comprise, to a major degree, a dopaminergic terminal system, they are described together with other DA projection systems in PERIVENTRICULAR SYSTEM, p. 186, and only the more caudal portions are covered here.

The caudal periventricular system can be observed at the level of the nucleus tractus solitarius, where the A2 cell group possibly contributes ascending fibers to it. The fibers extend rostrally from this area under-

FIG. 8. Periventricular CA fiber system rostral to locus coeruleus. Figure is composite of somewhat different paramedian sagittal planes. dmh, Dorsomedial hypothalamic n.; DPB, dorsal periventricular bundle; DTB, dorsal tegmental bundle; mh, medial habenular n.; MP, mammillary peduncle; pf, parafascicular n.; pvh, paraventricular hypothalamic n.; pvt, paraventricular thalamic n.; rh, rhomboidal n.; and VPS, ventral periventricular system. [From Lindvall and Bjorklund (297).]


neath the ependyma of the fourth ventricle as a rather sparse bundle. At the level of the locus coeruleus, the system increases considerably in width and in the number of fibers it contains, because the locus coeru-

caudatus-putamen and the dorsal interstitial nucleus of the stria terminalis.

Medial Forebrain Bundle leus (and possibly other pontine and medullary CA cell groups) contributes ascending fibers to the system. From the region dorsal and medial to the locus coeruleus, the periventricular fibers can be followed rostrally in the lateral part of the periventricular gray (Fig. 8). Some fibers then turn sharply ventrally and gradually rostrally into the VTA. Other CA fibers deviate from the periventricular system and run dorsally into the inferior colliculus and ventrorostrally along the tegmental radiations. In the mesencephalic periaqueductal gray, the axons form the well-defined dorsal periventricular bundle that runs within the dorsal longitudinal fasciculus. This bundle sends axons into the superior colliculus and gives rise to the diencephalic part of the periventricular CA fiber system (See PERIVENTRICULAR SYSTEM, p. 186).

Nigrostriatal Pathway The DA fiber tract from the substantia nigra to the

neostriatum has been demonstrated by a variety of microscopic techniques (146, 228, 297, 355, 525, 527). The following description of this nigrostriatal DA pathway is based on our observations in the rat of tissue treated with glyoxylic acid [Fig. 9; (297)l.

The nigral axons are initially directed medially. Medial to the substantia nigra they are joined by axons from the A8 and probably also from the A10 cell groups. The axons turn sharply rostrally and form a bundle that ascends in the Hz field of Fore1 immediately dorsolateral to the MFB system. At the level of the subthalamic nucleus, the most dorsal fibers bend sharply laterally (above crus cerebri) and then rostrally and run into the internal capsule from the caudal side toward the caudal neostriatum. The somewhat more ventral fibers in the bundle deviate less sharply and run in a rostrolateral direction through the subthalamic region and into the internal capsule. The central and ventral fibers in the bundle run rostrally along and partly within the dorsomedial edge of the internal capsule. Along this course, the more dorsal fibers in the nigrostriatal pathway deviate in a rostrolaterodorsal direction into the internal capsule, toward the central parts of the nucleus caudatus-putamen. The ventral portion of the pathway continues rostrally up to the globus pallidus. Most of the fibers then fan out in rostrodorsolateral directions and run along the myelinated fascicles through the globus pallidus into the head of the nucleus caudatus-putamen. Some of these axons give off collateral branches that terminate in the globus pallidus (300). The most ventral portion of the nigrostriatal pathway continues further rostrally, just dorsal to the MFB, to the anterior commissure; the axons pass ventral to the commissure and run into the ventromedial nucleus

The MFB is composed of a highly heterogenous system of CA fibers connecting the brain stem reticular formation with diencephalic and telencephalic regions. The fibers assemble at the mesodiencephalic junction, medial to the substantia nigra. The NE fibers are primarily derived from the pontine and medullary cell groups outside the locus coeruleus and to some extent from the periventricular system. In addition the mesencephalic DA neurons give rise to a prominent ascending DA axon system within the MFB, which projects mainly to limbic and cortical regions, forming the mesolimbocortical pathway. Further rostrally, the dorsal tegmental NE bundle joins the MFB in the middle hypothalamus, and the ascending CA fiber system is thickest at this level.

DOPAMINERGIC FIBER TRAJECTORIES. The DA fibers in the MFB run immediately ventromedial to and are closely associated with the nigrostriatal pathway. Some of the DA axons leave the MFB laterally along the ventral amygdaloid bundle-ansa lenticularis system toward the amygdala, the piriform and perirhinal cortices, and the ventral entorhinal area. Most DA fibers continue on rostrally in the MFB and then separate into different components: one branch deviates dorsally into the nucleus accumbens; another sends fibers rostroventrally into the olfactory tubercle; a third runs dorsally along the diagonal band of Broca into the septum; and a fourth bends dorsally along the rostrolateral aspect of the nucleus accumbens, fanning out over the external capsule and innervating the prefrontal cortex and part of the head of the caudate putamen.

Most DA axons leave the MFB at the rostra1 septum and run in a dorsomediorostral direction along the medial and medioventral aspects of the nucleus accumbens. Rostromedial to the nucleus accumbens, the bundle separates into four main branches. The densest branch runs into the deep layers of the prefrontal cortex and also projects along the external capsule; a second branch runs dorsally and caudally above the corpus callosum into the anterior cingulate cortex; a third branch runs dorsocaudally into the septum; and the last branch continues rostrally along the medial olfactory tract and runs into the anterior olfactory nuclei and olfactory bulb. NORADRENERGIC FIBER TRAJECTORIES. The course of the locus coeruleus projection system’s axons is well known; however, the organization of the systems originating in other pontine and medullary cell groups is not as well known.

The locus coeruleus axons run predominantly in the dorsomedial MFB. The majority of these axons leave the MFB laterally and run along the ventral amyg-


FIG. 9. Horizontal section through dorsal part of MFB system, ventral part of nigrostriatal pathway (NSP), and ansa lenticularis (AL). Compare with sagittal drawings in Figs. 6 and 7. Figure is composite of slightly different horizontal planes. AC, anterior commissure; ACC, n. accumbens; can, central amygdaloid n.; CTT, central tegmental tract; dmh, dorsomedial hypothalamic n.; and st, interstitial n. of stria terminalis. [From Lindvall and Bjorklund (297).]

daloid bundle-ansa lenticularis system toward the piriform lobe and the ventral hippocampus (250,297). In the rostra1 hypothalamus some locus coeruleus fibers turn dorsally into the reticular thalamic nucleus; 0th- ers run along the stria medullaris into the anterior thalamic nuclei (297) and the habenular complex

(250). Some ventrally directed locus coeruleus axons run into the supraoptic decussations. Somewhat further rostrally, locus coeruleus fibers leave the MFB dorsally to join the stria terminalis and the fornix. Within the stria terminalis, the axons run all the way to the amygdala (239, 250, 297, 428, 453, 525). The


fibers running along the fornix enter the hippocampus (173, 250, 297). Some locus coeruleus fibers join the diagonal band of Broca and innervate the septum (250, 305a).

Some locus coeruleus fibers deviate rostrally at the rostral septum and run into the anterior olfactory nuclei and the olfactory bulb, but most of these fibers turn dorsomediorostrally along the septohypothalamic and diagonal tracts. Just ventral to the genu of the corpus callosum, the bundle of locus coeruleus fibers divides into caudal and rostral branches. The caudal branch runs underneath the corpus callosum in the fornix superior all the way back to the hippocampus (173, 239, 297). The rostral branch turns caudally above the corpus callosum, within the cingulum and the supracallosal striae (13, 239, 250, 297, 428, 507, 525). The fibers within the cingulum continue on caudally and sweep around the splenium of the corpus callosum, entering the hippocampus from the caudal side. Morrison and co-workers (366) have described other locus coeruleus axons that enter the neocortex via the frontal pole (rostral and lateral to forceps minor) and then turn caudally, fanning out over the dorsal and lateral neocortex. The exact course of the axons before they reach the frontal cortex is unclear, but at least part of the fibers probably ascend in the MFB, traverse the ventral striatum, and then penetrate the external capsule (366). Other axons probably leave the MFB more rostrally in the basal telencephalon but also reach the frontal cortex via the external capsule (250).

The non-locus coeruleus axons running in the MFB reach their hypothalamic terminal areas via several branches. A loosely arranged system of fibers from the most ventral part of the MFB turns ventromedially toward the mediobasal hypothalamus and the median eminence. A rich system of non-locus coeruleus fibers projects broadly into the dorsomedial hypothalamic nucleus, and a well-defined branch turns medially and rostrally from the dorsal MFB into the paraventricular nucleus. At the level of the retrochiasmatic region, an abundance of fibers leave the MFB ventromedially and pass into the supraoptic decussation, where they intermingle with decussating locus coeruleus fibers. The exact course and termination of the different components of these decussating CA fibers are not known in detail, but along their course the fibers give off collaterals dorsomedially into the anterior hypothalamus and dorsally into the anterior periventricular nucleus. Non-locus coeruleus fibers from the supraoptic decussation also run rostrally into the preoptic region and the supraoptic nuclei. Some of the decussating CA fibers continue laterally and caudally and join the optic tract to reach the metathalamus, where they probably contribute to the innervation of the geniculate bodies (286, 297, 319).

A major projection route for the non-locus coeruleus NE axons runs laterally along the ventral amygdaloid

bundle-ansa lenticularis system toward amygdala. Further rostrally, non-locus coeruleus fibers leave the MFB dorsally, enter both the ventral part of the bed nucleus of the stria terminalis and the septum, and then run ventromedially into the medial preoptic area.

DOPAMINERGIC PROJECTION SYSTEMS

Our understanding of the anatomy of central dopaminergic neurons has increased considerably during the last decade. Largely because of methodological developments, several new termination areas for dopaminergic neurons have been found, increasing our understanding of the topographical arrangement of the DA projection systems. Table 4 lists the major dopaminergic projection systems in the rat brain. The present description focuses on the projections of the mesencephalic and diencephalic DA cells. [For more information about periglomerular DA neurons and the retinal DA system, see Ehinger (135) and Hokfelt et al. (230a).]

Mesotelencephalic System The telencephalic projections of the mesencephalic

DA-containing cell groups were originally separated into two systems: the nigrostriatal system (originating in A9) and the mesolimbic system (originating in A10) [Table 5; (11, 525)]. More recent studies have shown that the projections of the A9 and A10 cell groups overlap in several terminal areas, and thus the mesencephalic DA neuron system is best viewed as an entity with at least a crude topographical order of projection not only to limbic and striatal areas, but also to parts of the neocortex. Moreover, our view of the organization of the forebrain has changed, mainly because of Heimer and Wilson’s (217) introduction of the ventral striatum concept. In their classification a part of the “limbic” basal forebrain, most importantly the nucleus accumbens and the olfactory tubercle, is included as a ventral extension of the neostriatum. The ventral striaturn concept serves a very useful purpose for a wider integration of the DA system in the striatal and limbic neuronal circuitries. These considerations justify introducing a new terminology, in which the term mesotelencephalic system refers to the entire ascending projection to telencephalic areas from dopaminergic neurons in the mesencephalon. As Table 5 shows, this system comprises two major subsystems: the mesostriatal system, which includes projections to the entire striatal complex (including nucleus caudatus-putamen, nucleus accumbens, bed nucleus of stria terminalis, and olfactory tubercle; Fig. lOA), and the mesolimbocortical system, which comprises projections to limbic, allocortical, and neocortical areas (Fig. 10B). The term mesolimbic DA system corresponds to components of both the mesostriatal system (e.g., projections to nucleus accumbens and

174

TABLE 4. Major Dopaminergic Projection Systems

HANDBOOK OF PHYSIOLOGY - THE NERVOUS SYSTEM IV

System Cells of Origin Projections

Mesostriatal

Mesolimbocortical

Diencephalospinal

Periventricular

Incertohypothalamic

Tuberohypophysial

Periglomerular dopamine neurons

Substantia nigra (A9); ventral tegmental area (A10); retrorubral nucleus (AS)

Ventral tegmental area; substantia nigra, retrorubral nucleus

Dorsal and posterior hypothalamus; zona incerta; caudal thalamus ( A l l )

Mesencephalic periaqueductal gray; periventricular gray of caudal thalamus ( A l l )

Zona incerta; periventricular hypothalamus (Al l , A13, A14)

Arcuate and periventricular hypothalamic nuclei (A12, A14)

Olfactory bulb (A15)

See Table 5

See Table 5

Spinal cord

Periaqueductal gray; medial thalamus and hypothalamus

Zona incerta; anterior, medial preoptic, and periventricular hypothalamus; septum

Median eminence; pars nervosa and pars intermedia of pituitary

Dendritic processes to olfactory glomeruli

Retinal dopamine neurons

TABLE 5. Subdivision of Dopaminergic Projection Systems From Mesencephalic Cell Groups

Inner nuclear layer of retina Local dendritic projections

System Origin* Terminal Area

Nigrostriatalt Substantia nigra Nucleus caudatus-putamen (dorsal striatum)

Mesostriatal$,§

Dorsal part Substantia nigra Nucleus caudatus-putamen (dorsal striatum)

Ventral part Ventral tegmental area

Mesolimbict Ventral tegmental area

Nucleus accumbens; tuberculum olfactorium; bed nucleus of stria terminalis (ventral striatum)

Nucleus accumbens; tuberculum olfactorium; bed nucleus of stria terminalis; septum; amygdala

Mesolimhocorticalt Ventral tegmental area, medial substantia Septum; amygdala; piriform, entorhinal, prefrontal, and anterior nigra cingulate cortices; hahenula and limbic brain stem regions

* Predominant location of cell bodies of origin. t Old terminology. 4 New terminology. § This definition is a slight modification of terminology used previously (298, 299, 356), in that we now include projections to the olfactory tubercle and bed nucleus of the stria terminalis within the mesostriatal system rather than the mesolimbocortical system.

olfactory tubercle) and the mesolimbocortical system (e.g., projections to amygdala and septum).

Fallon and Moore (146) proposed that the mesotelencephalic system is organized according to several general principles (see Figs. 12 and 13; Table 6). 1) It has inverted dorsal-to-ventral topography: ventral cells tend to project to more dorsal structures in the forebrain (e.g., septum, nucleus accumbens, and neostriatum), and dorsal cells project to more ventral structures (e.g., olfactory tubercle and amygdala; see also ref. 147). 2) It has medial-to-lateral topography: medial cells project to more medially located terminal areas, and neurons in lateral sectors of the mesencephalic cell groups project to more laterally located areas in the forebrain. 3) It has anterior-to-posterior topography: anterior cells project more anteriorly and posterior cells project more posteriorly in the fore-

brain. No general agreement presently exists about all of the aspects of these topographical arrangements of the mesencephalic DA neurons.

The different projections of the mesostriatal and mesolimbocortical systems comprise both dopaminergic and nondopaminergic neurons (7, 32, 112, 155, 207, 215, 307, 313, 502, 517, 532, 533, 564). The vast majority of neurons in the mesostriatal system are dopaminergic, and only 5% or less of the nigral (pars compacta) or VTA neurons projecting to the nucleus caudatus-putamen have been reported to be nondopaminergic (532). Similarly the nigral and VTA projections to the nucleus accumbens have been estimated to contain 10%-15% nondopaminergic neurons (502). According to Swanson’s (502) study the nondopaminergic component of the system is generally larger in the limbic and cortical projections, although it varies


A \ I B \ I FIG. 10. Mesostriatal (A) and mesolimbocortical ( B ) dopamine (DA) projection systems. Stippling

indicates innervated areas. a, N. accumbens; ACC, anterior cingulate cortex; AN, amygdaloid nuclei; CE, entorhinal cortex; cp, n. caudatus-putamen; MCG, mesencephalic DA cell groups; OB, olfactory bulb; PFC, prefrontal cortex; pi, piriform cortex; sl, lateral septal n.; and tu, tuberculum olfactorium.

markedly from area to area. He thus calculated that the dopaminergic component constitutes 72% of the total VTA projection to the lateral septum, but only 33% of that to the pregenual frontal cortex. At least in the VTA, dopaminergic and nondopaminergic cells projecting to a particular terminal area seem to be essentially intermixed.

Single DA neurons in both the VTA and substantia nigra project to more than one terminal area via collateral branches. Thus DA axons running into the frontal cortex send collaterals into the septum, and axons ascending in the MFB send collaterals toward the amygdaloid-piriform lobe (297). Furthermore some single, presumably DA neurons in the VTA have been shown with electrophysiological methods to branch to the following areas: septum and nucleus accumbens; septum and nucleus caudatus-putamen; and possibly also septum and frontal cortex (112). After injections of fluorescent retrograde tracers, Swanson (502) and Albanese and Minciacchi ("a) observed that a minority of VTA cells were labeled concomitantly from injections in different DA terminal sites (e.g., nucleus accumbens and frontal cortex; lateral septum and frontal cortex; frontal cortex and entorhinal cortex; and habenula and nucleus accumbens). This seems to confirm the fact that only a few VTA neurons are widely collateralized but that the vast majority of the nigral and VTA neurons have telencephalic projections that are fairly circumscribed. One should also keep in mind that the labeling of axons-of-passage may in certain cases yield erroneous results in double-label studies with retrograde tracers, and thus the occurrence of double-labeled cells after topographically separate injections does not constitute final proof of axons terminating in the injected areas. Swanson (502) found no evidence of the existence of mesencephalic neurons with one ascending and one

TABLE 6. Origin of Projections From Mesencephalic Dopamine Neuron System

Terminal Area Origin

Mesostriatal system Globus pallidus Nucleus accumbens Nucleus caudatus-putamen

Ventral part Anteromedial part

Olfactory tubercle Interstitial nucleus of stria

terminalis Islands of Calleja Subthalamic nucleus

Mesolimbocortical system Olfactory bulb Anterior olfactory nuclei Lateral septal nucleus Piriform cortex Amygdala Ventral entorhinal cortex Suprarhinal cortex Pregenual anteromedial cortex Supragenual anteromedial cortex Perirhinal cortex and temporal

association cortex Lateral habenular nucleus Locus coeruleus

A9 A10, medial A9, A8* A9 A8 A10 (lateral partt) A10 (lateral part?) A10

A9, AlO* A9

A10, medial A9 A10, medial A9 A10 (medial part?) A10, medial A9 A10, medial A9 A10 (lateral part?), A8* Dorsolateral A10 A10 (medial part?) A9 Lateral A10, A9

Medial A10 A10. A9

* Minor projection. t Predominant location of cells of origin within nucleus.

descending axon collateral. The only projection with a more extensive collateralization was from the VTA to the locus coeruleus, in which 15% of the neurons innervated both sides. This study did not attempt to distinguish between cells that did and did not contain DA. Swanson (502) concluded that with the exception of the projection to the locus coeruleus, essentially separate populations of neurons in the VTA (and adjacent regions, including substantia nigra) project


A 4 +

0 3 + m2+ ' +

HI

H I A

a'


B

/ \ MFB 101

Y A 7 2

hi 11 A 5 9

-CP

- C l

C P

CAI

cp


13 A 4 9 14

17 _. A 2 6

D

20 A 0 6

FIG. 11. Twenty-four frontal planes showing distribution and density of DA terminals in CNS of rat. Terminal densities: very dense (4+), dense (3+), medium dense (2+), least dense ( l+) . Terminal distribution of incertohypothalamic and tuberohypophysial DA systems is not shown. AA, area amygdaloidea anterior; ab, n. amygdaloideus basalis; abl, n. amygdaloideus basalis, pars lateralis; abm, n. amygdaloideus basalis, pars medialis; ac, n. amygdaloideus centralis; aco, n. amygdaloideus corticalis; al, n. amygdaloideus lateralis; ala, n. amygdaloideus lateralis, pars anterior; alp, n. amygdaloideus lateralis, pars posterior; AM, anteromedial system; am, n. amygdaloideus medialis; CA, commissura anterior; CAI, capsula interna; CCA, corpus callosum; CFV, commissura fornicis ventralis; cgm, corpus geniculatum mediale; cl, claustrum; CO, chiasma opticum; CP, commissura posterior; dcgl, n. dorsalis corporis geniculati lateralis; ep, n. entopeduncularis; FH, fimbria hippocampi; FMI, forceps minor; GCC, genu corporis callosi; gp, globus pallidus; HI, hippocampus; HIA, hippocampus anterior; hl, n. habenulae lateralis; hm, n. habenulae medialis; hpv, n. paraventricularis hypo- thalami; ic, insulae Calleja; iCM, insula Calleja magna; mi, massae intercalatae; mml, n. mamillaris medialis, pars lateralis; mmm, n. mamillaris medialis, pars medialis; na, n. arcuatus; ncs, n. centralis superior; ndm, n. dorsomedialis; nha, n. hypothalamicus anterior; nhp, n. hypothalamicus posterior; nist, n. interstitialis striae terminalis; nistd, n. interstitialis striae terminalis, pars dorsalis; nistv, n. interstitialis striae terminalis, pars ventralis; npl, n. prelateralis mamillaris; nsc, n. suprachiasmaticus; nso, n. supraopticus; nvm, n. ventromedialis; oam, n. olfactorius anterior, pars medialis; oap, n. olfactorius anterior, pars posterior; 01, n. tractus olfactorii lateralis; P, tractus corticospinalis; p, n. pretectalis; PCS, pedunculus cerebellaris superior; pf, n. parafascicularis; pol, n. preopticus lateralis; pom, n. preopticus medialis; pv, n. paraventricularis thalami; S, subiculum; sf, n. fimbrialis septi; SG, supragenual system; sl, n. lateralis septi; SM, stria medullaris thalami; sm, n. medialis septi; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; SR, sulcus rhinalis; SRH, suprarhinal system; ST, stria terminalis; sut, n. subthalamicus; tam, n. anterior medialis thalami; TD, tractus diagonalis Broca; td, n. tractus diagonalis Broca; tl, n. lateralis thalami; tlp, n. lateralis posterior thalami; tml, n. medialis thalami, pars lateralis; tmm, n. medialis thalami, pars medialis; TO, tractus opticus; TOI, tractus olfactorius intermedius; TOL, tractus olfactorius lateralis; tol, n. tractus optici, pars lateralis; tom, n. tractus optici, pars medialis; tr, n. reticularis thalami; tv, n. ventralis thalami; and vcgl, n. ventralis comoris geniculati lateralis. (Data from refs. 34, 63, 143, 145, 148, 169, 172, 226, 228, 229, 295, 297, 300, 302, 303,805, i05a, 349, 354, 482, 483, 525.)


to each of the terminal fields. However, seemingly in discordance with these findings, Fallon and Loughlin (144, 313a) have reported (from technically similar study) that as many as 50%-70% of medial substantia nigra cells and 5%-15% of cells in the VTA are double labeled after injections into various forebrain areas. They have also found a few triple-labeled cells in the medial substantia nigra after injections (for example) into the prefrontal cortex, septum, and medial caudate (313a). Thus their data indicate that collateralization could be an important organizational principle for the mesotelencephalic system. These studies did not identify the double- and triple-labeled cells as being dopaminergic.

The mesotelencephalic DA system, previously believed to innervate only ipsilateral forebrain areas (see ref. 299), has minor contralateral projections as well. After injections of retrograde tracers into the nucleus caudatus-putamen, a small but significant population of labeled neurons was found in the contralateral substantia nigra and/or VTA (149, 312a, 450a, 535). In fact Swanson (502), using retrograde fluorescent tracers in combination with tyrosine hydroxylase immunohistochemistry, observed significant contralat- era1 labeling of both dopaminergic and nondopaminergic cells in the VTA from all striatal, limbic, and cortical areas. The simplest way to reconcile these data with the previous findings obtained in histofluorescence studies is to assume that the axons innervating the contralateral forebrain cross the midline a t the mesodiencephalic junction and ascend together with the uncrossed fibers in the MFB or nigrostriatal pathway.

MESOSTRIATAL SYSTEM. The nucleus caudatus-putamen and the areas of the so-called ventral striatum (i.e., nucleus accumbens, olfactory tubercle, and bed nucleus of stria terminalis) are all densely supplied with DA fibers [Fig. 11, levels 2-10; (169)l. In the globus pallidus a sparse plexus of DA-containing terminal axons is distributed throughout the gray matter (300). These fibers are collaterals from axons running in the nigrostriatal bundle and originate in substantia nigra (146, 300).

The DA terminal plexus in the nucleus caudatus-putamen (i.e., dorsal striatum) originates not only in the substantia nigra (9, 12, 31, 232, 355, 431) but also in the A8 (146, 381, 525, 530) and the A10 cell groups [Fig. 12; Table 6; (30, 76, 146, 478, 479, 515, 530)]. The topographical relationships between the mesencephalic DA cells and their areas of termination in the nucleus caudatus-putamen have been the subject of a number of studies, and several topographical principles have been proposed for this neuron system (Fig. 12). The medial-to-medial and lateral-to-lateral topography is now well established [Fig. 124, C; (30, 76, 122, 146, 206,496)], although considerable overlap has been found between nigral cells projecting to the medial and lateral parts of the nucleus cauda-

FIG. 12. Topographical organization of mesostriatal DA projections, as viewed in frontal (A, B ) or horizontal ( C ) planes. Compare with Figs. 1, 3, and 11. acc, N. accumbens; ncp, n. caudatus-putamen; ot, olfactory tubercle; and rrn, retrorubral n. (A8).

tus-putamen (530). Some investigators have also described an anterior-posterior topography with rostra1 nigral cells projecting anteriorly and caudal cells projecting posteriorly in the striatum (146, 510). Beck- stead and co-workers (30) did not observe any topographical organization along the sagittal axis but found that the nigrostriatal fibers originating in each part of the nigra are distributed over the entire length of the striatum. The only exception noted in their study was that the projection from the most lateral nigra avoided the anterior pole of the striatum. More- over, the projection area of the A8 cell group (retrorubral nucleus), which can be regarded as a caudal extension of the substantia nigra, has been shown to be the ventral putamen [Fig. 12B; (30, 146, 381)]. A modification of the medial-to-lateral topographical principle has been proposed by Veening and co-workers (535). From their horseradish peroxidase (HRP) data they concluded that the nigrostriatal projection is organized along an oblique longitudinal axis in the caudate putamen, from rostromedial and dorsal to caudolateral and ventral. Injections of HRP into the caudate putamen along this axis resulted in a gradual shift of the DA cell labeling, from the medial part of the substantia nigra and the ventral VTA to a labeling of the lateral and dorsal parts of the substantia nigra- VTA complex. Several studies have indicated that the neostriatal projection from the A10 group (mainly its lateral part) is confined to the anteromedial part of the head of the nucleus caudatus-putamen (76, 146, 478); other experiments have implied that the afferents from the VTA are more widely distributed in the entire ventromedial half of the nucleus caudatus-putamen (30, 530).

The DA innervations of the ventral striatal areas, the nucleus accumbens, the olfactory tubercle, and the


bed nucleus of the stria terminalis originate primarily in the A10 cell group, but a significant portion is localized also in the medial part of the substantia nigra, pars compacta [Fig. 12A; (30,76,146,305a, 381, 478, 479, 502, 525, 545)]. In addition there is a minor projection to the nucleus accumbens from cells in the A8 group (381, 502). The DA cells projecting to the ventral striatal areas have a general medial-to-lateral topographical arrangement in relation to their terminal area [Fig. 12A; (146, 305a)l.

The islands of Calleja (Fig. 11, levels 3-7) are anatomically related to the olfactory tubercle, but they are not included in the ventral striatum (217). They are surrounded by a dense plexus of DA terminal axons. Within each island the central core of neuropil has a moderately dense DA innervation, whereas only a few scattered DA fibers are found between the granule cells (see ref. 148). The cell bodies from which these axons arise have not been located. On the basis of lesions and injections of radioactive amino acids, Fallon and co-workers (148) concluded that the VTA innervates the medial islands, whereas the substantia nigra innervates the lateral islands (Table 6). How- ever, after similar tracer injections into the VTA, Beckstead and co-workers (30) found labeling over the entire olfactory tubercle, but not in the islands of Calleja. This variance with the results of Fallon and

co-workers (148) indicates that the DA cells projecting to the islands are separate from those connected with the olfactory tubercle, an arrangement that our own lesion data support. Thus an electrolytic lesion of the A10 cell group, which removed the majority of DA fibers in the olfactory tubercle, spared the innervation to the islands (0. Lindvall, unpublished observations).

MESOLIMBOCORTICAL SYSTEM. Apart from its periglomerular DA cells (208), the olfactory bulb contains scattered DA terminals in all layers, particularly in its caudal half (145). A DA innervation of sparse-to- moderate density has been observed in the anterior olfactory nuclei (145). The density is higher in the medial and dorsal anterior olfactory nuclei than in the lateral nucleus. It is proposed that these innervations originate in the A10 and medial A9 cell groups (145).

Almost the entire mesencephalic DA innervation to the septum is restricted to the lateral septal nucleus (Fig. 11, levels 4-13; see refs. 305a and 354). It originates in the A10 cell group, mainly in its medial part [Fig. 13A; Table 6; (17, 76, 146, 295, 301, 305a, 316, 354, 478, 502)]. The HRP data of Fallon and Moore (146) indicate a rostral-caudal topography in this projection.

The piriform cortex receives a DA input of low- to-moderate density [Fig. 11, levels 1-16; (145, 297,

B

FIG. 13. Topographical organization of mesolimbocortical DA projections to some limbic and allocortical (A) and neocortical ( B ) areas. Compare with Figs. 1,3, and 11. AM, anteromedial system; C, corpus callosum; CC, crus cerebri; CPF, piriform cortex; DG, dentate gyrus; EC, external capsule; ERC, entorhinal cortex; H, hippocampus; ic, internal capsule; ip, interpeduncular n.; LS, lateral septal n.; SG, supragenual system; and SR, suprarhinal system.


305)]. Dopaminergic fibers are distributed through layers I1 and 111, with the highest density medially. In layer 11, small clusters of cells are innervated by a DA terminal plexus. A rich DA innervation occurs at the junction between the medial piriform cortex and cortical amygdaloid nucleus.

In the amygdala the DA fibers are concentrated in the central, basolateral, and intercalated nuclei and in the posterior nucleus of the lateral nuclear complex [Fig. 11, levels 10-17; (143, 169, 172, 525)]. Dopamine innervations of sparse-to-moderate density are found in the cortical and medial nuclei and in the anterior amygdaloid area (143).

The DA innervations of the piriform cortex and the amygdala originate in the VTA and the medial substantia nigra [Fig. 13A; Table 6; (30, 76, 143, 146, 172, 397, 398, 478, 502)J. The projection is topographically arranged in both anterior-to-posterior and medial-to- lateral directions (146). The majority of DA afferents reach the amygdaloid-piriform region via the ansa lenticularis and, as a loosely arranged system of fibers, via the ventral amygdaloid bundle (137, 146, 297). No significant population of DA fibers seems to reach the amygdala via the stria terminalis (137,143). According to Meibach and Katzman (350), the arrangement is somewhat different in the cat. Their data indicate that the DA innervation in the central nucleus originates in the lateral and dorsal VTA and in the most dorsal portion of the pars compacta of the substantia nigra, whereas the innervation in the lateral nucleus originates in the pars lateralis of the substantia nigra. The latter projection does not join the other ascending axons from the mesencephalic DA cells in the MFB but occupies a lateral position adjacent to the cerebral peduncle and joining the ventral amygdaloid bundle.

The DA innervation of the ventral entorhinal cortex is confined to its anterior part, where the fibers form a series of clusters, localized mainly in the second and third layers [Fig. 11, levels 17 and 18; (33, 84, 143, 172, 226, 303)]. Scattered DA terminals are found in the posterior entorhinal cortex. The cell bodies of origin are distributed in the VTA, principally in its lateral part [Fig. 13A; Table 6; (28, 30, 143, 146, 172, 303, 478, 502)]. In addition some evidence suggests there is a minor projection from the A8 DA cell group to the entorhinal cortex [Fig. 13A; (502)l.

There is also some evidence for a minor DA input to the hippocampus. First, bilateral 6-hydroxydopamine (6-OHDA) injections in the ascending noradrenergic pathways, which almost completely deplete hippocampal NE, reduce DA to a markedly lesser degree, and do not affect the hippocampal dihydroxyphen- ylacetic acid (DOPAC) level (38). If these injections aye combined with lesions in the A9 and A10 cell group area, further reductions in hippocampal DA and DOPAC content are observed (464). Second, Simon and co-workers (478) have found some labeled terminals in the gyrus dentatus region and at the internal edge of the hippocampus after injections of [3H]leu-

cine into the posterior VTA. No such labeling was observed in another study after injections of anterograde tracers into the VTA or substantia nigra, however (30). After injection of HRP (561) or labeled wheat germ agglutinin (465) into the hippocampus, labeled neurons have been found both in the VTA and in the substantia nigra. In contrast, Riley and Moore (443) found no such labeling in the VTA or substantia nigra after hippocampal HRP injections. However, Swanson (502) has reported that injections of the fluorescent tracer true blue into the dorsal hippocampus labeled cells in both the VTA and substantia nigra. A small number of these cells were identified as dopaminergic with tyrosine hydroxylase immunohistochemistry. Third, the effect of drugs on hippocampal homovanillic acid (HVA) and DOPAC levels is similar to that observed in other limbic areas innervated by DA neurons (38, 238). Finally, data indicate that DA- sensitive receptor sites exist in the hippocampus (see ref. 464).

On the basis of these findings it has been postulated that the hippocampus receives a sparse DA input from the A9 and A10 cell groups (464,502). In animals with extensive neurotoxin-induced depletion of forebrain NA, aldehyde histofluorescence and tyrosine hydroxylase immunohistochemistry have demonstrated only some very few scattered CA fibers in the dorsal hippocampus (305,535a). The density of these presumed dopaminergic axons is higher in the ventral hippocampus, but here also they are sparse. Hokfelt and co- workers (230), using the glyoxylic acid method, described a previously unknown minor CA input to the hippocampus, which on the basis of its reaction to various pharmacological manipulations, was considered to be dopaminergic. However, in a subsequent immunohistochemical study (229), only a few possibly DA-containing terminals were seen in the hilar area of the dentate gyrus, immediately below the granular cells.

Neocortical projections of the mesencephalic DA neurons were first suspected on the basis of the biochemical studies of Thierry and co-workers (518), and they were subsequently corroborated by histochemical studies (33, 226, 303). The DA innervation of the frontal neocortex occurs via the terminal ramifica- tions of three different projection systems: the anteromedial, suprarhinal, and supragenual systems (see ref. 302 for detailed description of terminal patterns). The terminals of the anteromedial system distribute mainly in the basal layers of the pregenual part of the anteromedial frontal cortex and originate principally in the medial A10 cell group [Fig. 11, levels 1-4; Fig. 13B; (27, 30, 76, 138, 146, 302, 303, 478, 479, 502)J. The terminals of the suprarhinal system are found predominantly in the deep cortical layers dorsal to the rhinal sulcus (i.e., in the sulcal cortex in the frontal lobe; Fig. 11, levels 1-4). The cell bodies of origin lie in the dorsolateral part of the A10 cell group [Fig. 13B; (143, 146, 183, 302, 303)J, and it seems unlikely


that the substantia nigra contributes in any significant degree to this fiber system (183,302). The supragenual system, which gives rise to a dense innervation of the second and third layers of the anterior cingulate cortex (Fig. 11, levels 5-8), originates in the substantia nigra (76, 138, 146, 302, 303, 502), and lesion experiments ixidicate that the cell bodies are distributed along the mediolateral extent of the pars compacta [Fig. 13B; (302)l. A contribution from the A10 cell group is also possible (see ref. 502), but the labeling in this area after tracer injections into the anterior cingulate cortex may very well be due to tracer uptake into fibers belonging to the caudal extension of the anteromedial system in the basal cortical layers (Fig. 11, levels 5- 7).

It is interesting to note that the projection field of the DA afferents to the frontal cortex coincides very closely with the areas of termination of the afferents from the mediodorsal thalamic nucleus (27, 34, 118, 120). This area is usually defined as the prefrontal cortex. The prefrontal cortex appears to be a prime target for the mesocortical DA projection not only in rodents, but also in other mammals (118), including primates (40, 65, 66, 432). Biochemical studies in primates indicate that the neocortical DA innervation is densest in the prefrontal areas but that it extends over a wide area of the frontal lobe (40, 65, 66). In addition the DA levels point to a significant DA innervation of the temporal association cortex. The HRP data of Porrino and Goldman-Rakic (432) indicate that the DA innervation of the prefrontal cortex in the monkey, as in the rat, originates in the VTA and pars compacta of the substantia nigra. The topographical arrangement observed was similar to that found in the rat, in that areas on the ventral surface of the frontal lobe, including the orbitofrontal cortex, are innervated from the VTA; the areas on the dorsal surface of the frontal lobe are innervated from the VTA and the medial nigra, whereas the medial cingulate areas are innervated also by cells in the more lateral parts of the substantia nigra.

The terminals of the perirhinal system are localized along the rhinal sulcus mainly in the deep cortical layers, in close relationship to the claustrum [Fig. 11, levels 5-20; (143, 302) 1, extending -2 mm above the rhinal sulcus. It merges rostrally with the suprarhinal system and at caudal levels extends, with a low density of fibers, into an area of the posterior temporal cortex suggested to correspond to the temporal association cortex in primates (I. Divac, 0. Lindvall, and A. Bjork- lund, unpublished observations). This is consistent with biochemical findings in the monkey (40, 65), which indicate the presence of a more extensive DA innervation to the temporal lobe in primates. The perirhinal system of the rat seems to originate both in the lateral A10 cell group and in the substantia nigra [Table 6; (143, 146, 30211.

It should be mentioned that in a recent study in the cat Markowitsch and Irle (324) found labeled neurons

in the VTA after HRP injections into many neocortical areas (including posterior regions), where no DA terminal axons have been observed in the rat. Al- though this may be a species difference, it is also possible (as they pointed out) that the projections to areas outside the boundaries of the established mesocortical DA innervations are by nondopaminergic VTA neurons. However, with HRP tracing in combination with CA histofluorescence, evidence has been obtained for a dopaminergic projection from the A10 cell group to the visual cortex in the cat (522). No such projection has been observed in the rat brain.

Diencephaiic Projections of Mesencephalic Dopaminergic Cell Groups

The diencephalic projections of the mesencephalic DA cell groups have not yet been clarified in detail. So far interest has focused mainly on three regions: the habenula, subthalamic nucleus, and hypothalamus. The DA innervation of the habenula is now well established. Because of the intimate connections between the lateral habenula and the limbic system circuitry this innervation is called the mesolimbocortical system (Table 6). The medial part of the lateral habenular nucleus contains a dense aggregation of delicate dopaminergic terminal axons [Fig. 11, levels 14 and 15; (228,298,304,427,483)l. There is substantial evidence both from lesion experiments (271, 427, 483) and from studies with anterograde (30, 478) and retrograde (221, 415, 426, 483, 502) tracers that the DA innervation of the lateral habenula originates in the A10 cell group (Table 6).

The cells labeled after injections of retrograde tracers into the lateral habenula lie a t and near the midline of the VTA (426, 483, 502). However, only a few of these cells contain DA, which indicates that the habenular projection from the VTA is largely nondopaminergic (483,502). Anterograde tracer studies indicate that the VTA neurons may project to the habenula both via the fasciculus retroflexus (30, 478) and the stria medullaris (478). Both of these tracts have been shown to carry CA axons (297). Microknife lesions in combination with CA histochemistry demonstrate, however, that the fasciculus retroflexus is the most important route for the VTA-habenular DA projection (483).

The subthalamic nucleus contains significant amounts of DA (536), and in the rat and cat (63,349), as well as in the human fetus (389), a loose plexus of CA fibers has been demonstrated in this nucleus. No CA cell bodies are found in the rat, but in the cat DA cells have been observed in the posterior part of the nucleus. It is not clear whether this presumed DA fiber plexus (Fig. 11, levels 15 and 16) originates from the nigrostriatal bundle (e.g., via collaterals) or from separate DA cells (e.g., in pars reticulata of substantia nigra or in the cat subthalamic nucleus itself). Because of the functional relations between the subthalamic nucleus and the striatal output systems (see General


Organizational Features, p. 188), the DA projection to this nucleus is included within the mesostriatal system (Table 6).

Hypothalamic DA has been considered to be associated exclusively with the periventricular, tuberohypophysial, and incertohypothalamic systems. How- ever, Kizer and co-workers (271) found significant reductions of DA levels in the hypothalamus after large electrolytic lesions of the A8-AlO cell groups, and Zaborszky (565) has reported a 35% reduction of DA in the arcuate region after electrolytic lesion of the A8 cell group region. Palkovits and co-workers (404) found axonal degeneration in the median eminence after large mesencephalic lesions and after 6- OHDA injections into the same areas. This led Kizer et al. (271) to suggest that the mesencephalic cell groups contribute to the DA innervation of the hypothalamus. However, other data do not support this hypothesis. First, Weiner et al. (550), Brownstein et al. (67), and Gudelsky et al. (202) found reduced NE levels but no significant changes in DA levels in the mediobasal hypothalamus after complete hypothalamic deafferentation. Although Palkovits and co- workers (402) measured a slightly decreased mean DA level in the median eminence after total deafferentation of the medial hypothalamus, this change was not statistically significant. Second, unilateral 6-OHDA injections into the substantia nigra, which also reached neurons in the VTA, caused no change in hypothalamic DA levels (452). It could be argued, however, that some A10 cell group neurons were un- affected by that lesion since it had no denervating effect, e.g., in the septa1 area. Third, tracer studies have given conflicting results. Thus Fallon and Moore (146), Day et al. (106), Wiegand and Price (555), and Berk and Finkelstein (35) found no evidence for a mesohypothalamic DA pathway, and Beckstead and co-workers (30) found only a few labeled fibers in the posterior hypothalamus after injections of [3H]leucine and [3H]proline into the VTA. In contrast, Simon and co-workers (478) observed significant labeling in the medial hypothalamus, including the median eminence, after injection of [3H]leucine into the VTA, and Za- borsky (565) has reported retrograde labeling in the region of the A8 and A10 cell groups after HRP injections into the medial basal hypothalamus. It must be pointed out that no attempt was made to identify these as dopaminergic connections. It is not known why the results conflict, but it is clear that the existence of a mesohypothalamic DA pathway is not defi- ni tely established.

Descending Projections From Mesencephalic Dopaminergic Cell Groups

Evidence is accumulating for the existence of descending dopaminergic connections from the mesencephalon to various mesencephalic and pontine nuclei,

especially the locus coeruleus, the parabrachial region, and the dorsal raphe nucleus. Since these areas are intimately related to the mesencephalic limbic region, these descending dopaminergic projections are included within the mesolimbocortical DA system as defined previously (Table 5; Fig. loll). The evidence for a DA projection to the locus coeruleus is fourfold. 1) The locus coeruleus reportedly contains significant amounts of DA (536), but no DA-producing cell bodies have been found. 2) Studies with the Fink-Heimer technique after VTA lesions (477) and anterograde transport after 3H-labeled amino acid injections into the VTA (30, 480) indicate that VTA neurons project bilaterally to the locus coeruleus. 3) Swanson (502) has identified labeled dopaminergic cells in both the VTA and the substantia nigra after injections of a retrograde fluorescent tracer into the locus coeruleus region. This mesocoeruleal DA projection has both ipsilateral and contralateral projections, and some individual DA neurons seem to innervate the locus coeruleus on both sides via collateral branches. 4 ) Geffard et al. (181a) have recently reported sparse immunoreactive fibers in the locus coeruleus stained with an antiserum to DA.

Hedreen (214) has proposed that part of the CA innervation of the lateral parabrachial nucleus is dopaminergic. This conclusion was based on the appearance of degenerating terminals in the ventrolateral part of the nucleus, after intraventricular 6-OHDA7 stained with the Fink-Heimer technique. This method has been reported to stain only degenerating DA terminals and not NE terminals after 6-OHDA treatment (214, 215). The existence of a dopaminergic input to the lateral parabrachial nucleus is supported by findings with retrograde tracers combined with tyrosine hydroxylase immunohis tochemis try (502), which showed some scattered, presumably dopaminergic cells in the VTA that were labeled after injection into the parabrachial area. However, the possibility that the injected tracer was taken up by axons passing through the area on their way to the locus coeruleus cannot be ruled out.

On the basis of tracer studies and changes in DA levels after lesions, it has been suggested that the VTA and substantia nigra have other descending projections than those already described. However, more experimental evidence is required before the DA nature of these projection systems can be definitely established. The available data on these possible descending connections of the mesencephalic DA neurons are discussed below.

Tritiated leucine and proline injected into the VTA (30, 122, 478) and substantia nigra (30) are trans- ported to the dorsal raphe nucleus. A projection from the substantia nigra is also indicated by labeling after HRP injection into the dorsal raphe nucleus of the rat (323) and cat (454). Since the dorsal raphe nucleus contains high levels of DA (see refs. 290 and 536), it


has been suggested that the afferents originating in the VTA and substantia nigra contain DA (478). Such a dopaminergic projection has not been definitely demonstrated, and it should be remembered that the dorsal raphe nucleus contains dopaminergic cell bodies (228, 297, 372, 394), which should account for a t least part of its DA content.

The CA afferents to the cerebellum in the rat were thought to be exclusively noradrenergic (see ref. 299). However, Kizer and co-workers (271) reported a 50% decrease in cerebellar DA levels after lesions of the A8-Al0 cell groups, suggesting that some afferents to the cerebellum might be dopaminergic and originate in the mesencephalon. The existence of such a system is still unconfirmed. Thus, although Simon and co- workers (479) have reported anterograde transport of [3H]leucine to the cerebellum after injection into the VTA, similar experiments by Beckstead and co-workers (30) showed no such labeling. Furthermore large injections of retrograde tracers into the cerebellum did not label any presumably dopaminergic cells in the mesencephalon (456, 502).

In the spinal cord, Commissiong and co-workers (88) observed a decrease in DA levels after lesioning the substantia nigra, which suggests the existence of

B

a nigrospinal DA projection. However, no labeled DA cell bodies have been found in the substantia nigra after tracer injections into the spinal cord of the rat (see ref. 482). It is possible that the lesions performed by Commissiong and co-workers (88) severed fibers of passage from the more rostra1 hypothalamic DA neurons innervating the spinal cord.

Projections of Diencephalic Cell Groups

DIENCEPHALOSPINAL SYSTEM. Biochemical studies first provided evidence that DA in the spinal cord is not only a precursor of NE, as previously believed, but is also an independent transmitter in a separate DA neuron system (87, 90, 158, 321). This idea was corroborated in studies with transmitter-specific retrograde tracing techniques, which showed that DA-containing neurons in the diencephalon can be retrogradely labeled after injections into the spinal cord in the rat and rabbit [Fig. 14.4; (48, 52, 231, 508)]. The terminal distribution of this diencephalospinal DA projection system has subsequently been mapped with the histofluorescence technique (482). Since the density of DA terminals in the spinal cord is much lower than that of the NE fibers, the mapping of the dopa-

FIG. 14. A: diencephalic DA projection systems, including incertohypothalamic, tuberohypophysial, periventricular, and diencephalospinal systems. H, hypothalamus; ME, median eminence; P, pituitary gland PO, preoptic area; S, septa1 area; SP, spinal cord; and T, thalamus. B: proposed arrangement of diencephalospinal DA system.


minergic innervation was carried out in rats with extensive neurotoxin-induced depletion of spinal NE.

The presumed DA axons are fairly evenly distributed along the spinal cord (Fig. 11, levels 21-24). In the dorsal horn they are most abundant in the lateral parts of the superficial layers and in the adjoining reticular nucleus. The highest density of these DA fibers is found in the intermediolateral cell column and in the area surrounding the central canal at thoracic and upper lumbar levels. The presumed DA innervation is not uniform along the intermediolateral column but forms clusters or patches of varicose fibers, which are connected with each other and with the innervation along the central canal by thinner strands of parallel fibers. The fiber patches most likely correspond to the clustering of preganglionic sympathetic neurons along the intermediolateral column and within the intermediate spinal gray.

Using the transmitter-specific retrograde tracing technique, the spinal DA projection system in the rat was found to be largely uncrossed and to originate exclusively in the A l l cell group [Fig. 14; (48, 231, 482, 482a)l. The labeled DA cell bodies are located in the dorsal and posterior hypothalamus, the zona incerta, and the caudal thalamus. According to Swanson and co-workers (508), labeled cells are also found in the paraventricular hypothalamic nucleus. Blessing and Chalmers (52) found labeling of the A13 cell group in the dorsal hypothalamus in the rabbit after tracer injections into the spinal cord, but these cells are not labeled in the rat. This discrepancy has not been explained, but it might be due to species differences in the topography of the All-A13 cell groups.

As described in the next section, the A l l cell group is probably a major source of fibers innervating diverse diencephalic areas via the periventricular fiber system, and the diencephalospinal DA pathway represents its first known descending projection. Lindvall and co- workers (304) observed that the axons of some A l l cells bifurcate in a T-shaped manner, giving rise to an ascending and a descending branch, thus suggesting that intradiencephalic and spinal cord projections could be established by collateral axonal branches of the same neurons. Although the projection route of the diencephalospinal system in the brain stem is not yet known, there is some evidence that at least some of the axons may descend within the dorsal longitudinal fasciculus (368). The axons in the spinal cord appear to descend partly within lamina I of the dorsal horn and the adjoining parts of the dorsolateral funiculus and partly along the central canal (Fig. 14B).

PERIVENTRICULAR SYSTEM. The rostral part of the periventricular fiber system comprises CA axons from several different sources. Apart from fibers from the periventricular cell system (which is almost exclusively dopaminergic), NE axons are also derived from the locus coeruleus and possibly from other pontine and medullary cell groups as well. The relative contri-

bution of these different sources, however, is not known in detail.

As described previously (see Periventricular System, p. 170), the dorsal periventricular CA fiber system forms a well-defined bundle at rostral levels, known as the dorsal periventricular bundle (see Fig. 8). On entering the diencephalon, this bundle splits into several branches, which enter the pretectal area, the habenula, and the paraventricular and parafascicular thalamic nuclei. The major portion of the bundle turns ventrally along the periventricular gray of the caudal thalamus and runs through the posterior hypothalamus into the dorsomedial hypothalamic nucleus, where the dorsal periventricular bundle merges with the ventral periventricular system. Some of the dorsal periventricular fibers turn rostrally, dorsal to the dorsomedial nucleus, to form a distinct bundle in the medial zona incerta. This bundle sends fibers dorsally into the rhomboidal nucleus.

The ventral periventricular CA fiber system (see Fig. 8) forms in the supramammillary region and runs rostrally, in a periventricular position, through the posterior hypothalamus and into the dorsomedial hypothalamic nucleus. After receiving fibers from the dorsal periventricular bundle, it continues rostrally as a broad system dispersed on the lateral aspect of the periventricular nucleus. It then enters the paraventricular hypothalamic nucleus and sends some fibers into the bed nucleus of the stria terminalis. Most of its axons sweep dorsally and caudally as periventricular thalamic fibers and terminate in the paraventricular thalamic nucleus.

The evidence that a major portion of the diencephalic part of the periventricular system is dopaminergic and is formed by neurons distributed along the system can be summarized as follows. First, extensive neurotoxin-induced depletions of forebrain NE have only minor effects on DA levels and spare substantial innervations (-20%-30%) in several areas of termination for the periventricular fibers [e.g., dorsomedial, periventricular, paraventricular hypothalamic nuclei and paraventricular thalamic nucleus; Fig. 11, levels 11-15; (305).] The DA innervation of the supraoptic nucleus (Fig. 11, level 11) may also arise from the periventricular system. These regions contain significant, nonprecursor levels of DA (400, 536). Second, tyrosine hydroxylase immunohistochemistry, which preferentially (although not exclusively) demonstrates DA axons, revealed terminal systems in these areas (228). Third, a dopaminergic fiber plexus in the paraventricular and supraoptic nuclei has been demonstrated immunohistochemically with a specific anti- body against DA (67b). Fourth, a substantial part of the periventricular fibers show a desipramine-resistant uptake of exogenous CAs, further supporting their dopaminergic nature (298). Fifth, the periventricular DA cells in the A l l cell group project axons along the periventricular system (297), and some hypothalamic HRP injections label cells in the area of the A l l cell


group, although these cells were not identified as containing DA (523,565).

INCERTOHYPOTHALAMIC SYSTEM. The incertohypothalamic system, which is essentially an intradiencephalic dopaminergic projection system (Figs. 14 and 15), has been demonstrated both by fluorescence histochemistry (44, 304) and immunohistochemistry (228). It consists of short, locally projecting neurons whose fibers have an unusual and peculiar fluorescence structure. The fibers arborize extensively soon after they leave the cell bodies and exhibit very fine, weakly fluorescent varicosities, with the intervaricose segments only partly visible.

The incertohypothalamic fibers can be separated topographically into a caudal and rostral part [Fig. 15; (44)]. The caudal part extends from the DA cell bodies in the caudal thalamus, the posterior hypothalamic area, and the medial zona incerta ( A l l and A13 cell groups) into the dorsal part of the dorsomedial nucleus and the dorsal and anterior hypothalamic areas. The rostral part, probably originating from the rostral periventricular cell bodies of the A14 cell group, is distributed in the periventricular nucleus of the anterior hypothalamus and in the periventricular, supra- chiasmatic, and medial preoptic nuclei, up to the level of the anterior commissure. The system extends into the most caudal part of the lateral septa1 nucleus.

The relationships between the incertohypothalamic fibers and the periventricular and spinal DA projections remain to be clarified. Their cells of origin may represent entirely separate neuronal populations in the A l l , A13, and A14 cell system, but they may also originate in the same DA neurons. If the incertohypothalamic fibers are derived from those diencephalic neurons that give rise to the periventricular and spinal

projections, then the incertohypothalamic fibers could represent a dendritic, rather than axonal, terminal network. The peculiar structure of these fibers, which resembles the dendritic terminals in the substantia nigra, supports this hypothesis. More studies are ob- viously needed to clarify the precise organizational features of the diencephalic DA projection systems.

TUBEROHYPOPHYSIAL SYSTEM. The dopaminergic tuberohypophysial neurons constitute a part of Szen- tagothai’s (51 1) parvocellular neurosecretory system. The cell bodies are located in the arcuate nucleus and in the portion of the periventricular nucleus just dorsal to the arcuate nucleus, the A12 cell group (see DIEN- CEPHALIC CELL GROUPS, p. 162). Their axons project in a seemingly ordered manner to all parts of the median eminence, the hypophysial stalk, the neural lobe, and the pars intermedia of the pituitary (41, 45, 168, 252, 292, 311, 483a). The entire dopaminergic input to the median eminence-pituitary region appears to originate in the mediobasal hypothalamus, whereas the noradrenergic innervations originate in the lower brain stem and in the sympathetic superior cervical ganglion (45). The peripheral sympathetic innervation is, in the rat at least, confined to some of the larger vessels in the neural lobe. These vascular fibers disappear after bilateral extirpation of the superior cervical ganglia (45).

The central noradrenergic innervation of the pituitary complex is probably confined to the median eminence. The reticuloinfundibular NE pathway originates in the medullary A1 and A2 cell groups (347, 406, 463). Biochemical measurements indicate that NE constitutes -30% of the total CA content in the median eminence (98). The noradrenergic afferents terminate mainly in the internal and subependymal

FIG. 15. Distribution of incertohypothalamic fiber system at 6 representative frontal levels (a-f). Locations of CA-containing cell groups ( A l l , A13, A14) are also indicated. ah, Anterior hypothalamic n.; dh, dorsal hypothalamic area; dm, dorsomedial hypothalamic n.; MT, mammillothalamic tract; OC, optic chiasm; ph, posterior hypothalamic n.; pom, medial preoptic n.; PPN, periventricular preoptic nuclei; pv, periventricular hypothalamic n.; st, interstitial n. of stria terminalis; and vm, ventromedial hypothalamic n. [From Bjorklund et al. (44).]

a


layers, but some innervate the external layer as well (41,45, 98, 311). According to the quantitative microfluorometric study of Lofstrom et al. (311), the NE terminals constitute -80%-90% of the total CA innervation in the subependymal layer, -25%-50% in the medial part of the external layer, and <20% in the lateral external layer.

Figure 16 illustrates the basic organizational features of the tuberohypophysial DA system. The innervation of the median eminence and the stalk originates in cell bodies in the arcuate nucleus (41, 45, 170, 171, 252, 292). Our lesion experiments show that these tuberoinfundibular DA neurons could be separated into two groups on the basis of their mode of projection (Fig. 16B). One group, situated in the rostral part of the arcuate nuclei, projects more diffusely to all levels of the median eminence and the stalk (as well as to the pars intermedia and neural lobe). The second group, having a more regular dorsoventrally oriented projection, appears to connect each portion of the arcuate nucleus (i.e., rostral, middle, or caudal portion) with a corresponding part of the median eminence below it.

The tuberoinfundibular DA neurons project to all layers of the median eminence and the stalk (Fig. 16C). The terminals are more abundant in the external layer, where they are very densely packed in a pali- sade-like manner, close to the capillaries of the portal vessels. The fibers have a regular, finely varicose

appearance, often ending with a strongly fluorescent dropletlike enlargement. It is likely that some fibers in the internal layer are preterminal, running parallel to one another in the sagittal and frontal planes. However, some appear to ramify with the reticuloinfundibular NE fibers, forming irregular patterns in the deeper layers, partly in association with the capillary loops of the portal vessels.

In a quantitative ultrastructural study, Ajika and Hokfelt (5) found that the monoaminergic fibers constitute -33% of all boutons in the lateral part of the external layer and -13% in its medial part. By comparison, the same authors found that 2.6% of the boutons in the arcuate nucleus were monoaminergic. The CA fibers in the zona externa do not seem to form any true synaptic connections with other tissue elements but do come in close contact with nonmonoam- inergic axons and ependymal cells, as well as with the pericapillary space of the hypophysial portal vessels (5, 223a).

Dopaminergic fibers have also been detected by microspectrofluorometric analysis around the endocrine cells of the pars intermedia and in the neural lobe of the rat (41). In the neurointermediate lobe it is likely that the NE detected biochemically (42) derives exclusively from the peripheral sympathetic vascular supply and that the central innervation is exclusively dopaminergic. Experiments with small lesions of the arcuate nuclei indicate that the DA fibers of the neurointermediate lobe originate in the rostral portion of the arcuate nucleus, with the cells innervating the pars intermedia lying immediately rostral to those innervating the neural lobe (Fig. 16B). The DA fibers are distributed throughout the neural lobe and form a network surrounding the endocrine cells of the pars intermedia. In the neural lobe the fibers often terminate with one or several DA-filled droplets or bulbous swellings, thus resembling the peptidergic neurosecretory axons in the same region. Ultrastry- turally, the DA fibers form close contacts (80-120 A), without membrane thickenings, with neurosecretory axons and pituicyte processes in the neural lobe, and with endocrine cells in the pars intermedia (23). It seems likely therefore that the DA fibers in the median eminence and the neurointermediate lobe have similar terminal arrangements and that they act both on neighboring cells and axons across nonjunctional contacts and by being released into the local blood circulation.

MESOTELENCEPHALIC DOPAMINERGIC NEURONS AND ORGANIZATION OF STRIATAL AND LIMBIC FOREBRAIN CIRCUITRY

FIG. 16. Arrangement of tuberohypophysial DA system in rat. A : distribution of CA-containing terminals in median eminence, neural lobe (NL), pars intermedia (PI), and pars distalis (PD). VIII, 3rd ventricle. B and C projection patterns from paraventricular (HPV) and arcuate (AR) nuclei to median eminence and pituitary. [From Bjorklund et al. (42).]

General Organizational Features Dopamine was originally associated with the neo-

striatum through the nigrostriatal pathway and was thus implicated in extrapyramidal motor control. It


was later realized that the mesencephalic DA system also projects to a number of limbic areas and that DA might be involved in the regulation of a wider range of behaviors. After Heimer and Wilson (217) formu- lated the ventral striatum concept, it became evident that a dense dopaminergic innervation is characteristic of the deep, subcortical nuclear masses of the telencephalon that collectively form the striatal complex. As Figure 17 illustrates, this striatal complex comprises dorsally and caudally the nucleus caudatus-putamen and ventrally the bed nucleus of the stria terminalis, the nucleus accumbens, ar,d the medium- celled part of the olfactory tubercle. Although the neostriatum (i.e., dorsal parts of striatal complex) is classically associated with extensive and highly organized projections from the neocortex, the ventral striatal areas are the targets of projections from the limbic, cortical, and subcortical regions. The dorsal striatum in turn projects to the dorsal pallidum (globus pallidus and entopeduncular nucleus), and the ventral striatum projects to the ventral or subcommissural pallidum, which forms part of the substantia innominata (217, 509).

The A10 cell group of the mesencephalic DA cell complex (located in VTA and adjacent regions) projects to the entire subcommissural part of the ventral striatum, as well as to the ventromedial part of the head of the caudate putamen (Fig. 18A). The substantia nigra proper (defined as cells overlying pars reticulata of substantia nigra) innervates the entire caudate putamen, except its most rostromedial part. Ap-

parently the rostromedial part of the head of the caudate putamen is a transitional zone in which the two innervation territories overlap. Beckstead (27) and Kelley et al. (259) have demonstrated that the extension of the innervation territory of the VTA neurons coincides closely with those of the afferents of the prefrontal cortex and amygdala (Fig. 18B). This combined innervation territory thus seems to deline- ate the limbic part of the striatum. Afferents from other parts of the allocortex, notably the hippocampus and the entorhinal, perirhinal, and piriform cortices, have more restricted distributions in the ventral striatum. As Figure 18B illustrates, the afferents from the piriform cortex terminate in the olfactory tubercle and the ventral part of the nucleus accumbens (217); the afferents from the hippocampus (originating mainly in subiculum) terminate in a circumscribed area of the medial part of the nucleus accumbens (197, 217, 258, 505), and the afferents from the entorhinal and perirhinal cortices terminate in a wider area of the accumbens and in the olfactory tubercle (197, 258, 276, 382, 383). The bed nucleus of the stria terminalis receives its limbic and allocortical projections mainly from the amygdala and hippocampus (505,552).

Whereas the dopaminergic projections from the VTA overlap with the limbic and allocortical projections in the striatal complex, the innervation territory of the substantia nigra proper appears to coincide with that of the somatic sensorimotor neocortex in the rat [Fig. 18A, B; (264a, 54911. Because of the overlap of the limbic and nonlimbic cortical afferents in the

THALAMUS

FIG. 17. Anatomical relationships between cerebral cortex, striatal complex, thalamus, and ventral mesencephalon. Left-tilted hatching, areas innervated by substantia nigra; right-tilted hatching, areas innervated by DA neurons of A10 cell group. ACC, n. accumbens; CP, n. caudatus-putamen; DP, dorsal pallidum; HL, lateral habenular n.; MD, mediodorsal thalamic n.; OT, olfactory tubercle; ST, bed n. of stria terminalis; VL + VA, ventrolateral and ventral anterior thalamic nuclei; and VP, ventral pallidum.


Projection from substantia nigra proper Projection from A 10 (VTA)

Afferents from neocortex Afferents from prefrontal cortex and amygdala

<,,...;. Afferents from hippocampus via fimbria- fornix ::> Afferents from entorhinal and perirhinal cortex 0 Afferents from piriform cortex

_..._.

FIG. 18. Comparison of areas within striatal complex receiving afferents from nigral and DA neurons of A10 cell group (left) and from different parts of cortical mantle and amygdala (right).

striatum, only the dorsal and lateral parts of the caudate putamen are entirely nonlimbic in their con- nectivity (259). The dopaminergic innervation of this part of the neostriatum is derived exclusively from the substantia nigra proper (30, 206, 530). Behavioral studies show that this anatomical heterogeneity of the striatal afferent connections reflects a functional heterogeneity of the neostriatum (117,121,130,131,448). Thus restricted electrolytic or neurotoxin-induced lesions in different parts of the caudate putamen produce different selective behavioral impairments. In particular, lesions in the anteromedial and ventrolat- era1 parts of the caudate putamen, which in the rat are innervated by the different parts of the prefrontal cortex, selectively produce cognitive and regulatory impairments of the type otherwise associated with prefrontal cortex damage.

In the monkey the motor cortex projects almost exclusively to the putamen (108a, 279b), whereas the prefrontal cortex projects heavily and almost exclusively to the caudate nucleus (185b). This indicates that the anteromedial limbic part of the neostriatum in the rat (Figs. 17 and 18) is equivalent to the caudate nucleus in the monkey, and that the dorsolateral and caudal nonlimbic parts are equivalent to the putamen. Thus, if the rat had a massive internal capsule, as does the monkey, it ought to run along the overlapping cross-hatched zone in Figure 18.

The principal efferent outputs of the dorsal striatum are channeled via the striatopallidothalamic and striatonigral pathways (Figs. 17 and 19). The nucleus caudatus-putamen projects to both segments of the dorsal pallidum and from the internal segment (equiv-

DORSAL STRIATAL COMPLEX

NEOCORTEX

DESCENDING OlJTPUT

FIG. 19. Some major pathways and transmitter characteristics related to nigral DA projection to dorsal part of striatal complex (i.e., n. caudatus-putamen). ENK, enkephalin; SP, substance P; and nc. entoped., n. entopenduncularis.

alent to entopeduncular nucleus in rat) further on to the ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus. The VL-VA complex then projects to the motor cortex. Besides this classic striatopallidothalamocortical loop, the efferents of the internal pallidum are also channeled via the lateral

habenular nucleus (221,379,415,531). This habenular output pathway provides access, via the efferents of the lateral habenular neurons, to wide areas of the mesencephalic reticular formation (including median and dorsal raphe nuclei, superior colliculus, central gray, and locus coeruleus) and to the pars compacta of the substantia nigra, as well as to the lateral hypothalamus, the preoptic area, and other regions of the ventral forebrain (6, 221, 500).

The striatonigral projection comprises a direct connection from the caudate putamen to the pars reticulata of the substantia nigra, as well as an indirect connection via the globus pallidus [not depicted in Figs. 17 and 19; (see refs. 125, 188 for reviews)]. The striatonigral pathway has been shown to innervate both the dopaminergic and the nondopaminergic neurons of the substantia nigra (110, 111, 115, 187, 212, 487, 546). This suggests that the striatonigral projection can function both as a feedback loop onto the nigrostriatal DA neurons and as an output pathway relayed via the neurons of the pars reticulata to the thalamus (mainly ventromedial nucleus) and the mesencephalic reticular formation (including deep layers of superior colliculus).

The anatomically well-established connections in the output systems of the dorsal striatum have also been demonstrated functionally in the rat with the autoradiographic deoxyglucose method after drug-induced DA receptor stimulation. Systemic administration of apomorphine thus leads to increased glucose usage in the regions linked by the striatopallidothalamocortical pathway (striatum, entopeduncular nucleus, ventrolateral thalamic nucleus, and sensorimotor cortex) and the striatopallidonigral, nigrothalamic, and nigrotectal pathways [striatum, globus pallidus, pars reticulata of substantia nigra, ventromedial thalamic nucleus, or deep layers of superior colliculus (64, 260,334,335)l. The projection areas of the striatopal- lidohabenular system show an increased (striatum, entopeduncular nucleus) or a reduced (lateral habenular nucleus) glucose usage after administering apomorphine (64, 260, 334, 335). It is not yet known whether these effects on glucose consumption result partly from the activation of DA receptors in the globus pallidus, substantia nigra, and lateral habenular nucleus or whether they result solely from dopaminergic stimulation in the striatum, with subsequent alteration in the activity of the striatal outflow systems. The involvement of striatal DA receptors in the response is demonstrated by the effects of intrastriatal DA injections, which mimic the changes in glucose usage caused by systemic apomorphine in the stria- topallidohabenular and striatonigrotectal systems (64). This is also illustrated by the attenuation of apomorphine-induced changes in glucose consumption (e.g., in globus pallidus, entopeduncular nucleus, and ventromedial thalamic nucleus) after striatal kainic acid lesions (260).


The striatopallidothalamic and striatonigral output pathways of the dorsal striatum have correlates in the ventral striatal system (Figs. 17 and 20). Thus all areas of the subcommissural striatum (nucleus accumbens, olfactory tubercle, and bed nucleus of stria terminalis) project into the general area of the ventral pallidum (217, 350b, 381-383). According to Mogen- son et al. (350a), the striatal projections to the dorsal and ventral pallidal regions are organized topographically along both mediolateral and dorsoventral gradients. The projection from the caudate putamen appears to be confined to the globus pallidus (i.e., dorsal pallidurn), whereas the projection from the nucleus accumbens to the ventral pallidal region extends into the ventral part of the globus pallidus, as well as into the anterior part of the lateral hypothalamic area.

Like the dorsal pallidum, the ventral pallidum also projects to the thalamus. The thalamic targets of the dorsal and ventral pallidum are, however, different: whereas the dorsal striatopallidal system projects to the VL-VA complex (innervating motor cortex), the prime target for the ventral striatopallidal complex appears to be the mediodorsal nucleus (196, 216). The mediodorsal nucleus selectively innervates the prefrontal cortex. Similar to the dorsal pallidum, the

VENTRAL STRIATAL COMPLEX

I LIMBIC CORTEX

GABA

MESENCE PHALlC

g

DESCENDING OUTPUT

FIG. 20. Some major pathways and transmitter characteristics related to DA projection from VTA and medial substantia nigra to ventral part of striatal complex and to limbic cortex. MD, mediodorsal thalamic nucleus; and BNST, bed n. of stria terminalis.


ventral pallidum also projects to the lateral habenula (221). The lateral habenula thus represents a convergence point for the efferents of the dorsal and ventral striatal complexes. Indeed, in a recent study, Garland and Mogensen (180) have demonstrated electrophys- iologically that afferents from the internal pallidal segment and the ventral forebrain (more precisely lateral preoptic area) converge onto the same output neurons in the lateral habenula. Another convergence point for outflow from the dorsal and ventral striatum lies in the pedunculopontine nucleus of the mesencephalic reticular formation, which receives direct projections from the entopeduncular nucleus (379) and the ventral pallidal region (507a).

The striatonigral output pathway of the dorsal striatum has a counterpart in the ventral striatal complex in its direct connections with the region containing the mesencephalic dopaminergic cell groups. Antero- grade and retrograde tracing studies have revealed a prominent projection from the nucleus accumbens in particular, but also from the olfactory tubercle and the bed nucleus of the stria terminalis to the VTA and the medial part of the substantia nigra (91, 381, 424, 487, 504, 506, 528, 542). Whereas the projection from the bed nucleus of the stria terminalis appears to terminate primarily in the VTA (506), the projection from the nucleus accumbens terminates mainly in the medial part of the substantia nigra, in both the pars compacta and the pars reticulata (381, 487, 528). In an ultrastructural study, Somogyi et al. (487) have shown, using a combination of anterograde degeneration and retrograde HRP labeling, that some of the nigral afferents from the nucleus accumbens synapse on nigral neurons projecting to the dorsal striatum (nucleus caudatus-putamen). The substantia nigra thus seems to be another convergence point for efferent regulatory control from the dorsal and ventral striatal complexes.

The descending mesencephalic projection from the ventral striatum is not limited to the area of the dopaminergic cell groups. Thus the efferents from both the nucleus accumbens (381) and the bed nucleus of the stria terminalis (506), as well as from the ventral pallidum (507a), continue further caudally and involve the dorsal and medial parts of the mesencephalic reticular formation (cuneiform and parabrachial regions, central gray, and raphe nuclei), including the so-called mesencephalic locomotor region (507a) and the pedunculopontine nucleus. As Figures 19 and 20 show, the different descending output pathways from the dorsal and ventral striatal systems all feed into the dorsal and medial areas of the mesencephalic reticular formation. This is true both for the direct connections and for those relayed via the substantia nigra and the lateral habenula. The preoptic and hypothalamic areas also have prominent projections to this area of the mesencephalon. This area of the mesencephalic reticular formation is an important

sensorimotor integration center, with multimodal sensory inputs and pronounced influences on motor responses (133, 193). Di Chiara and collaborators (115, 116), among others, have shown that motor responses elicited in the neostriatum, such as postural asymmetry and turning behavior, are channeled through the dorsal mesencephalic reticular formation (including deep layers of superior colliculus). This area is also intimately associated with the mesencephalic locomotor region, from which locomotion can be driven in decerebrate cats (193). This region reportedly contains an abundance of neurons projecting to the spinal cord (507a), and according to Sirkin and Teitelbaum (481), the descending output pathway for striatal motor control is channeled to the spinal cord through the contralateral medial pontine reticular formation.

The subthalamic nucleus is positioned so as to exert control over the output from both the dorsal and ventral striatum. The subthalamic nucleus projects mainly to both segments of the dorsal pallidum (75b, 377b) and to the pars reticulata of the substantia nigra (75b, 256a, 377b, 441a). There is also evidence for a projection from the subthalamic nucleus to the ventral pallidum (377b, 441a). Electrophysiological evidence suggests that the same neurons supply axon collaterals to both the globus pallidus and substantia nigra ( l l l a ) ; tracer studies indicate that this occurs in at least 94% of the neurons in the subthalamic nucleus (532a). In addition to these major efferent connections, the subthalamic nucleus projects to the striatum (29a, 377b), the neocortex (238a), and the pedunculopontine nucleus (238b, 377b). The pedunculopontine nucleus is located within the sensorimotor integration area of the dorsal mesencephalic reticular formation. The pedunculopontine nucleus projects back to the subthalamic nucleus (75b, 238c, 350d, 389a, 456a) but also has afferent and efferent connections with other structures in the striatal forebrain circuitry such as the substantia nigra and the dorsal and ventral pallidum (30,75c, 238c, 267a, 285a, 350d, 377a, 389a, 456a, 507a).

The major input to the subthalamic nucleus comes from the globus pallidus (external segment of dorsal pallidum), which projects topographically to the subthalamic nucleus (75a, 75b, 267a, 333a, 532b). The subthalamic nucleus also receives an input from the frontal cortex, with the main projection arising in the precentral motor cortex and with less-extensive contributions from the premotor and prefrontal areas (211a). Afferent projections to the subthalamic nucleus from the substantia nigra (349, 443a) and the dorsal striatum (29a) have also been proposed.

The rich connections of the subthalamic nucleus with the striatal output nuclei suggest a powerful role for this nucleus in the control of basal ganglia function. It is therefore not surprising that lesions of the subthalamic nucleus cause hemiballismus, a dramatic movement disorder involving involuntary, often vio-


lent movements of contralateral limbs (75d, 554a). The subthalamic nucleus probably has an important role in initiating locomotion (see ref. 193). Stimulating the subthalamic nucleus (subthalamic locomotor region) in the decorticate cat elicits locomotion. This effect must be relayed in the brain stem but it is unclear which pathways are involved.

Transmitter Characteristics The mesostriatal DA projection systems were the

first connections in the striatal circuitries whose transmitter content was identified. Over the last decade the transmitter characteristics of other links in the corticostriatopallidonigral conduction system have gradually been unraveled. A detailed review of this actively developing field is beyond the scope of this chapter. Figures 19 and 20 provide a simplified summary (for further discussion and review, see refs. 124, 125, 188a, 199, 340).

The mesotelencephalic DA neurons appear to inter- act with at least six other chemically characterized neuron types in the striatal circuitries: glutamate-, GABA-, acetylcholine-, enkephalin-, somatostatin-, and substance P-containing neurons. Evidence (primarily from biochemical studies on high-affinity uptake of glutamate and glutamate release) indicates that glutamate-containing neurons constitute a prominent excitatory component of the corticostriatal projections, both from the somatic neocortex to the dorsal striatum (119,267,340a7 440,449) and from the limbic and prefrontal cortical areas to the ventral striatum (539, 541, 543).

GABAergic neurons are well-established components of both the striatonigral and the striatopallidal projections (see refs. 161, 340 for review). It appears from the work of Walaas and Fonnum (540, 542), Strahlendorf and Barnes (498a), and Mogenson and Nielsen (350a) that homologous GABAergic projections also exist in the ventral striatum; i.e., from the nucleus accumbens to the ventral pallidum, the medial part of the substantia nigra, and possibly also to the VTA. GABAergic neurons may also exist in the projection from the globus pallidus to the substantia nigra (340), from the globus pallidus (internal segment or entopeduncular nucleus) to the lateral habenula (340, 372a), and in the nigrothalamic and nigromesence- phalic projections (115, 538). GABAergic neurons likely also act as interneurons in the neostriatum (161, 339).

Cholinergic neurons are abundant in both the dorsal and ventral striatal complexes (268, 269). In the caudate putamen, evidence indicates that they are all local interneurons and that the entire cholinergic innervation of the caudate putamen probably derives from them (199, 337, 339, 559). Cholinergic neurons also occur within and close to both the dorsal and ventral pallidum. These neurons belong to the system

of magnocellular basal forebrain neurons (sometimes referred to as nucleus basalis) that is a major source of cholinergic afferents to wide areas of the neo- and allocortex (37, 154, 269, 485).

Finally, there is evidence that substance P- and enkephalin-containing neurons exist in the efferent pathways from the dorsal striatal complex and for enkephalin- and somatostatin-containing interneurons in the caudate putamen (511a). The pars reticulata, and partly also the pars compacta, of the substantia nigra is densely innervated by substance P- containing terminals (308). Lesion studies indicate that this innervation originates in the neostriatum, particularly in its rostra1 parts (177, 233, 256, 369), and to a lesser degree in the globus pallidus (246). These pathways are likely to be excitatory (125). The electron-microscopic immunocytochemical study of Somogyi et al. (489) indicates that the substance P- containing afferents synapse on neurons in both the pars compacta and pars reticulata. Since intranigrally injected substance P activates the nigrostriatal DA neurons (79, 242, 242a), it seems likely that the striatonigral substance P pathway is excitatory on the cell bodies or dendrites of the nigral DA neurons. Other lesion studies in the rat indicate that the striatal enkephalin-containing neurons innervate the caudate putamen locally and give rise to a dense innervation of the globus pallidus (99, 108, 233, 430, 489). Some of these enkephalin terminals probably synapse directly on the striatonigral output neurons (489). The ventral pallidum is also densely innervated by enkephalin-containing fibers (457, 509,544), but their origin is not clear.

Histochemical studies reveal that several transmitter-related markers have an inhomogeneous, patchy, or mosaic-like distribution in the neostriatum. This is true for acetylcholinesterase (187a, 222a), for enkephalin, somatostatin, and substance P immunoreactivity (182a, 188a, 4301, and for opiate receptor binding (187a, 421a). The nigrostriatal DA projection is also inhomogeneous in that a subset of terminals, confined to discrete islands or patches, develops earlier and has a lower DA turnover rate than the remaining innervation (396a, 389). These patterns may indeed represent a functional heterogeneity in the striatum, since both the corticostriatal and thalamostriatal afferents have similar patchy distributions (182a, 185a, 255a, 279a, 435a, 450) and since these patches seem (at least partly) to coincide with those defined by acetylcholinesterase, enkephalin, and opiate receptor distributions (182a, 188a, 222a, 435a). According to Gerfen (182a), the patches (characterized by dense enkephalin- and substance P-positive terminals and opiate receptor binding) in the dorsal caudate-putamen in the rat represent areas with preferential limbic cortical inputs and predominant outputs to the pars compacta of the substantia nigra, whereas the surrounding matrix compartment (characterized by dense acetylcholines-


terase- and somatostatin-positive terminals) represents a subcompartment with preferential sensorimotor cortical inputs and outputs to the pars reticulata of the substantia nigra. The striatal patches may thus be subcompartments that are functionally defined by differences in cortical (and/or thalamic) afferent inputs and striatonigral outputs. For a more detailed discussion of this topic, see the review by Graybiel and Ragsdale (188a).

FUNCTIONAL ASPECTS O F MESOTELENCEPHALIC DOPAMINE SYSTEM

The anatomical data summarized in the previous section form a simplified model of forebrain function, in which the behavioral control of the cortical mantle is mediated by the dorsal and ventral striatal complexes and then channeled downstream via the striatopallidal and striatonigral output systems. The mesotelencephalic system provides a dense dopaminergic innervation to the entire striatal complex, plus certain limbic cortical areas related to the ventral striatal complex. In this model the classic nigrostriatal pathway (Fig. 19) would be defined as that part of the system innervating the dorsal striatum (i.e., nucleus caudatus-putamen); the mesolimbic pathway of Un- gerstedt (525) would be defined as that part innervating the ventral striatal complex (i.e., nucleus accumbens, olfactory tubercle, and bed nucleus of stria terminalis; Fig. 20). The mesocortical pathway is represented by projections to the allocortical and frontal cortical areas, most prominently the prefrontal cortex, piriform cortex, amygdala, septum, entorhinal cortex, and perirhinal cortical strip (Fig. 20).

Dopamine- Deficiency Syndrome Complete bilateral lesions of the mesotelencephalic

DA system in rats result in a severe state of general behavioral unresponsiveness (see refs. 327, 444, 499, and 526 for review). The symptoms include akinesia, catalepsy, hunched posture, sensory inattention or neglect, aphagia, and adipsia. Sensory inattention in particular reflects the lesioned animal’s inability to initiate coordinated movements in response to or to orient toward a sensory stimulus. The pharmacological analysis of this syndrome promotes the view that DA neurons form a level-setting or permissive system that determines the threshold for the behavioral responses of the animals. The mesostriatal DA system thus seems to act as a tonic regulatory system, which sets the level of activity or the gain in the striatal output pathway systems.

R

INTACT

I

DA LESION

U

FIG. 21. Proposed model for action of mesostriat.al DA system. Behavioral response (R) evoked by an activating sensory input (I ) is modulated by DA system via inhibitory control mechanism. Dopaminergic denervation (bottom) results in inhibition of behavioral response.

threshold for behavioral responses (R) to diverse sensory inputs (I). Each sensory stimulus has two effects: a specific effect, activating neurons involved in eliciting some appropriate motivated behavior, and a nonspecific effect (mediated by the mesostriatal DA neurons), removing an inhibitory influence and thereby permitting a response. Removing this dopaminergic control function (Fig. 21B) results in inhibition of striatal function. Most of the symptoms of this “DA- deficiency syndrome” in animals with complete lesions of the mesotelencephalic DA system can be eliminated by drugs that activate DA receptors (123, 306, 326, 328) and by intrastriatal grafts of dopaminergic neurons (50, 129). These effects indicate a disinhibition of the striatal machinery through reinstatement of dopaminergic neurotransmission.

The neurological impairments seen in patients with damage to the mesostriatal DA system associated with Parkinson’s disease are usually characterized as a deficit in the initiation of voluntary movements (325). This deficit is in line with the permissive mode of action of the DA system and is also seen in rats with 6-OHDA lesions of the mesostriatal DA pathway. This is particularly well demonstrated in a conditioned turning test, in which the rat is trained to turn in circles in order to obtain a reward of sugar water (562). A unilateral lesion of the mesostriatal DA pathway substantially impairs the rat’s ability to initiate turning in the direction contralateral to the lesion (128). Since the lesion does not impair the rat’s performance of the task in the ipsilateral direction, the effect does not seem to be attributable to primary motor or motivational impairments. This is compatible with the view that the mesostriatal DA pathway is involved in the selection and coordination of alternative motor sequences initiated by commands from the cortical mantle (see refs. 92, 444).

Stricker and Zigmond (see ref. 499 and their chapter in this Handbook) provide a simple model of how the DA system may regulate behavioral responsiveness by modulating an inhibitory striatal control mechanism. In this model (Fig. 21) the DA neurons reduce the

Simplified Scheme for Dopaminergic Regulation of Striatal Output Functions LEVEL-SETTING ACTION. In Figure 22A, the permissive or level-setting model of DA function in Figure

A

L

THALAMUS VL+VA

Pyramids; tract

I 0 0 1 CORTEX

GLU GLU I I I

CAUDATE - PUTAMEN

GLOBUS PALLIDUS

SUBST NlGRA

I I I GABA

MESEN - CEPHALON

Sensory input


B 1

P THALA-

MUS

CORTEX ! I GLU 1 GLU I

CAUDATE - PUTAMEN

SUBST. NlGRA

FIG. 22. Simplified scheme illustrating some possible interactions between systems containing DA, GABA, glutamate (GLU), and acetylcholine (ACh) in basal ganglia. A: level-setting action; B: gating action. r, Reticulata; and c, compacta.

21 is adapted to a highly simplified scheme of the corticostriatopallidal and corticostriatonigral conduction systems, Unfortunately the precise cellular interconnections between different identified neuron types in the striatal machinery are largely unknown. Con- sequently the interrelationships drawn in Figure 22A are to a large extent hypothetical and are primarily based on effects induced by pharmacological or neurochemical manipulations. (For a more extensive discussion on neurotransmitter interactions in neostriatum, see refs. 115, 124, 185, 199, 270, 288a.)

In this scheme the nigrostriatal DA pathway regulates the activity of the GABAergic output pathways to the globus pallidus and the substantia nigra by acting on inhibitory striatal interneurons (or on local circuits formed by collaterals of inhibitory projection neurons). These GABAergic output neurons are driven by the corticostriatal afferents, here assumed to be identical to the excitatory glutamate-containing cortical projection system. In this model the DA neurons are presumed to be exclusively inhibitory in the striatum, although excitatory actions of DA may operate as well (see refs. 124, 125, 270, 356, 445a, and the chapter by Siggins and Gruol in this Handbook). The model would, however, include excitatory DA afferents terminating directly onto the striatal effer-

ent neurons, as proposed by Kitai (270), but this arrangement was not included in the figure. According to Kitai (270) activation is the primary net effect (direct or indirect) of the nigrostriatal afferents on the striatal output neurons. For the sake of clarity the nigrothalamic connection was also omitted from the figure, as was the feedback connection of the striatonigral pathway onto the DA neurons in the pars compacta of the substantia nigra. Another obvious shortcoming of the scheme is that it does not account for, e.g., the known enkephalin- and substance P- containing neurons in the striatum. Their role in the system is unclear.

Figure 22A is based primarily on interpretations derived from pharmacological and behavioral data, and it may provide a simple explanation of behavioral and neurological consequences of gross (or pathologi- cal) changes in function of the mesotelencephalic dopamine system.

Reduced dopaminergic transmission, such as occurs in Parkinson's disease, results in underactivity of the striatal output system. This is reflected in the rat in akinesia, catalepsy, postural abnormalities, sensory neglect, aphagia, and adipsia; in the parkinsonian patient it results in akinesia (or hypokinesia), postural abnormalities, rigidity, and tremor.


Increased dopaminergic transmission, such as L- dopa, amphetamine, or DA receptor agonists produce, results in overactivity of the striatal output system. This appears in the rat as hyperactivity and stereotypy and in patients as involuntary choreiform movements, dystonia, stereotypy, agitation, excitement, and even psychosis. Against this background, the hyperkinetic syndrome seen in Huntington’s chorea may be an overfunction of the striatum resulting from a loss of the striatal inhibitory interneurons and leading to a disinhibition of the residual striatal output neurons. This is also consistent with the clinical observations that the choreic symptoms of patients with Hunting- ton’s disease are markedly worsened if the patient is given L-dopa and are improved by DA receptor block- ers.

Experimental evidence supports some elements of the level-setting model of nigrostriatal DA control. The electron-microscopic studies of Somogyi et al. (486,488) in which they used a combination of anterograde degeneration, HRP transport, and Golgi staining demonstrate direct synaptic connections between the corticostriatal neurons and the striatonigral output neurons, as well as between the striatonigral neurons and the efferent neurons in the substantia nigra pars reticulata. Biochemical experiments indicate that DA receptor activation in the striatum results in increased GABA release in the substantia nigra. This suggests that DA activation results in activation of the GABAergic output neurons, consistent with the electrophysiological findings (270). There is also electrophysiological evidence from intracellular recordings by Kitai and co-workers (270, 273a) that the activating inputs from the cortex and substantia nigra converge onto the same striatal output neurons.

Several lines of evidence indicate that cholinergic and dopaminergic neurotransmission in the neostriatum have opposite, or balancing, effects on striatal function (see refs. 288a, 337). Likewise, pharmacological evidence indicates that the dopaminergic afferents make direct inhibitory synapses on the striatal cholinergic interneurons (4, 213, 337, 435). The pharmacological evidence, as discussed in detail by Lehmann and Langer (288a), suggests that these synapses may be nonjunctional, acting mainly on the axonal terminals of the cholinergic interneurons. In Figure 22A, the cholinergic interneurons have been allowed to interplay with the dopaminergic afferents on the same striatal target neurons, while the cholinergic neurons themselves receive inhibitory DA input. This is consistent with studies on the effects of cholinergic antagonists and agonists, which potentiate or depress, respectively, the functional effects induced by DA receptor activation in the striatum (167c, 169a, 271a, 434a).

The disinhibitory action of the DA afferents pre- supposes the existence of a local inhibitory link me- diating the DA effects. Currently the most likely can-

didates for such a link are not inhibitory interneurons but are instead local collateral projections of the striatal output neurons themselves. The medium spiny neurons of the neostriatum, which constitute -95% of all striatal neurons, were earlier thought to be interneurons. However, studies show that most or perhaps all medium spiny neurons are projection neurons (see refs. 59a, 188b, 199). In an electron-microscopic immunocytochemical study using antibodies to tyrosine hydroxylase, Freund et al. (167b) showed that the vast majority (-90%) of all DA synapses in the neostriatum contact the dendritic shafts and spines of the medium spiny projection neurons. In addition to their projecting axons, the medium spiny neurons give rise to a local collateral terminal plexus that synapses on other striatal projection neurons in the vicinity of the parent neuron (38a, 257a, 486). These connections are at least partly GABAergic and are thought to underlie lateral inhibitory interactions between the striatal efferent neurons (199, 257a, 418a). In Figure 22A, DA action on one set of medium spiny efferent neurons (arrows with question marks) can thus disinhibit other sets of efferent neurons via their local axonal collaterals.

GATING ACTION. Cortical and nigral afferent inputs converge onto the dendrites of the striatal projection neurons (167b, 264a, 270), and electrophysiological and iontophoretic studies in both the dorsal and the ventral striatum (accumbens) suggest that the nigral DA afferents can modulate the response of striatal neurons to cortical excitation (222b,222c, 264a, 445a). From these studies, it appears that the nigrostriatal DA input is predominantly inhibitory, although Hir- ata et al. (222c) have reported that a conditioning nigral stimulation (or DA application) can both attenuate and enhance the excitatory effects of cortical stimulation. Freund et al. (167b), in their tyrosine hydroxylase immunocytochemical study, demonstrated a close association between DA synapses on spine necks and non-DA synapses, probably of cortical origin, on the heads of the same spines of the medium spiny neurons. Freund et al. (167b) therefore suggested that the inhibitory DA input can selectively filter out excitatory cortical inputs impinging on the striatal efferent neurons, whereas Rolls et al. (445a) characterized the effect of DA as a regulation of the response of striatal neurons to cortical inputs through a change in signal-to-noise ratio.

The modulatory effects of DA may function as a gating mechanism for the cortical afferent signals (Fig. 22B). In this model a patterned activity in the DA afferent input permits certain cortical synapses to gain access to the striatal target neurons while others are shunted off. The gating mechanism of the nigrostriatal DA afferents could also be reflected in the interplay between different subsets of striatal efferent neurons via their reciprocal inhibitory collateral connections.


Thus a dopaminergic inhibition of one set of neurons would lead to a disinhibition of adjacent, noninhibited striatal neurons.

RESPONSE SELECTION AND ACTIVATION OF MOTOR RESPONSES. Level setting and gating may be simul- taneous actions of the nigral DA afferents in the striatum. This idea is compatible with current theories of the role of the striatum in behavioral response selection and in the initiation and switching between different preformed motor programs (19b, 92, 121a, 127a, 325, 499). In the absence of striatal afferent DA input (e.g., in Parkinson’s disease), the threshold for motor response, movement initiation, and activation of preformed motor programs appears to be elevated. On one hand, patterned activity in the nigrostriatal DA system would disinhibit subsets of striatal efferent neurons and, on the other hand, allow the “switching in” of different functional segments of the neocortex, thus facilitating the voluntary initiation of purposeful motor acts.

Sensory activation of the nigral DA neurons (80, 185) may normally be important for the patterned activation of the corticostriatopallidal and corticostriatonigral pathways. The striatopallidal and striatonigral neurons, which are predominantly GABAergic, are assumed to act on a second set of inhibitory (probably also GABAergic) output neurons in the globus pallidus and the pars reticulata of the substantia nigra, respectively, activating (or disinhibiting) the three principal targets of the striatal output system: the thalamic VL-VA complex, the mesencephalic reticular formation, and the ventromedial thalamus (Fig. 22A).

The striatopallidothalamocortical loop is the classic route by which the striatal output system influences the motor cortex. Lesions of the globus pallidus or ventrolateral thalamus, in humans or monkeys, abolish the ballistic choreiform dyskinesias induced by destruction of the subthalamic nucleus (108a) and abolish or reduce involuntary movements resulting from L-dopa therapy (particularly in limbs) (524a). DeLong and Georgopoulos (108a) have suggested that such dyskinesias are a form of less-organized stereotyped behavior, which is characteristically elicited by DA release in the neostriatum. This suggests that DA- mediated involuntary movements and stereotypies may be channeled primarily via the pallidothalamo- cortical route.

Studies in rats have emphasized the descending striatonigral system as the primary route for the expression of striatal motor responses such as turning behavior, postural asymmetries, and catalepsy (115, 116, 287). The GABAergic neurons of the pars reticulata of the substantia nigra project partly to the thalamus (particularly ventromedial nucleus, with widespread projection over neocortex) and partly to the mesencephalic reticular formation (including deep

layers of superior colliculus and raphe nuclei; see refs. 30, 188, 379). The striatonigral pathway channels striatal responses through the latter route into an area of the mesencephalon with highly complex sensorimotor coordinating functions. This area is closely associated with descending motor control systems and the mesencephalic locomotor region (centered in caudal part of cuneiform nucleus; see refs. 178, 179, 193, 280). In addition Swanson et al. (507a) have demonstrated a direct projection from the ventral pallidal region (and some adjoining areas) to the mesencephalic locomotor region (cuneiform and pedunculopontine nuclei). The striatonigromesencephalic and accumbenspallidomesencephalic conduction systems are thus the likely routes by which the striatal and limbic systems gain access to the descending motor pathways exclusive of the pyramidal tracts. Garcia- Rill et al. (178, 179) have demonstrated a direct, albeit sparse, projection in the cat from the posterior substantia nigra to that area of the cuneiform nucleus from which locomotion could be elicited. Locomotion could also be induced by electrical stimulation of the same sites in the substantia nigra. Likewise, the nucleus accumbens has a well-known role in the mediation of DA-induced locomotor responses (see ref. 261). Dopamine and DA receptor agonists injected into the accumbens elicit locomotion. Mogenson and Nielsen (350b) have reported that injecting the GABA antagonist picrotoxin into the ventral pallidum (which is target of direct, probably GABAergic, input from accumbens) has a similar locomotor-stimulating effect. Moreover, Swerdlow et al. (508a) have reported that excitotoxic lesion of the neuronal elements in the general area of the ventral pallidum strongly atten- uates locomotion elicited by DA receptor activation in the nucleus accumbens. These various observations suggest that striatal and limbic effects on motor behavior and locomotion (mediated via caudate putamen or nucleus accumbens) could, at least in part, be relayed along the striatonigromesencephalic and the accumbenspallidomesencephalic routes, respectively.

These anatomical arrangements are interesting in view of the fact that independent and interacting dopaminergic effects on motor behavior can be elicited both from the dorsal striatum and from the accumbens of the ventral striatum. Dopamine release in the nucleus accumbens has been implicated as eliciting locomotor responses, and DA release in the nucleus caudatus-putamen has been implicated as eliciting stereotypic movements, turning behavior, and postural asymmetry (156, 263, 434). Moreover, muscle rigidity, such as is seen after reserpine treatment, appears to be elicited in the caudate putamen (16a) and can be abolished by injecting DA or apomorphine into this region but not into the nucleus accumbens or elsewhere (247a). From experiments on drug-induced turning behavior, Kelly and Moore (261, 262) propose that DA activity in the accumbens amplifies


or energizes motor responses elicited by activity in the caudate putamen. The convergence of the striatoni- gralmesencephalic output pathways from the two areas means it is possible that such interactions can occur at the mesencephalic level.

Dopaminergic Modulation of Neurotransmission in Substantia Nigra Through Dendrites of Nigral Neurons

Dopamine is released not only from the axonal terminals but also from the dendrites of the nigral dopaminergic neurons (43, 182, 274, 275, 385-387). Golgi staining or monoamine fluorescence histochemistry shows that the dendrites of neurons in the pars compacta of the substantia nigra have long slender dendrites that run either horizontally, ramifying within the pars compacta, or vertically, ramifying within the pars reticulata (43, 70, 147, 255). Glyoxylic acid histofluorescence and tyrosine hydroxylase immunohistochemistry show that the vertically projecting dendrites give rise to a loose, partly varicose network that extends throughout the pars reticulata (43, 547). About one-third of the DA in the substantia nigra is found in the pars reticulata (140), and it is probably derived from the dendrites of the pars com- pacts neurons (and a few scattered DA cell bodies located here) (78, 546).

Experimental evidence indicates that dendritic DA has a variety of effects on signal transmission within the substantia nigra (Fig. 23).

HIBIT ACTIVITY OF DOPAMINERGIC CELLS. Dopamine applied to the dopaminergic neurons (or released by amphetamine in vivo) inhibits the firing rate of neurons in the pars compacta, an effect that is blocked by neuroleptic drugs (3,68,200,451). This could mean that the released DA suppresses firing in the neurons from which it is released (1 in Fig. 23). Such autoinhibition may keep the neuronal firing rate within a certain range (274) and may also regulate the responsiveness of the dendritic field to synaptic inputs impinging on the nigral DA dendrites (308a). Alterna- tively, DA released from the dendrites of phasically activated neurons could inhibit other less-activated dopaminergic neurons (2 in Fig. 23). Korf (274) proposed this as a mechanism for lateral inhibition, which could increase contrast in the activity between groups of cells.

LEASE. Nigral DA receptors are located on dopaminergic neurons, nondopaminergic neurons, and striatonigral afferent fibers. The receptors on striatonigral fibers seem to be coupled to a DA-sensitive adenylate cyclase (373, 425, 491). Nigral nondopaminergic neurons can be either activated or suppressed by DA (126, 451), and GABA release in the substantia nigra can be modified by DA, both in vitro and in vivo (441,

DENDRITIC DOPAMINE APPEARS TO TONICALLY IN-

DENDRITIC DOPAMINE MAY MODULATE GABA RE-

II Ah.. II II

-4 CONTRA LA^ NlGRA Ir

MESENCEPHALON

FIG. 23. Possible modes of action of DA released from dendrites in substantia nigra. I , Autoinhibition of dopaminergic neurons; 2, lateral inhibition; 3, modulation of GABA release from striatonigral afferents and GABAergic interneurons; 4, direct activation of reticulata neurons; and 5, attenuation of inhibitory action of GABA at afferent synapses.

529a). This suggests that DA released from dendrites can modulate GABA release from the striatonigral afferent fibers and perhaps also from GABAergic interneurons (3 in Fig. 23).

DENDRITIC DOPAMINE CAN ACTIVATE PARS RETICU- LATA EFFERENT NEURONS. Ruffieux and Schultz (451) have reported that about one-third of the identified nigrothalamic neurons in the pars reticulata are excited by DA, and the excitation is blocked by the neuroleptic fluphenazine. This effect may be due to a direct action on the reticulata neurons (4 in Fig. 23). Alternatively, it could also be due to an attenuated inhibitory action of GABA at afferent synapses, as the results of Waszczak and Walters (548) suggest ( 5 in Fig. 23).

There are thus several mechanisms by which DA released from the dendrites of the nigrostriatal neurons can affect the striatal output pathway relayed via the pars reticulata. Jackson and Kelly (238e) have shown that bilateral injections of DA into the substantia nigra can, at least in high doses, stimulate locomotor activity and that bilateral nigral injection of the DA receptor antagonist haloperidol reduces the locomotor response evoked by systemic injections of amphetamine. Likewise contralateral turning can be elicited by unilateral injection of DA, amphetamine, or DA receptor agonists into the substantia nigra, pars reticulata (238d, 27513). Since this effect is abolished by destruction of the striatonigral neurons (275b), Jackson and Kelly (238d) have suggested that DA may act synergistically in the striatum and the substantia nigra. In this scheme, DA released from the axons in the caudate putamen and accumbens increases the activity of the striatonigral GABAergic projection neurons. In contrast, DA released from the dendrites


in the substantia nigra potentiates the release of GABA from the striatonigral terminals in a manner dependent on their firing rate. According to Glowinski and co-workers (78, 388), this mechanism may also allow “cross talk” between the nigrostriatal neurons in each hemisphere, probably via a nigrothalamic polysynaptic link. They reported that increased DA release in one substantia nigra reduces DA release in the other, while inducing opposite changes in the striatum on the two sides (78, 388).

Taken together there is substantial pharmacological evidence that the nigrostriatal DA neurons have a double polarity, in the sense that their neurotransmitter machinery operates both in their axonal and dendritic terminal networks. The dendritic mechanism probably differs from the axonal mechanism in several ways: 1) the transmitter is probably stored in the endoplasmic reticulum rather than in vesicles; 2) the release is Ca2+-dependent but independent of fast Na+ channels; and 3) the release may not occur at specialized synaptic junctions (see refs. 78, 308a, 546). Al- though dendrodendritic synapses have been described in the substantia nigra (557), Wassef et al. (546) report that the vast majority (295%) of identified dopaminergic processes have no synaptic specializations and show no close appositions to nigral perikarya or dendrites. Such nonjunctional release of the transmitter is consistent with the observations of Nieoullon et al. (384) that the changes induced in nigral DA release (e.g., by sensory stimulation) are protracted and out- last the stimuli for at least 20-40 min. The dendritic end of the nigrostriatal system may thus best be viewed in terms of a tonic modulation of several aspects of signal processing in and through the nigra.

TABLE 7. Major Noradrenergic Projection Systems System Cells of Origin

NORADRENERGIC PROJECTION SYSTEMS

On the basis of the topography of the noradrenergic cells in the lower brain stem (see Noradrenergic Cell Groups, p. 160), three projection systems have been distinguished: the locus coeruleus system, the lateral tegmental system, and the dorsal medullary system (Table 7). The topographical organization of the lateral tegmental and dorsal medullary NE systems is less well known than that of the locus coeruleus system. This is largely explained by the difficulties in interpreting results after lesions of the more disseminated NE cell groups and their projection pathways. Selective ablations of these cell groups are virtually impossible, and transections of the axon bundles from the individual groups can easily sever other projection systems. However, the new retrograde tracing methods, in combination with techniques for identification of labeled CA cells, have greatly expanded the possi- bilities for precise mapping of the projection systems of the medullary and pontine NE systems. In the next section we describe the projections from the locus coeruleus apart from those of the disseminated pontine and medullary NE cell groups. The organization of the non-locus coeruleus projections is covered to the extent present knowledge permits.

Locus Coeruleus System

GENERAL ORGANIZATIONAL FEATURES. Despite the limited number of NE neurons in the locus coeruleus, it projects to almost all of the regions of the CNS (Fig. 24; Table 7). This is accomplished by an extensive collateralization of the individual neurons. The locus

Projections

Locus coeruleus (LC) LC and subcoeruleus (SC)

Forebrain LC (mainly Neocortex; hippocampus; amygdala; olfactory bulb; olfactory nuclei; dorsal part) piriform cortex; septum; medial hypothalamus; thalamus; geniculate

bodies; tectum

Cerebellar LC and SC Cerebellar cortex

Brain stem

Spinal cord

Lateral tegmental and dorsal medullary

Forebrain

Brain stem

LC and SC Sensory and spinal trigeminal nuclei; cochlear nuclei; pontine gray; interpeduncular nucleus; raphe nuclei

LC (ventral Ventral and intermediate gray, at all levels of spinal cord part) and SC

A1 and A2 Preoptic region; paraventricular. supraoptic, dorsomedial, ventromedial, and arcuate nuclei; median eminence; septum; amygdala

A l , A2, A5, and A7

Nucleus tractus solitarius; cranial nerve motor nuclei (vagal, facial, hypoglossal); raphe nuclei; LC; parahrachial nuclei; spinal trigeminal nucleus

SDinal cord A5 and A7 Dorsal and intermediate pray. at all levels of sDinal cord


FIG. 24. Pontine NE projection systems, with cell bodies in locus coeruleus-subcoeruleus complex, as well as A5 and A7 cell groups. APL, amygdala-piriform lobe; CC, cerebral cortex; CER, cerebellum; H, hypothalamus; HI, hippocampus; OB, olfactory bulb; S, septa1 area; SP, spinal cord; T, thalamus; and TE, tectum.

coeruleus has long been considered a homogeneous nucleus with each individual neuron projecting to most terminal areas. However, this opinion has been challenged, particularly by Mason and Fibiger (332). They have reported that the distribution of HRP- positive cells in the locus coeruleus differs markedly depending on the site of HRP injection. As Figure 25 shows, the labeling patterns of HRP-positive cells suggest certain topographical principles for the origins of the locus coeruleus projections to various terminal areas. I) Along the dorsoventral axis the innervation in the septum originates in the dorsal half of the dorsal compact part of the locus coeruleus, the hippocampal NE projection (at least to the dorsal-anterior hippocampus) originates in the entire dorsal locus coeruleus (see ref. 443), and the innervation in the spinal cord originates in the ventral tip of the locus coeruleus (see refs. 205, 460). 2) Along the anteroposterior axis the hypothalamic innervation originates mainly in the anterior pole, and the thalamic innervation originates mainly in the posterior pole of the locus coeruleus. 3) Diffusely within the nucleus both the projections to the neocortex and to the amygdala-piriform cortex seem to originate in scattered cells located throughout the compact part of the nucleus, except in the ventral tip (see ref. 314). The coeruleocerebellar projection originates from cells distributed throughout the nucleus, including the ventral tip. Corresponding results were obtained by Room and co-workers (446) with fluorescent tracers for locus coeruleus projections to the hippocampus, thalamus, neocortex, and cerebellum. It is fairly well established that the locus coeruleus system comprises a number of subsystems, but

more work is needed before the details of the regional topography within it are known.

Although it seems that some of the locus coeruleus neurons have more restricted projection areas than was previously believed, there is convincing evidence that a subpopulation of the neurons innervates widely different regions in the brain and spinal cord via collateral branches. This collateralization of the locus coeruleus neurons was suggested by fluorescence histochemical observations (see refs. 297, 395, 525), but was not well studied until Kuypers and co-workers introduced the multiple fluorescent-retrograde tracer technique. This method has provided evidence for a number of branching patterns for individual locus coeruleus neurons (371, 446, 495): for example, to the ipsilateral neocortex and hippocampus, the neocortex and thalamus, the hippocampus and thaiamus, the neocortex and cerebellum, the cerebellum and spinal cord, the hippocampus and spinal cord, and the thalamus and spinal cord. Nagai and co-workers (371) estimated that after combinations of injections into the neocortex and cerebellum, the number of double- labeled neurons was 10%-30% of the total of single- labeled neurons. Fallon and Loughlin (144) have distinguished two subdivisions in the nucleus based on the relative degree of axonal collateralization to the forebrain. In particular, medium-sized multipolar neurons in the dorsal compact part of the nucleus were more often (50%-70%) double labeled after multiple injections in the forebrain than were neurons of the extreme dorsal, ventral, or anterior regions of the locus coeruleus and of the nucleus subcoeruleus (5%-20%; see ref. 446).

The locus coeruleus also has contralateral projections. At least five commissures have been described for the ascending part of the system (see Dorsal Teg- mental Bundle, p. 167, Medial Forebrain Bundle, p. 171, and refs. 298 and 357). All terminal areas of the locus coeruleus neurons seem to also receive projections from the contralateral nucleus (2, 248, 446). Jones and co-workers (248) suggested that 20% of the locus coeruleus cells may project contralaterally, whereas the results of Room et al. (446) indicated that only 5%-10% do so. Using homotopic bilateral tracer injections, AdGr et al. (2) and Room et al. (446) showed that the axons of some locus coeruleus neurons bifurcate and project bilaterally to the thalamus, hippocampus, and cortex via collateral branches. The ratio of double- and single-labeled cells in the locus coeruleus varied from 1:20 in the thalamus to 1:30 in the cortex and 1:40 in the hippocampus (446). After heterotopic bilateral injections, it was found that an individual locus coeruleus neuron can innervate one region on the ipsilateral side and another on the contralateral side [e.g., hippocampus on one side and thalamus on the other, cortex on one side and thalamus on the other, or hippocampus on one side and cortex on the other (2, 446)]. Whether any of these cells innervate


SEPTUM

B. "LC

A.

HPP OCAMPUS

B. HYPOTHALAMUS

CEREBELLUM or CAUDATE-PUTAMEN

8.

THALAMUS

D.

FIG. 25. Retrograde labeling of cells in locus coeruleus after horseradish peroxidase injections into various forebrain areas. VLC, ventral locus coeruleus; ALC, anterior locus coeruleus; MV, mesencephalic n. of trigeminal nerve; and 4, 4th ventricle. A, C, and D are coronal sections at mid, anterior, and posterior levels of nucleus; B is parasagittal section. [From McNaughton and Mason (348).]

more than two terminal areas is not known. When interpreting these data obtained with the double-labeling technique, it is important to realize that erroneous results can occur through the labeling of axons passing through the area of one injection on their way to the area of the other injection. For example, this can easily happen with two cortical injections.

FOREBRAIN PROJECTION. Thalamus. The thalamus is richly supplied with NE terminal axons originating in the locus coeruleus (for details on regional arrangements, see ref. 304). The densest innervation is found in the anterior nuclei, particularly in the anteroventral nucleus, but practically all areas of the thalamus receive afferents from the locus coeruleus. Lindvall and co-workers (304) concluded that the specific or principal thalamic nuclei (as well as geniculate bodies; see ref. 279a) are innervated exclusively by NE neurons from the locus coeruleus, whereas medial and midline nuclei (as well as habenula) receive NE fibers from several different sources, including the locus coeruleus. The terminals originating in the locus coeruleus were in these latter regions particularly found in the mediodorsal and gelatinous nuclei.

Hypothalamus. Only a minor part of the NE innervation of the hypothalamus arises from the locus coeruleus. The projections to the periventricular and paraventricular nuclei are the best established (35, 250, 273, 312, 346, 462, 463, 523, 566). From autora-

diographic studies after injections of radioactive amino acids, the locus coeruleus appeared to project only to certain subnuclei within the paraventricular nucleus (see refs. 346 and 463). In addition there is now good evidence that the locus coeruleus also has significant projections to some other hypothalamic nuclei, notably the supraoptic and dorsomedial nuclei (35, 250, 462, 566). However, the major part of the hypothalamic NE innervation originates in the medullary NE cell groups.

Hippocampus. The hippocampal NE innervation seems to originate exclusively in the locus coeruleus (250, 304, 312, 315, 320, 332, 420, 428, 443, 446, 465, 467, 525, 561). This projection is 75%-93% ipsilateral (315,446,561). The terminal distribution of NE fibers in the hippocampal formation (Fig. 26) has been described in detail by Blackstad et al. (51), Swanson and Hartman (507), Moore (353), Bjorklund et al. (47), and Loy et al. (315).

The locus coeruleus NE axons reach the hippocampus along three routes (Fig. 27). 1) They gain access partly through the septa1 area, entering the hippocampus rostrally; partly through the most caudal septum, along the postcommissural fornix; and partly through the rostra1 and dorsal septum, along the fornix superior (173, 250, 297, 315). 2) In addition they enter above the corpus callosum, along the cingulum bundle and/or the supracallosal striae, sweeping around the splenium of the corpus callosum and into the hippo-


afferents coming via the dorsal and ventral routes. The supracallosal pathway contributes -60% of the innervation in the dorsal hippocampus and -25% in the ventral hippocampus, whereas the ventral pathway contributes -70% of the innervation in the ventral hippocampus but only -15% in the dorsal hippocampus. According to Loy et al. (3151, the hippocampal CA1 and CA3 fields receive their NE input principally from the ventral path. The innervation of the dentate gyrus is to a large extent bilateral, with the greatest contribution arising from the ipsilateral supracallosal route and nearly equal proportions of fibers entering via the contralateral supracallosal route, the fornix, and the ventral path.

Septum. In the rat, the locus coeruleus afferents have a widespread distribution in the septal area (see refs. 250,305a, 312,316,354,428,468,525). The axons form a moderately dense innervation in the hippocampal rudiment, the medial septal nucleus, and the bed nucleus of the stria terminalis, and a sparse innervation in the lateral septal nucleus and the septofimbrial nucleus. With the exception of the hippocampal rudiment, the locus coeruleus fibers in all areas are mixed with NE axons originating in the cell groups of the medulla oblongata.

The NE innervation of the amygdala originates partly in the locus coeruleus (143, 250, 297, 312, 332, 397,428,469, 567). The terminals are found throughout the amygdala, forming a moderately dense innervation in the central and basolateral nuclei and a less- dense innervation in other areas (see ref. 143). Scat- tered NE fibers from the locus coeruleus are also found in the piriform cortex (145, 250, 428).

The olfactory bulb and the anterior olfactory nuclei contain a moderately dense NE innervation, primarily of locus coeruleus origin (104, 113, 141, 145, 297, 352, 507, 525). In the anterior olfactory nuclei, the NE innervation is denser in the medial and dorsal nuclei than in the lateral nucleus (145). The olfactory tubercle also reportedly receives an input from the locus coeruleus (145, 203).

Neocortex. It is well established that the locus coe-

FIG. 26. Terminal distribution of locus coeruleus NE afferents to rat hippocampus, in 7 equally spaced coronal levels through hippocampal formation. [From Bjorklund et al. (47).]

campal formation from the dorsal and caudal side (250, 297, 315, 428, 507). 3) They can also enter from the MFB, along the ventral amygdaloid bundle-ansa lenticularis fiber system, through the piriform and entorhinal cortices, and into the hippocampal formation at its temporal pole [ventral path (176a, 297, 315)]. According to the biochemical data of Gage et al. (176a), the supracallosal route contributes -45% Of the hippocampa’ NE innervation’ the fimbria- fornix route ‘Ontributes -15’9 and the path contributes -40%. Their results also demonstrate the septotemporal gradients in the distribution of the

FIG. 27. Various routes for locus coeruleus axons to hippocampus, with their percent contribution to total noradrenergic innervation of hippocampal formation. CB, cingulum bundle; DTB, dorsal tegmental bundle; FF, fimbria-fornix; LC, locus coeruleus; and VP, ventral path. [Adapted from Gage et al. (176al.l


ruleus gives rise to the NE innervation of the entire neocortex (see ref. 299). The distribution of NE fibers and their terminal arrangements in the neocortex of the rat have been studied extensively with the more sensitive fluorescence histochemical and immunohistochemical techniques (see refs. 289, 302, 363, 365, 507). In the rat the pattern of locus coeruleus innervation is fairly similar in different areas; however, the NE afferents to the primate neocortex exhibit a far greater degree of regional variation (275a, 290a, 361, 362). Morrison and co-workers (362) pointed out that the extensive phylogenetic development and differ- entiation of neocortex in the primate brain is paralleled by an elaboration and specialization of the locus coeruleus innervation.

Several routes of entry for the locus coeruleus axons to the necortex have been proposed: I ) via the rostra1 septum and the cingulum (173, 250, 297, 525); 2) via the internal capsule, passing through the nucleus caudatus-putamen (239, 250, 453, 520a); and 3) via the ventral amygdaloid bundle and the ansa lenticularis (250, 297). However, recent studies by Morrison and co-workers (364, 366), using cortical and subcortical lesions, have shown that the cingulum bundle is not a major intracortical noradrenergic pathway. Thus only a marginal contribution to the innervation of the medial cortex from this bundle was detected, whereas the dorsal and lateral cortices were not innervated via the cingulum bundle a t all. Instead, the medial cortex is innervated by noradrenergic fibers that ascend through the septum, curve over the genu of the corpus callosum, and then run caudally in the supracallosal stria (i.e., medial to cingulum bundle; Fig. 28). These results indicate that the dorsal and lateral cortices are innervated chiefly by NE fibers running through the striatum to the frontal pole (Fig. 28). From there the axons turn dorsally over the anterior portion of the forceps minor and continue caudally within the deep layers of the frontal and dorsolateral cortex. No substantial contribution was- observed from the ventral amygdaloid bundle-ansa lenticularis system to the innervation of the neocortex.

Double-label studies with fluorescent retrograde tracers suggest that a locus coeruleus neuron may innervate different parts of the neocortex via collateral branches (314, 371). The results of Loughlin and co- workers (314) indicate that the axons of individual neurons may collateralize extensively in the anterior- to-posterior dimension but only to a limited extent in the medial-to-lateral dimension. This is supported by the lesion data of Morrison and co-workers (366), and it is possible that an individual locus coeruleus cell may innervate a longitudinal slice of the neocortex, extending from the frontal areas back to the occipital cortex. It should be mentioned though that other data (548a) indicate some degree of topography in the projections of the coeruleoneocortical NE system; i.e., at least some of the neurons have more restricted terminal fields within the cortex. After injections of

FIG. 28. Proposed arrangement of noradrenergic fiber trajectories to neocortex. Medial cortex is mainly innervated by fibers that ascend through septum (s), curve over genu of corpus callosum (CC), and then run caudally in supracallosal stria. Dorsolateral cortex is innervated by axons from MFB that reach the frontal pole, turn dorsally over forceps minor (FMI), and continue caudally within deep layers of frontal and dorsolateral cortex. ncp, N. caudatus-putamen. [Adapted from Morrison et al. (364).]

HRP into the occipital cortex, Waterhouse and co- workers (548a) found labeled cells located somewhat more caudally and dorsally than after injections into the frontal and sensorimotor cortex. However, these distributions overlapped extensively.

CEREBELLAR PROJECTION. The NE innervation of the cerebellum originates primarily in the locus coeruleus (for details on terminal arrangements, see refs. 58,59, 224, 284, 370, 395), where the cell bodies of origin are distributed over the entire nucleus (332,371, 395,419, 446, 525). A minor contribution from the nucleus subcoeruleus to the innervation of the cerebellar cortex has been reported by Pasquier and co-workers (419). They also found evidence of the existence of sparse cerebellar afferents from the pontine A5 and A7 cell groups (see ref. 419). The locus coeruleus neurons, as well as the other possible sources of the cerebellar NE innervation, have both ipsilateral and contralateral projections (273, 419). It has been estimated that the contralateral projection from the locus coeruleus amounts to -50%-75% of that going to the ipsilateral side (419).

BRAIN STEM PROJECTION. The distribution of CA axons in the lower brain stem of the rat has been covered in several earlier studies (169, 403, 507), but Levitt and Moore (290) have provided the first detailed analysis of the organization of the CA innervation in the mesencephalon, pons, and medulla oblongata. The following account of the topography of the locus coeruleus projections to the lower brain stem is based primarily on their descriptions. The dorsal compact


part of the locus coeruleus cell group seems to be the only source of the moderately dense NE innervation in the superior and inferior colliculi (see refs. 273, 297, 507), the cochlear nuclei (278, 279), and the interpeduncular nucleus (323). Together with the subcoeruleus, the locus coeruleus gives rise to the major part of the moderately rich NE fiber patterns in the pontine gray nuclei and the principal sensory trigeminal nucleus. In the spinal sensory trigeminal nucleus the locus coeruleus fibers are mixed with afferents from other NE cell groups. The locus coeruleus innervation reportedly emanates both from the ipsilateral and contralateral sides (471). The reticular formation (all levels) and the central gray contain a low-to-moderate number of axons that probably originate in the locus coeruleus (290). From these data Levitt and Moore (290) concluded that the prime brain stem targets for the locus coeruleus system are the primary sensory and association nuclei.

The NE innervations of other brain stem nuclei, some of which were thought to originate mainly in the locus coeruleus, were not affected by bilateral locus coeruleus lesions (also comprising subcoeruleus area), as determined by NE levels and fluorescence histochemistry of terminal densities (290). For example, this was true for the dense innervations in the nucleus tractus solitarius, the dorsal motor nucleus of the vagus, and the nucleus commissuralis (312,396). How- ever, in the HRP study of Takahashi and co-workers (512), a small portion of the innervation in the nucleus tractus solitarius originated in the ventral locus coeruleus. The trigeminal and facial motor nuclei, the inferior olive, and several raphe nuclei were thought

to receive significant inputs from the locus coeruleus (see refs. 81, 273, 312, 428, 507). Levitt and Moore (290) verified only a minor contribution to the NE innervation of these nuclei, although some locus coeruleus afferents to the medullary raphe nuclei could not be excluded.

SPINAL CORD PROJECTION. The coeruleospinal NE system bilaterally innervates the ventral horn, the intermediate gray, and the ventral part of the dorsal horn at all levels of the cord (Fig. 29A). Thus bilateral lesions of the locus coeruleus-subcoeruleus complex cause an almost complete disappearance of the NE innervation in these parts of the spinal cord (392). Furthermore, bilateral locus coeruleus lesions (whose encroachment on subcoeruleus is unclear) cause 30%- 40% reductions in total NE or DBH content in the rat spinal cord (la, 89, 447) and an -80% reduction in NE in the ventral horn in the cat (157, 158). According to Karoum and co-workers (257) and Com- missiong (85), 50% of the coeruleospinal NE projection is crossed, with the crossing probably taking place at the segmental level.

The projection to the spinal cord originates in the ventral part of the locus coeruleus and in the nucleus subcoeruleus. Injections of HRP into the spinal cord in the rat predominantly label multipolar cells in the ventral subdivision of the locus coeruleus and the subcoeruleus area and only a few of the smaller fusiform cells in the dorsal subdivision (la, 205, 459, 460, 553). Zemlan and co-workers (568) used restricted unilateral HRP injections into the white matter of the thoracic cord and found that the axons descend ipsi-

I / TEGMENTO-SPINAL PATHWAY \

FIG. 29. Proposed arrangement of coeruleospinal (A) and tegmentospinal ( B ) noradrenergic systems.


laterally in the ventral and ventrolateral funiculi (Fig. 29A). This is consistent with the findings of Basbaum and Fields (20), who used HRP injections in combination with partial lesions of the cord, and with the fluorescence histochemical observations of Nygren and Olson (392) in rats with bilateral coeruleus-subcoeruleus lesions.

Guyenet (205) has provided electrophysiological evidence that a significant proportion of the coeruleospinal neurons have collaterals that ascend in the dorsal tegmental bundle. Double-label studies with fluorescent retrograde tracers support the existence of such collateral arrangements. Thus a small portion (-10%) of the cells labeled by tracers injected into the spinal cord are double labeled with a second tracer injected either into the cerebral cortex, hippocampus, or thalamus (446) or into the cerebellum (371).

Lateral Tegmental and Dorsal Medullary Systems FOREBRAIN PROJECTION. Hypothalamus and preoptic region. The CA innervation of the hypothalamus has been studied extensively; for details on the distribution and arrangement of the NE axons in this region, see the reviews by Fuxe and Hokfelt (171), Bjorklund et al. (42), and Moore and Bloom (357). The relative distributions of the different NE afferent systems in the hypothalamic-preoptic region have caused some controversy, mainly because of difficulties in interpreting lesion data. These problems have, however, been largely resolved with the introduction of the transmitter-specific retrograde tracing methods. Stud- ies based on the use of such methods have established that the bulk of the NE innervation in the hypothalamus and preoptic region arises from the medullary neuron systems (Fig. 30), whereas the contribution of the locus coeruleus is only minor. We describe the current understanding of the distribution of different NE projection systems in the hypothalamus, with special emphasis on recent findings in the rat, in the next section.

The NE innervation of the medial preoptic area seems to be derived almost exclusively from the medullary A1 and A2 cell groups (35, 106, 347, 442, 455). The projection is mainly ipsilateral, but a substantial number of cells innervate the contralateral side. There is also evidence for a minor contribution from the locus coeruleus (35). Previous lesion studies indicated that the A5 and A7 cell groups contributed to the NE innervation of this region (396, 492). On the basis of the HRP data of Day and co-workers (106) it seems likely, however, that the reported lesion effects were due to transection of fibers ascending from the more caudally located A1 and A2 NE cell groups.

The dense NE innervation of the paraventricular nucleus originates in the A1 cell group, which contains the majority of cell bodies of origin (35, 56, 310, 347, 406, 462, 463, 523) in the A2 cell group (35, 56, 310, 442,462, 463, 523), and partly in the locus coeruleus.

FIG. 30. Medullary noradrenergic projection systems, with cell bodies in A1 and A2 cell groups. AM, amygdala; H, hypothalamus; PO, preoptic area; S, septa1 area; and T, thalamus.

All of the brain stem projections to the paraventricular nucleus are partially crossed. Based on results from studies with the anterograde autoradiographic tracing technique, the A1 neurons seem to project to most parts of the parvocellular division, as well as to those portions of the magnocellular division of the nucleus in which vasopressin-containing cells are concentrated (462, 463; see also ref. 346). The A2 projection distributes substantially to the parvocellular division, where it mingles with afferents from the A1 cell group, but it does not seem to innervate the magnocellular division (462, 463).

The supraoptic nucleus is innervated mainly by the A1 NE cell group (56,346,347,462,463), with at most only minor inputs from the A2 cell group and the locus coeruleus (see refs. 462,463). All of the projections to the supraoptic nucleus are partially crossed. The A1 projection seems to be massive in those portions of the nucleus in which vasopressinergic cells are concentrated (462,463).

Studies with anterograde and retrograde tracers indicate that the medullary NE cell groups also project to the dorsomedial nucleus (35, 347, 442). Using biochemical determinations of NE levels and electron- microscopic identification of nerve terminal degeneration after lesions, Palkovits and co-workers (406) obtained evidence that the NE afferents to the median eminence and the arcuate nucleus originate in the A1 and A2 cell groups. The projection to the arcuate nucleus from the A2 cell group is supported by studies with both anterograde and retrograde tracers (442). Furthermore the median eminence is labeled after injections of anterograde tracers into the A1 cell group (347,463), but it has not been possible to label A1 and A2 neurons after injections of HRP into the median eminence (555).


Earlier fluorescence histochemical work has emphasized the pontine part of the lateral tegmental NE neuron system as a source of the hypothalamic NE innervation. It is remarkable therefore that in studies with retrograde tracers, no labeling of A5 and A7 cells was reported after injections into the hypothalamic nuclei. It could be argued that possible hypothalamic projections from these cell groups take up the tracer less efficiently than do other NE systems. However, this seems unlikely because A5 and A7 cells innervating the spinal cord are easily labeled after tracer injections. The most reasonable explanation is that the A5 and A7 cell groups contribute very few or no fibers to the NE innervations in the hypothalamus.

In the thalamus the non-locus coeruleus NE projections seem to be confined to the paraventricular nucleus (Fig. 30), where they constitute the major part of the dense NE innervation (304). The septal area receives a substantial noradrenergic input from the medullary NE cell groups [Fig. 30; (305a, 354)]. The axons form a very dense innervation in the ventral part of the bed nucleus of the stria terminalis (347, 442), a moderately dense innervation in the nucleus of the diagonal band and the lateral septal nucleus, and a sparse innervation in the medial septal nucleus, the septofimbrial nucleus, and the dorsal part of the bed nucleus of the stria terminalis. The NE fibers of non-locus coeruleus origin in the amygdala are concentrated in the central nucleus (143, 567) but can also be found in the basolateral nucleus and scattered in the lateral nuclei and anterior amygdaloid area. Although no attempt was made to identify labeled cells as catecholaminergic, the HRP study of Ottersen (397) suggests that the non-locus coeruleus NE fibers in the amygdala originate in the medulla oblongata (Fig. 30). Thus A1 cells seem to project to the contralateral amygdala and A2 cells to the ipsilateral amygdala (442).

BRAIN STEM PROJECTION. The distribution of NE fibers in the brain stem was first described by Fuxe (169) and was later studied with more sensitive histochemical methods by Swanson and Hartman (507) and Levitt and Moore (290). The predominant part of the noradrenergic input to the lower brain stem originates in the lateral tegmental and dorsal medullary cell groups, and only a minor portion originates in the locus coeruleus (see previous section). We give only a brief account of the major projection areas. For a more detailed account, see the study by Levitt and Moore (290). The lateral tegmental and dorsal medullary NE neurons innervate mainly primary motor and visceral nuclei, i.e., areas that do not receive any locus coeruleus afferents. Some cranial nerve nuclei are heavily innervated by NE fibers of non-locus coeruleus origin such as the motor trigeminal, facial, hypoglossal, and ambiguus nuclei, as well as the dorsal motor nucleus of the vagus, the nucleus tractus solitarius, and the nucleus commissuralis. The non-locus coeruleus NE

systems also give rise to dense terminal patterns in the ventral mesencephalic central gray, the medial pontine nucleus, the parabrachial nuclei, the ventral tegmental nucleus, and the principal inferior olivary nucleus.

The raphe nuclei in the medulla oblongata, pons, and mesencephalon are richly supplied with NE fibers that originate primarily in the lateral tegmental and dorsal medullary cell groups. The raphe pallidus, ob- scurus, magnus, and dorsalis are the most heavily innervated nuclei, whereas the nucleus raphe pontis and the rest of the raphe nuclear complex contain low-to-moderate densities of NE terminals (169, 290, 507).

Very little is known about the location of the neurons from which the different brain stem NE innervations arise. Several different sources for the dense NE terminal patterns in the nucleus tractus solitarius have been proposed on the basis of lesion studies, but data from a combined lesion and HRP study (where labeled CA cells were identified) indicate that the A2 cell group in the nucleus commissuralis is the main source of this innervation (512; see refs. 400, 507). The projection from the A2 cell group seemed to be bilateral but with a slight ipsilateral predominance. The A1 cell group in the ventrolateral medulla also innervates the nucleus tractus solitarius, as well as other parts of the dorsal vagal complex (54, 310, 462, 463,525). It has been reported that there is a reciprocal projection from the nucleus tractus solitarius to the A1 cells, but this connection seems to be almost exclusively nonnoradrenergic (54, 405, 462, 463).

Injections of HRP into the locus coeruleus, which contains a moderately rich NE innervation, reportedly label neurons in the areas of the Al, A2, A6, and A7 cell groups (77a, 83). With the transmitter-specific retrograde tracing techique, a majority of the labeled cells in the A1 cell group have been identified as noradrenergic (463). The projection from the A1 cell group to the locus coeruleus has also been demonstrated with anterograde tracers (462, 463).

Several studies of importance to our understanding of the anatomy of NE systems in the lower brain stem have used the HRP method without any attempt to identify the transmitter of the labeled cells. Thus HRP injections into the spinal sensory trigeminal nucleus have been reported to label neurons in the ipsilateral A1 area and in the contralateral A5 area (471). Neu- rons in the A1 area are also labeled after injection of retrograde tracers into the parabrachial nucleus (310). Sakai and co-workers (454) found labeling in the A1 area after HRP injections into the dorsal raphe nucleus of the cat. SPINAL CORD PROJECTION. The locus coeruleus system is responsible for -30%-40% of the spinal NE innervation in the rat. The remaining spinal NE afferents, which primarily innervate the intermediolat- era1 column and the area around the central canal


(and the fiber strands connecting these two areas), as well as the outer layers of the dorsal horn, originate primarily in the pontine A5 and A7 cell groups (Fig. 29B). Observations of retrograde cell changes after spinal transection led Dahlstrom and Fuxe (103) to emphasize that the medullary CA cell groups, i.e., the A1 and A2 cell groups, were the source of NE fibers to the spinal cord. However, more recent retrograde tracing studies (55, 282, 309, 345, 347, 459, 460, 463, 553) have shown that the NE neurons of the lateral tegmental cell system that project to the spinal cord of the rat are confined to the pons and that at most only a very small portion is located in the A1 and A2 cell groups. In the rat and rabbit, the vast majority of cells in the A1 and A2 cell groups that can be retrogradely labeled from the spinal cord are noncate- cholaminergic (49, 55, 345, 347, 484, 553). Similarly a significant proportion of the neurons that project to the spinal cord in the A5 cell group are noncate- cholaminergic (49, 309).

Some information is available on the trajectory of the tegmentospinal NE pathway. Nygren and Olson (392) reported that the CA-containing axons remaining after a bilateral lesion of the coeruleus-subcoeruleus complex, i.e., the axons of the tegmentospinal system, were confined to the dorsolateral funiculus. This is consistent with the observations of Basbaum and Fields (20) that retrograde labeling of cells in the A1 and A5 cell groups remained in animals where the dorsolateral funiculus was spared but not in those where the ventral quadrant was spared. Finally, Loewy et al. (309) traced axons autoradiographically from the pontine A5 cell group, ipsilaterally to the medial part of the lateral funiculus. These axons terminated bilaterally in the intermediolateral column and adjoining parts of the intermediate zone.

NORADRENERGIC SYSTEMS VIEWED AS COMPONENTS O F BRAIN STEM RETICULAR FORMATION

The early work of Dahlstrom, Fuxe, and co-workers (11, 73, 103, 169) emphasized the widespread ascending and descending projections of the brain stem noradrenergic system. Loizou (312) and Ungerstedt (525) later drew attention to the remarkable and highly collateralized projections of the locus coeruleus cell group to the cerebral and cerebellar cortices. The noradrenergic systems now are some of the best known components of the brain stem reticular formation. Because of the unique possibility of manipulating these systems with a range of pharmacological tools and selective neurotoxins, the noradrenergic systems (like other monoaminergic pathways) play an important role as models for study of the organizational and functional features of the brain stem reticular core.

Although the organization of the brain stem noradrenergic system is diffuse in the sense of having widespread afferent inputs and widely dispersed pro-

jections, this does not mean that the system lacks structural or functional specialization. In fact, the more detailed knowledge assembled during the last few years demonstrates “job-sharing” among the different subsystems. Thus the locus coeruleus proper is the source of the noradrenergic afferents to the entire neo- and allocortex, the specific thalamic nuclei, the tectum, and the cerebellum. The ventral locus coeruleus, the nucleus subcoeruleus, and the A5 cell group give rise to the descending projections to the spinal cord. The medullary A1 and A2 cell groups are the main sources for noradrenergic innervation in the hypothalamic-preoptic areas, as well as some parts of the basal forebrain.

The principal difference between the pontine and medullary noradrenergic systems is further under- scored by electrophysiological studies of the influence of sensory activation on noradrenergic neurons. Whereas pontine noradrenergic neurons in the locus coeruleus complex and the A5 cell group are activated by both somatic and visceral sensory stimuli (15, 77, 163, 235, 236, 375, 5131, noradrenergic medullary A2 neurons respond to visceral (vagus nerve) but not somatic (sciatic nerve) sensory inputs (359). The medullary NE neurons thus seem to be concerned more with interoceptive than exteroceptive cues, regulating hypothalamic, preoptic, and limbic forebrain areas concerned with neuroendocrine and autonomic regulation, and emotive, motivational, and instinctive behaviors (Fig. 31). The pontine noradrenergic neurons, the locus coeruleus complex in particular, appear to “see” a wider part of the external world, both exteroceptive and interoceptive, and regulate a wider range of cerebral, cerebellar, and spinal systems.

The locus coeruleus and subcoeruleus neurons are activated by a wide variety of afferent stimuli, including visual, auditory, tactile, noxious, and visceral modalities (77, 163, 235, 236, 375, 513). Each cell seems to have a large somatosensory receptive field and several sensory modalities converge onto each cell.

Electrophysiological studies indicate that sensory signals reach the pontine and medullary NE neurons

A r - NA afferent

+++ A-

FIG. 31. Relationship of pontine and medullary noradrenergic projection systems to some major functional systems in brain and spinal cord. A: neuromodulatory action; increased signal-to-noise ratio. Left, blockade of background activity; right, potentiation of phasic excitation. B: level-setting action; disinhibition or gain control. Left, lateral geniculate nucleus; right, olfactory bulb. G, granule cells; +, excitation; and -, inhibition.


predominantly over long-latency polysynaptic routes, although monosynaptic connections also occur. Stud- ies with HRP suggest direct afferent connections to the locus coeruleus from lamina I of the spinal cord, from the principal and spinal trigeminal nuclei, and from the vestibular nuclei (77a, 204). In addition the locus coeruleus receives afferents from widely distributed areas throughout the brain. The major sources of afferents are 1 ) the hypothalamus and basal forebrain (including central amygdaloid nucleus, bed nucleus of stria terminalis, medial and lateral preoptic nuclei, and several hypothalamic nuclei); 2) reticular and raphe nuclei (including lateral reticular nucleus, pontine reticular formation, and dorsal and pontine raphe nuclei); and 3) some sensory relay nuclei (e.g., dorsal horn of spinal cord, trigeminal nuclei, vestibular nuclei, and solitary complex) (77a, 83,454a). Cedarbaum and Aghajanian (77a) have interpreted these findings to mean that the locus coeruleus is “wired in parallel” with several neuronal systems, relaying sensory information to forebrain areas and descending messages from the forebrain to lower centers.

Thus, whereas the afferents to the brain stem noradrenergic neurons are characterized by a convergence of oligo- and polysynaptic sensory inputs with inputs from forebrain integrative centers (above all limbic and preoptic-hypothalamic areas) and from other parts of the reticular formation, the efferent projections have traditionally been described as diffusely collateralized over wide areas. There is, however, a regional specialization within the pontine and medullary NE cell groups (Figs. 24 and 31). The descending noradrenergic projection to the spinal cord (Fig. 29A, B ) originates in a subset of the pontine neurons located in the ventral part of the locus coeruleus, in the subcoeruleus, and in the A5 cell group. Moreover, the coeruleus-subcoeruleus neurons innervate the ventral horn and the ventral part of the dorsal horn, whereas the A5 neurons appear to project exclusively to the intermediolateral cell column and to adjacent parts of the intermediate zone (89, 157, 158, 309, 310, 392). In the ascending nonadrenergic projections, the hypothalamic-preoptic innervation originates almost exclusively in the medullary A1 and A2 cell groups, whereas the innervations of the entire cerebral cortex and the specific thalamic nuclei originate in the locus coeruleus proper. The cerebellar projection originates in a subset of widely collateralized locus coeruleus neurons. Thus, in a double-tracer study in the mouse, Steindler (495) showed that a large proportion (>50%) of the neurons projecting to the cerebellar cortex also have collateral branches innervating the cerebral cortex. This is consistent with the earlier proposal of Olson and Fuxe (395). Some neurons also have collateral branches to the spinal cord (371).

As mentioned previously (see General Organiza- tional Features, p. 188), the locus coeruleus complex comprises subsets of neurons with different modes of

projection. Thus, whereas a small proportion of the neurons have widely collateralized projections to different parts of the forebrain (e.g., neocortex, hippocampus, and thalamus) or to the forebrain, cerebellum, and spinal cord, most of these neurons appear to form distinct subsystems whose terminal projections are largely restricted to a particular region or level of the neuraxis. Within the ascending locus coeruleus projection, double-tracer studies in the rat have shown that from 2% to 30% of all the labeled neurons can be labeled simultaneously from different forebrain regions (371, 446). The studies of Morrison et al. (364, 366) and Loughlin et al. (314) within the neocortex indicate that the locus coeruleus neurons arborize along longitudinal, anterior-to-posterior trajectories, whereas the mediolateral collateralization is more limited.

On the basis of the quantitative data of Lapierre et al. (285) and Swanson (501), Moore and Bloom (357) estimated that each locus coeruleus neuron gives rise to at least 30 cm of total terminal arbors, with -100,000 axonal varicosities or terminal boutons. Be- cause this number of terminal boutons is similar to that given by Lapierre et al. (285) for the total number of NE terminals in 1 mm3 of neocortex, it is evident that the tangential terminal stripes formed by individual locus coeruleus neurons in the neocortex must overlap considerably. This is also suggested by the fact that a single tracer injection into the neocortex labels from 50 to 100 (446) and up to 350 (495) neurons in the ipsilateral locus coeruleus.

FUNCTIONAL ASPECTS O F BRAIN STEM NORADRENERGIC SYSTEMS

The anatomical features of the monoaminergic systems and the effects of pharmacological manipulations of their amine content have stimulated speculations on the involvement of these systems in the global regulation of diverse CNS functions, such as emotion, attention, arousal, sleep and waking, motivation, re- inforcement, and learning (see refs. 62, 96, 253, 265, 330a, 493). Already in 1962, Brodie and Costa (62) suggested that the central noradrenergic (and serotonergic) systems might modulate the transmission in systems operating with more classic neurotransmitters. They specifically proposed a role for the noradrenergic neurons as modulators of the afferent signals in the reticular activating system. These early neuro- pharmacological studies generated wide interest in the behavioral and physiological functions of the brain stem noradrenergic system, and the neuromodulatory character of noradrenergic function has gradually gained more substantial experimental support. We focus on this aspect of noradrenergic control functions in the next section. A more complete coverage of the literature on the functional role of NE in a wide


variety of central mechanisms is impossible in the present context. Several exhaustive reviews are available on these topics (8,82, 163a, 330, 330a, 348,437).

Neuromodulatory Actions Our understanding of the functional properties of

the brain stem noradrenergic systems rests largely on the cellular effects of iontophoretically applied NE or of electrical stimulation of noradrenergic afferents.

The early studies of Bloom and collaborators demonstrated that the direct action of NE in areas innervated by the locus coeruleus system is inhibitory, with a slow onset and a prolonged action (see refs. 163a, 357, and 558 for reviews). The mechanism of this slow and protracted effect of NE on its target cells is, however, different from that of a classic inhibitory amino acid transmitter, such as GABA, and it might be mediated by CAMP (474-476). This second-messenger hypothesis of noradrenergic action suggests that the function of the noradrenergic projections may not be explainable in terms of classic inhibitory effects. Rather it points to a more neurohumoral-like action that alters the functional properties of the target neuron through an intracellular mechanism.

Woodward et al. (558) have provided evidence that NE primarily modifies the responsiveness of the target neurons to convergent synaptic inputs. Norepineph- rine, or NE released by locus coeruleus stimulation, appears to inhibit ongoing background discharge while enhancing the responses to evoked excitatory or phasic inhibitory inputs in other afferent channels (165, 318, 445, 558). This effect (Fig. 31A) has been described as an increase in the signal-to-noise ratio in the transmission through the target area. The ability of NE to enhance the responsiveness to excitatory neurotransmitters has, on the membrane level, been ascribed to a decrease in the Ca2+-dependent potas- sium conductance (318, 534).

The direct effect of NE on the responsiveness of target neurons may not be the only mechanism by which the noradrenergic neurons modulate transmission in their target areas. In two sensory relay systems, the retinogeniculate and olfactory pathways (241, 374), the locus coeruleus afferents apparently facilitate synaptic transmission by suppressing adjacent inhibitory interneurons. Such a disinhibitory mechanism would provide a permissive or level-setting device to regulate the transmission of information through sensory relay neurons (Fig. 31B). The model proposed by Jahr and Nicoll (241) for the olfactory relay neurons (mitral cells) in the turtle olfactory bulb is shown in part B. The mitral cells (which relay olfactory impulses to cortex) are connected to the inhibitory granule cells through a reciprocal dendrodendritic inhibitory circuit. Impulses in the mitral cells activate the granule cells (through excitatory dendrodendritic synapses), which in turn release the

sensory cues

and autonomic

FIG. 32. Proposed models for neuromodulatory and level-setting actions of noradrenergic system. d, Dorsal; v, ventral. [Data from Woodward et al. (558), Nakai and Takaori (374), and Jahr and Nicoll (241).]

inhibitory transmitter GABA back onto the mitral cells. The noradrenergic afferents, which predominantly originate in the locus coeruleus, suppress the granule cells, causing them to release less GABA in response to the mitral cell activation. Thus the noradrenergic system acts as a tuning device, setting the gain in the reciprocal mitral cell-granule cell circuit.

Arousal and Attention Studies of the action of NE on target neuron re-

sponsiveness have been carried out in target areas of the locus coeruleus projection system (cerebellum, somatosensory and auditory cortex, lateral geniculate body, and olfactory bulb). The ability of the locus coeruleus inputs to enhance sensory transmission and increase the signal-to-noise ratio in sensory transmitting relay systems fits well with our understanding of this system’s role in arousal and attention. Bloom and co-workers (18, 19, 162, 251) more directly addressed this issue. They monitored the discharge patterns of locus coeruleus neurons under various conditions in freely moving or restrained rats. They found that fluctuations in the discharge rate of the locus coeruleus neurons consistently accompanied awakening, EEG spindling, and orienting behaviors. During the sleep-waking cycle the neuron’s spontaneous discharge was directly related to the level of vigilance. The discharge rate decreased during sleep, grooming,


and sweet-water consumption, but arousing stimuli, which interrupted these behaviors, were accompanied by bursting activity of the locus coeruleus neurons. These phasic changes in discharge rates were homog- enous throughout the nucleus and were synchronized within populations of adjacent neurons.

On the basis of these experiments, Aston-Jones and Bloom (19) proposed that the noradrenergic locus coeruleus system may facilitate transitions between behavioral states. Endogenously generated repetitive behaviors (e.g., sleep, grooming, and consumption) would depend on a low rate of discharge of the locus coeruleus neurons. A phasic, vigorous activation of the locus coeruleus system would interrupt such internally oriented behaviors and facilitate behavior oriented toward events in the external environment. In effect, the locus coeruleus seems to signal that something important may be going on, thus causing awakening from sleep, arousal from drowsiness, and orientation of attention toward relevant stimuli. Segal and Bloom (466) have presented evidence from recordings in the hippocampi of freely moving rats that locus coeruleus activity potentiates neuronal responses to behaviorally significant stimuli (in this case a tone correlated with food). They proposed that the locus coeruleus helps filter out irrelevant stimuli and increases the signal-to-noise ratio of behaviorally significant stimuli.

An attentional mechanism has also been used to explain certain behavioral effects seen after selective lesions of the ascending noradrenergic projection systems. In particular, Mason and Iversen (329,330,333) showed that rats subjected to bilateral 6-OHDA lesions of the ascending projection from the locus coeruleus in the dorsal tegmental bundle have a sig- nificantly impaired ability to extinguish previously acquired reinforced behaviors. This resistance to extinction, observed in a wide range of different behavioral tests, was interpreted as an inability of the lesioned animals to filter out irrelevant stimuli: “[the locus coeruleus] seems to be telling the forebrain when to attend incoming stimuli and when to ignore them” (329). Although this defect does not seem to affect the acquisition and retention of simple learning tasks (see ref. 444), Keverne and de la Riva (266) have reported an intriguing example of a short-term “neuroendocrine memory” that seems to depend on the integrity of the locus coeruleus system. This memory is seen in female mice after mating, where the odor (or pheromones) from strange males, but not from the stud male, blocks pregnancy. Apparently the odor cues to which the females are exposed shortly after mating are recognized by the female’s neuroendocrine system, thus preventing the stud male from blocking the pregnancy later on. This memory was impaired in animals with 6-OHDA lesions of the noradrenergic input to the olfactory bulbs; the females did not recognize the stud male, and the pregnancy was blocked by exposure

to him. This effect may possibly be reconciled with the proposed neuromodulatory effect of the locus coeruleus afferents, which can potentiate the sensory relay of behaviorally significant stimuli [Fig. 32; (466)J. Mason and Iversen (333) noted that

Activity in the dorsal bundle might inform the cortex that this stimulus was irrelevant and further information processing was not to occur; inform the hippocampus that this stimulus was irrelevant and memory traces were not to be laid down concerning it; inform the cerebellum that this stimulus was irrelevant and motor learning was not to occur using this stimulus; perhaps even inform the lateral geniculate, cochlear nucleus and trigeminal nucleus that this stimulus was irrelevant and that transmission of information up the visual pathway, auditory tract or tactile input concerning it was to be attenuated.

Descending Effects on Locomotion Neural control of inherited movements is believed

to be due to the functional properties of local neuronal networks, forming central programs and pattern generators. This concept also has important implications for understanding the role of supraspinal systems in the control of movements (see refs. 191-193, 472, 494 for reviews). Many of the basic motor programs generated by local neuronal networks are virtually independent of afferent feedback. These motor pattern generators can be activated (and probably also controlled under physiological conditions) by brain stem command systems. Brain stem command systems can tonically drive the pattern generators and maintain them a t different levels of activity.

Locomotion is generated in the spinal cord by neuronal networks intrinsic to it. These intraspinal locomotion generators are controlled by supraspinal command-driving systems, which appear to tonically regulate the degree of locomotor activity (191-193, 472, 494). In the decerebrate cat, which does not walk spontaneously, locomotion can be initiated and main- tained by electrical stimulation of the mesencephalic locomotor region (MLR), located in the cuneiform nucleus of the dorsal mesencephalon. This is part of the general area in the mesencephalon that receives descending projections from both the striatal and limbic forebrain circuitries (e.g., via substantia nigra, pars reticulata and lateral habenula; see Figs. 19 and 20). Grillner and Shik (194) have proposed that the activity of the MLR determines the intensity of locomotion via a tonic activation of the spinal locomotion generators. Figure 33 diagrams this arrangement.

Disconnecting the spinal cord from the supraspinal control systems results in a profound loss of motor functions, part of which may be attributed to the loss of activating brain stem systems needed to drive the segmental neuronal machinery (192, 193, 472). This suggests that the spinal locomotion-generating network is inhibited in the isolated cord and that the descending supraspinal command systems in the in-


FIG. 33. Command-driving function of mesencephalic locomotor region (MLR) in regulation of spinal locomotion generator. Pontine noradrenergic neurons may participate in this control. [Adapted from Grillner (191).]

tact animal regulate spinal locomotion by modulating an intraspinal inhibitory mechanism. As in the nigrostriatal system (see FUNCTIONAL ASPECTS OF MESO- TELENCEPHALIC DOPAMINE SYSTEM, p. 194), CAs have been implicated in this brain stem-activating control mechanism, probably by disinhibiting the spinal neuronal networks that form the locomotion generator (164, 190, 243, 244). Jankowska et al. (243, 244) reported that L-dopa injections can activate a segmental network in the spinal cord that involves mutual inhibition between interneurons with excitatory actions on flexors and extensors, i.e., a network that may serve as a locomotion pattern generator. Grillner (189) and Forssberg and Grillner (164) subsequently found that in cats with transected spinal cords, L-dopa and the a-adrenergic receptor agonist clonidine elicited walking on a treadmill. This effect was similar to that induced by stimulation of the MLR in decerebrate cats (194), thus suggesting that the CA systems may participate in the mediation of the MLR-induced effect.

The exact role of the descending noradrenergic projection system in the regulation of locomotion remains obscure. Noradrenergic denervation of the spinal cord by 6-OHDA, or a-adrenergic receptor blockade by phenoxybenzamine, causes no profound impairment of locomotion (360, 492a), although the stimulus strength to the MLR necessary to elicit locomotion may be increased (492a). Grillner (193) therefore suggested that the noradrenergic system regulates, or sets, the threshold for induction of locomotion by other, parallel, descending systems. This is consistent with the electrophysiological observations of Vander- Maelen and Aghajanian (534) and White and Neuman (554) that NE (like serotonin) increases the general excitability of motoneurons to excitatory inputs. Such gain control could indeed have features in common

with both the level-setting mechanisms proposed for the action of DA in the neostriatum (see Fig. 21) and for the action of NE in the olfactory bulb (Fig. 32). Indeed the descending CA system may exert more global effects on sensory, noxious, autonomic, and reflex neurotransmission at the level of the spinal cord (see ref. 86).

Blood Flow, Stress, and Epileptic Seizures

The locus coeruleus has been suggested to function as a central analogue of a sympathetic ganglion with the brain as its end organ (see ref. 8 for review). This hypothesis is supported by the observations of Hart- man, Raichle, and co-workers (350c, 436), which indicated that noradrenergic axons originating in the locus coeruleus contribute a functional system supply- ing brain microvessels with vasomotor fibers. The proposed vasoregulatory role of the locus coeruleus emerged from the microscopic observations that some of its axons follow closely the paths of small blood vessels (132,294,350~). A direct central noradrenergic innervation of brain microvessels has not yet been definitely established, although some data indicate that such an arrangement may exist, mainly at the capillary level. 1) 8-Adrenergic receptors, predominantly &adrenergic receptors, have been demonstrated on cerebral microvessels (210, 220, 272, 376, 377, 407); 2) purified brain microvessel preparations contain NE and its synthesizing and catabolizing enzymes (283, 551); and 3) there is electron-microscopic evidence that monoaminergic axons, at least in some places, may end on the capillary wall (503). Since the walls of brain capillaries contain contractile proteins (399), noradrenergic vasomotor fibers may directly influence local blood flow.

Stimulation in the area of the locus coeruleus reportedly reduces cerebral blood flow (107, 436). This appears to be analogous to the constriction of the peripheral blood vessels produced via sympathetic activation. However, other experiments did not reveal any significant physiological role for the locus coeruleus in regulating the cerebral microcirculation. Selec- tive lesions of the ascending noradrenergic fibers from the locus coeruleus do not affect forebrain blood flow under basal conditions (100, 390) or in hypercapnia (loo), a condition that reportedly activates locus coeruleus neurons (75, 136). Even if available data do not exclude locus coeruleus participation in the control of cerebrovascular tone in conditions other than those studied so far, the functional states in which this intrinsic vasoregulatory system is of any real importance have not been defined.

Although its effect on the vasculature is uncertain, it is well documented that the locus coeruleus, like the peripheral nervous system, is activated by stress (see ref. 8). In fact, the major role for the locus coeruleus may be to dampen the organism's response to stressors


(8). On a neural level this function appears as a direct inhibition of spike activity. This proposed stress- dampening activity of the locus coeruleus is compatible with the effects of central NE mechanisms on epileptic seizures.

Evidence indicates that central noradrenergic neurons can inhibit epileptic seizures, whereas dopaminergic neurons have, at most, a minor modulatory role in convulsions. For example, lesions of the CA neuron systems potentiate various types of experimental epileptic seizures. Intraventricular injections of 6-OHDA lead to pentylenetetrazol-induced convulsions of longer duration and greater severity than in controls (93). More selective lesions of different CA neuron systems indicate that NE, but not DA, reduces the brain’s susceptibility to seizures. Thus bilateral 6- OHDA injections into the dorsal tegmental bundle, causing profound depletion of forebrain NE, poten- tiated the seizures induced both by pentylenetetrazol and electroconvulsive shock (331). By contrast, lesion of the nigrostriatal dopaminergic pathway did not affect convulsive activity.

Genetically epilepsy-prone rats and mice show both biochemical and electron-microscopic abnormalities indicative of a dysfunction of central catecholaminergic, primarily noradrenergic, neurons. Such rats have anomalous tyrosine hydroxylase activity (105) and NE concentration levels (247), whereas DA concentrations are normal (247). Furthermore, in the temporal cortex of epilepsy-prone mice, presumed monoaminergic synapses constitute only 4% of all synapses, compared with 20% in normal mice (277). These abnormal mice develop seizures in response to loud auditory stimuli, and it has been proposed that the loss of inhibitory monoaminergic synapses could facilitate the propagation of an audiogenic seizure through the cerebral cortex (277).

The possible involvement of noradrenergic neurons in epileptogenesis has also been demonstrated in chronic cobalt-induced epileptic foci (524). In the area surrounding the cobalt-deposit zone, NE levels and the density of NE terminals were lower than in normal neocortex. These changes preceded the onset of epileptic activity, continued during the epileptic period, and disappeared at the end of it. Noradrenergic sprouting fibers had apparently invaded and reinnervated the perifocal area by the time the epileptic syndrome disappeared.

Available data thus strongly support the idea that increased activity in central NE neurons, which ac- companies epileptic seizures (71), leads to suppressed seizure activity. This is further substantiated by data from experiments with hippocampal transplants in the anterior eye chamber, reinnervated by sympathetic adrenergic nerves (166). Electrical stimulation of the NE input (from superior cervical ganglion) inhibited penicillin-induced seizures in these transplants and the effect was abolished by @-adrenergic

receptor blockade. Consistent with this, Libet et al. (291) have reported that stimulation of the locus coeruleus in rats suppresses pentylenetetrazol-induced epileptiform cortical EEG activity.

Other lines of evidence also indicate that the modulatory role of NE in epileptic seizures is a t least partly exerted via its action on central 6-adrenergic receptors, leading to increased formation of the second messenger CAMP. It is well known that epileptic seizures, induced in different ways, are accompanied by elevated concentrations of cAMP (152, 159, 160, 317, 461, 547). The accumulation of cAMP in pentylenetetrazol-induced convulsions can be attenuated or blocked after administration of reserpine, which de- pletes brain monoamines, or propranolol, a p-adrenergic receptor blocker. Both these drugs lead to more severe seizures (198). At least in bicuculline-induced seizures, the majority of the cAMP that accumulates in the neocortex and hippocampus appears to form as a result of the concomitant activation of the locus coeruleus system, because lesions of the locus coeruleus projections to the forebrain markedly attenuate the rise in cAMP associated with seizure activity (208, 237). The accumulation of cAMP requires, and is secondary to, seizure activity, based on the finding that subconvulsant doses of pentylenetetrazol did not change cAMP levels (152). It therefore seems less likely that this nucleotide is involved in seizure genesis. Noradrenergic neurons acting via cAMP are more likely involved in mechanisms suppressing the spread and duration of seizure activity.

The influence of CA neurons has attracted a particular interest in the kindling model of epilepsy. “Kin- dling” refers to a process whereby repeated administration of an initially subconvulsant stimulus (most often electrical) results in a progressive intensification of stimulus-induced activity, culminating in a gener- alized seizure (184, 185a). Because the amygdala is the region most sensitive to the kindling procedure (185a), it is the most common site of electrical stimulation in kindling experiments. In the first experiments with intraventricular 6-OHDA injections, which produced marked reductions of both DA and NE, there was a clear facilitation in the rate of amygdaloid kindling (16, 93). A similar effect was obtained after NE and DA depletion induced by reserpine pretreatment (16) or by the CA-synthesis inhibitor a-methyl-p-tyrosine (72). Subsequent studies, which separated the effects on DA and NE systems, indicate that in kindling, as in other types of seizures, the facilitatory effect of CA lesions is due to the removal of noradrenergic neurons. First, lesions of the ascending noradrenergic pathways with 6-OHDA (94), which depleted forebrain NE, made the animals more susceptible to the kindling procedure, whereas no such effect occurred in rats with selective depletion of forebrain DA. Second, if 6- OHDA was given intraventricularly to animals pre- treated with desmethylimipramine, which protects NE


but not DA neurons from the action of the neurotoxin, no effect on kindling was observed, despite the fact that DA levels were severely reduced (343,344). Third, local injections of 6-OHDA in the amygdala, which reduced regional NE but not DA levels, facilitated kindling in the amygdala (342).

Other studies, involving various types of drugs in- terfering with noradrenergic and/or dopaminergic neurotransmission, further substantiate the view that NE neurons suppress amygdaloid kindling and that the effect is mediated via P-adrenergic receptors. Thus administering propranolol enhances kindling, whereas dopaminergic as well as a-adrenergic receptor agonists and antagonists have no effect (72).

On the basis of these results, Corcoran and Mason (94) suggested that decreased activity in the forebrain NE projections, with a concomitant lessening of seizure suppression, could be part of the mechanism underlying kindling. However, conclusive evidence supporting this hypothesis is still lacking, because studies on DA and NE neurotransmission in kindled animals gave conflicting results (see refs. 72,139,458); more studies are therefore needed to clarify the exact role of CAs in kindling epileptogenesis.

Nevertheless, whatever the exact cellular mechanisms, the ascending NE projection systems, and the coeruleocortical pathway in particular, seem to protect or dampen the generation or spread of seizures. This effect, viewed in the context of a general stress- dampening role for the locus coeruleus system, may contribute to a better understanding and treatment of epilepsy in humans.

REGENERATIVE RESPONSES AND FUNCTIONAL RECOVERY AFTER BRAIN INJURY

The brain stem CA neurons are both functionally and morphologically highly plastic elements. It is evident that in a very general sense the CA neurons are involved in the adaptive responses of the brain and the organism. This is also true of the compensatory and regenerative responses that take place in the CNS after traumatic injury: under certain conditions the CA neurons can regenerate effectively after axotomy; they show collateral sprouting after various types of denervating lesions; and they exhibit powerful compensatory changes (e.g., transmitter hyperactivity and postsynaptic supersensitivity) in response to partial lesions. Finally, the plastic properties of the CA neurons are also demonstrated in their ability to reinner- vate denervated areas and to restore lost functions after grafting to a previously denervated target in the adult CNS.

Regeneration After Axotomy The DA and NE neurons have a high capacity for

regenerative sprouting after axotomy (42b, 49c,257b).

The outcome of the regenerative process depends very much on the nature of the damage. After substantial traumatic lesions, there is vigorous sprouting from the cut CA axon stumps into the necrosis of the lesion and in the tissue proximal to the lesion. Anomalous growth also occurs along myelinated fiber tracts and blood vessels, but the sprouting fibers do not grow across the lesion along the course of the original axonal pathway. However, if grafts of denervated peripheral tissue (e.g., iris) or of a segment of peripheral nerve are placed into the area of the lesion, they are extensively reinnervated by the regenerating CA axons (31b, 42b, 49a, 500a). In such a favorable environment the sprouts can regenerate over several centimeters (31b) and form functional connections with the denervated smooth muscle cells in the graft (42a).

After selective chemical axotomy, on the other hand, such as occurs after injections of monoamine neurotoxins, regeneration is much more efficient. Such lesions produce minimal scars or glial barriers and leave the general architecture of the tissue intact.

The most extensive regeneration seen so far is in noradrenergic projections after 5,7-dihydroxytryptamine (5,7-DHT) treatment (39a, 43a) or after low doses of 6-OHDA (391a, 393), both of which cause lesions to the distal portions of the axon tree while leaving the cell bodies largely untouched. Under these conditions the chemically axotomized NE neurons show true regeneration in the sense that they grow back to their original terminal areas and at least partly reestablish normal terminal patterns. Figure 34 shows an example of regeneration from the anterior hypothalamus in rats treated with an intraventricular injection of 150 fig of 5,7-DHT (43a). The lesioned NE axons in the medial forebrain bundle reestablish the complex collateral branching pattern of the axons decussating in the retrochiasmatic area and restore a relatively normal NE innervation pattern in the hypothalamic nuclei. This regenerative process takes several months. Biochemically, [3H]NE uptake in various parts of the brain and spinal cord was acutely reduced by 45%-85% after the 5,7-DHT treatment. Within 4-6 mo the levels were back to normal in the brain and to 50%-75% of normal in the spinal cord. This closely paralleled the restoration of NE terminal patterns seen histochemically (43a).

Little is known about the functional effects of regeneration after neurotoxin treatment. In a study in which the flexor reflex was used to monitor adrenergic supersensitivity after 6-OHDA-induced denervation in the spinal cord, Nygren and Olson (391a) obtained some indirect evidence that the regenerated spinal NE projection had reoccupied previously denervated receptor sites and normalized the denervation-induced supersensitivity. Another case of functional regeneration may be found in the study by Trottier et al. (524) on the reappearance of NE fibers in cobalt- induced epileptic foci (see BZood Flow, Stress, and


A NORMAL c 3WEEKS

B 1 WEEK D 3-6MONTHS

FIG. 34. A: normal CA innervation pattern in retrochiasmatic region of rat. B: extent of denervation and axotomy acutely (1 wk) after intraventricular injection of 5,7-dihydroxytryptamine (150 pg). C and D: subsequent sprouting and regrowth of lesioned CA axons (C, 3 wk; D, 3-6 mo). Illustrations are drawn from vibratome sections treated according to glyoxylic acid fluorescence method. AH, anterior hypothalamic area; PN, periventricular hypothalamic n.; PVN, paraventricular hypothalamic n. [From Bjorklund and Lindvall (43a).]

Epileptic Seizures, p. 211). The lesioned cortical NE axons apparently regenerated into the perifocal area with a time course that followed the disappearance of epileptic activity. Because NE seems to inhibit epileptic activity, the regeneration of the cortical NE afferents (in this case from locus coeruleus) around the focus could assist in switching off the focus.

Collateral Sprouting After Deafferentation

In the peripheral nervous system, collateral sprouting from intact axons is one of the basic mechanisms for reinnervation and restitution of function in a partially denervated target (64a, 131a). Collateral or terminal sprouting is also a common response to deaf- ferenting lesions in the CNS (see refs. 95a, 524b for review). Two different types of collateral sprouting phenomena can be distinguished in the CNS. I) Re- active synaptogenesis is a synaptic reorganization in the neuropil after removal of one set of afferents. Typically, this growth response has a short time course (starting within 4-5 days and waning within a few weeks) and is restricted to the immediate vicinity of the sprouting terminals (i.e., growth distances <50- 100 ym). The reactive synaptogenesis response is usually also nonselective and heterotypic, such that removing one set of afferents induces growth in other types of afferents with different transmitters. This response has also been observed in CA neurons, e.g., in the septum after hippocampal deafferentation

(355a), in the lateral geniculate body after visual cortex ablation (497), in the olfactory tubercle after olfactory bulb lesion (183a), and in the cerebellum after cerebellar peduncle lesions (427a). 2) Compensatory collateral sprouting is a mechanism for homotypic reinnervation of a partially denervated area by spared axons. This response, which has been most thoroughly described in the hippocampal formation (19a, 176, 176a, 394a), is slow in onset (first detectable between 1 and 3 mo after lesion), has a protracted time course (continues to at least 6 mo after lesion), and occurs over relatively long distances. In the hippocampal formation, compensatory collateral sprouting has been observed in the noradrenergic, serotonergic, and cholinergic afferents after partial hippocampal denervation. As Figures 27 and 35 show, the locus coeruleus NE afferents (like serotonergic and cholinergic afferents) reach the hippocampus along three discrete routes: -45% of the total NE innervation runs above the corpus callosum, in the cingulum bundle; -15% runs in the fimbria-fornix; and -40% runs in the ventral pathway (through amygdaloid-piriform lobe). Lesions of the cingulum bundle or the cingulum bundle plus the fimbria-fornix result in a partial adrenergic denervation of the hippocampus. Maximum denervation occurs after 2-4 wk. During the subsequent months the spared NE afferents sprout and expand over the initially denervated hippocampus. After the fimbria-fornix lesion, the NE innervation of the dorsal hippocampus recovers from 10%-20% of normal at 4


Normal 2 - 4 Weeks 4 - 6 Months

FIG. 35. Compensatory collateral sprouting of locus coeruleus NE afferents to hippocampal formation after lesion of supracallosal pathway [running in cingulum (CC) bundle, top] and after lesion of supracallosal plus fimbria-fornix (FF) pathways (bottom). In each case extent of spared NE innervation and its subsequent expansion over time is indicated by crosshatching. Compare with Figs. 26 and 27. [From Gage et al. (176b).]

wk to -70%-80% of normal at 6-10 mo after lesion. The distribution and terminal patterning of the expanded NE terminal plexuses were similar to those of the normal NE innervation, suggesting that the compensatory collateral sprouting may represent a relatively accurate reinnervation of initially adrenergi- cally denervated target sites.

Compensatory collateral sprouting may thus be a fairly specific process, whereby spared NE neurons compensate for lost NE innervation in a partially denervated area. Because of its slow and protracted time course and its ability to restore normal terminal innervation patterns, this compensatory mechanism may be of particular interest with respect to the mechanisms underlying the protracted behavioral recovery commonly seen both after experimental brain lesions and in patients with severe brain injuries. Gage et al. (176b) provide evidence to support this idea. They observed that the recovery of spatial learning in animals with bilateral lesions of the cingulum pathway (Fig. 35) closely followed the time course of reinnervation by monoaminergic and cholinergic fibers in compensatory collateral sprouting. Because the adrenergic locus coeruleus axons, the serotonergic axons from the mesencephalic raphe nuclei, and the cholinergic axons from the nucleus of the diagonal band of Broca all participated in the reinnervation process, the relative contribution of the NE fibers to the behavioral recovery is as yet unclear.

Compensatory Hyperactivity

Catecholamine synapses undergo adaptive changes after denervation. Two synaptic adaptive phenomena

likely have roles in functional recovery after denervating lesions: postsynaptic receptor supersensitivity and presynaptic increases in transmitter turnover and release. Receptor supersensitivity has been demonstrated in both noradrenergic and dopaminergic synapses in the brain (499, 526b). It may help to potentiate the effect of a decreased neurotransmitter release onto partially denervated target neurons. Compensa- tory hyperactivity occurs in spared CA axons after partial denervating lesions and is expressed as an increase in transmitter turnover and release in the spared axons. These effects were demonstrated in the nigrostriatal DA system (4a, 215a), the coeruleocortical NE projection (l), and the coeruleohippocampal NE projection in adult rats (176).

Several mechanisms purportedly underlie this hyperactivity response: 2 ) the spared neurons may be activated through cell body-mediated feedback regulation from the denervated target; 2) presynaptic autoreceptors may normally mediate an inhibition of CA synthesis and release by neighboring terminals, and thus hyperactivity would result from a removal of this lateral inhibitory mechanism; 3) local transmitter interactions within the innervated target may normally provide inhibitory feedback on CA turnover and release, e.g., via local interneurons or recurrent collaterals of projection neurons in the area (again, partial denervation would remove this local inhibitory feedback); and 4 ) local regulation of transmitter function may reflect atrophic interaction with the target tissue, mediated by neurotrophic factors released on deafferentation. In the latter case specific macromolecules could act as regulators of enzymes involved in transmitter biosynthesis and as agents inducing sprouting, which would promote regrowth and compensatory collateral sprouting from spared axons in the denervated area. Gage et al. (176) have demonstrated an interaction between the transmitter hyperactivity response and the more slowly progressing compensatory collateral sprouting in the hippocampal formation. After partial adrenergic denervation (Fig. 35), a compensatory increase in the NE synthesis rate develops within 3 wk and returns to normal levels when reinnervation from the spared NE afferents is complete. This hyperactivity response occurred only in the denervated portion of the hippocampus and not in other projection areas of the locus coeruleus neurons, which were not affected by the lesion. This topographical specificity and the interaction between the compensatory hyperactivity and the collateral innervation process suggest that the adaptive changes in transmitter turnover in spared CA afferents can be regulated by local mechanisms operating within the denervated target.

Reinnervation and Recovery of Function by Grafted Catecholaminergic Neurons

Some of the most striking examples of the regenerative and plastic potential of the catecholaminergic


neurons come from experiments with grafts of embryonic DA or NE neurons implanted into the brain or spinal cord of adult recipient rats. Locus coeruleus NE neurons and mesencephalic DA neurons can restore normal innervation patterns in previously denervated regions, such as the hippocampus (47), the spinal cord (390a), and the neostriatum (40a, 50a).

In the hippocampal formation in particular, where the normal NE innervation has a characteristic laminar distribution (see Fig. 26), the grafted locus coeruleus neurons establish a new terminal network whose laminar pattern very closely mimics the normal pattern (47). Electrophysiological studies have provided evidence that the connections established by the grafted locus coeruleus neurons are indeed functional (47). Electron-microscopic observations, both on grafts of brain stem neurons reinnervating the hippocampus (31a) and on mesencephalic DA neurons reinnervating the neostriatum (167a), have demonstrated that the ingrowing axons establish abundant synaptic contacts with neurons in the host brain. These morphologically and physiologically functional connections established by the grafted CA neurons with elements in the initially denervated host target areas probably explain the capacity of the grafts to restore a range of motor, sensorimotor, and cognitive behaviors in the lesioned hosts. A more thorough discussion of this topic is beyond the scope of this review. (For review of neural grafting experiments and their effects on striatal- and hippocampal-related behaviors, see refs. 49b, 49d, 128a-129a.)

SUMMARY

It is remarkable that so few CA neurons can influence such a wide spectrum of CNS subsystems. This may perhaps be due to the extreme divergence of the CA neurons; in humans the ratio of the number of nigrostriatal DA neurons to neostriatal neurons is estimated to be 1:2,300 (67a). Since -95% of the striatal neurons are likely to be projection neurons, which receive direct synaptic inputs from the DA neurons (167b), each nigral DA neuron probably contacts an average of at least 2,000 striatal cells. In the rat this synaptic divergence amounts to between 10% and 20% of all synapses in the neostriatum (15a, 427a). The locus coeruleus is an even more extreme case, where a few thousand cells apparently influence or regulate function in widely dispersed structures throughout the neuraxis. These features appear ideal for integrative systems underlying global regulation of the brain’s behavioral and neurological performance.

There are, however, several other properties of central CA neurons essential to an understanding of their functional role. We summarize some of their unconventional and perhaps most distinctive features in this section.

Catecholamine Neurons Can Operate in Both Synaptic and Neurohumoral Manners

Over the years the extent to which the target cell actions of the central CA neurons are specific (i.e., transmitted over specialized synaptic junctions) or nonspecific (i.e., mediated via a more diffuse neurohumoral release acting over greater distances) has been the subject of much debate (see refs. 26, 163a).

The best case for the nonjunctional release of the CA transmitter is the peripheral sympathetic neuron, where NE acts on its target cells over greater distances ( ~ 1 , 0 0 0 pm) and in the absence of morphologically recognizable synaptic specializations (223). On the other hand, there is an emerging consensus that in the striatum at least, the axons of central DA neurons make abundant morphologically specialized synaptic contacts with the striatal target neurons (15a, 113a, 113b, 167b, 198a, 212a). In this case, all neostriatal projection neurons (constituting -95% of total neuronal population in striatum) may be directly innervated (167b), and the DA synapses form between 10% and 20% of all synaptic contacts in the striatum (15a, 427a).

Morphologically recognizable synaptic contacts are also common along noradrenergic axons in various parts of the brain (see ref. 163a). Beaudet and Descar- ries (26), however, have argued that nonjunctional release sites, i.e., boutons without specialized synaptic contacts, are predominant along the noradrenergic axons, similar to the situation in peripheral noradrenergic neurons.

This controversy remains partly unresolved because of the difficulty in defining and identifying the CA release sites. On one hand, the CAs may be actively released from axon terminals and boutons, from large preterminal and nonvaricose segments of the axons, and from the outgrowing axons before they establish any contacts with their presumptive targets. On the other hand, it is equally possible that CA release is much more restricted and that the presence of bouton- like swellings, particularly along preterminal portions of the axons, does not necessarily signify release sites.

Nevertheless, the specific and nonspecific modes of action of central CAs are not mutually exclusive. In fact it seems most probable that they both operate in parallel and that they may mediate different effects with different relative importances in various target areas. In the nigrostriatal DA system, for example, the level-setting or permissive function of DA (see Sim- plified Scheme for Dopaminergic Regulation of Striatal Output Functions, p. 194), regulating the general excitability of the striatal machinery, may be related to a more diffuse, neurohumoral-like release of DA across nonjunctional cell-to-cell contacts. The more precise gating mechanism may be mediated via the synaptic contacts present on the striatal projection neurons, perhaps through a specific modulation of cortical ex-


citatory synapses on individual dendritic spines (167b). Similarly, postulated effects of the NE projection systems on, for example, microvessels (see Blood Flow, Stress, and Epileptic Seizures, p. 211), glia, and glycogenolysis (see ref. 237) may best be explained in terms of neurohumoral effects, whereas neuronal effects on the regulation of neuronal responsiveness and signal-to-noise ratio (see Neuromodulatory Actions, p. 209) may be referred to synaptic effects.

Catecholamines Function at Both Axonal and Dendritic Terminals

As summarized previously (see Dopaminergic Mod- ulation of Neurotransmission in Substantia Nigra Through Dendrites of Nigral Neurons, p. 198), there is considerable evidence that the nigrostriatal DA neurons have “double polarity” in the sense that DA is released and exerts its effects both at axonal terminals (in various forebrain target areas) and at dendritic terminals within the substantia nigra itself. In contrast to the axonal release, the dendritic DA release is spike independent but is probably mediated via changes in Ca2+ conductance (78, 308a). This double polarity may be a property of the central CA neurons in general. Thus, in the locus coeruleus NE neurons, NE is also stored and probably released from the dendrites within the nucleus. There is some evidence to suggest that dendritically released NE mediates recurrent inhibition of the locus coeruleus neurons (163a). Interestingly, there are dopaminergic interneu- ions in the CNS, which we have not discussed, that apparently lack axonal processes. These are the amacrine DA cells of the retina and the periglomerular DA cells in the olfactory bulb (see refs. 43b, 134, 208, 54813 for review). Their transmitter actions are likely mediated entirely through dendritic mechanisms.

Catecholamine Release Depends on Neuronal Activity and Local Transmitter Interactions

Transmitter release classically results from the propagation of action potentials along the axon. In brain stem DA and NE neurons, neuronal activity is likely globally regulated through the convergence of afferents onto the parent cell bodies, e.g., by inputs from a wide variety of sensory modalities (see FUNC- TIONAL ASPECTS OF MESOTELENCEPHALIC DOPAMINE

R E F E R E N C E S

1. ACHESON, A. L., M. J. ZIGMOND, AND E. M. STRICKER. Compensatory increase in tyrosine hydroxylase activity in rat brain after intraventricular injections of 6-hydroxydopamine. Science 207: 537-540, 1980.

la.ADER, J.-P., F. POSTEMA, AND J. KORF. Contribution of the locus coeruleus to the adrenergic innervation of the rat spinal cord: a biochemical study. J. Neural Transm. 44: 159-173, 1979.

SYSTEM, p. 194, and NORADRENERGIC SYSTEMS

FORMATION, p. 207). Such extensive convergence of sensory inputs onto the brain stem CA neurons is consistent with their integrative function in the brain. However, abundant experimental evidence indicates that transmitter release from CA neurons is not regulated solely by the changes in firing rate induced by afferents impinging on the cell bodies or dendrites but that axonal CA release is under the complex influence of local transmitter interactions within the innervated target areas.

In the nigrostriatal DA system, which has been most extensively studied in this regard (see refs. 124, 185), receptor binding sites for several intrinsic striatal neurotransmitters are present on the dopaminergic terminals. Studies on striatal DA release in vitro, and with push-pull cannulae in vivo, provide evidence that other striatal transmitter systems can modulate DA release through local influences. Thus acetylcholine, GABA, glutamate, and somatostatin all appear to stimulate DA release in the striatum. The effects of acetylcholine and glutamate are dependent on Ca2+ and are insensitive to tetrodotoxin, which suggests that the striatal cholinergic interneurons and the cortical or thalamic glutamate afferents exert direct presynaptic control over the DA terminals (185).

The effects of GABA and somatostatin are also dependent on Ca2+, but they are abolished by tetrodotoxin. This suggests that GABA and somatostatin interneurons, or the recurrent collaterals of the GABAergic projection neurons, exert a local effect on DA release in the striatum. This control may be in- directly mediated via other interneurons or afferents in the striatum (79a, 124, 185). In addition, DA itself inhibits striatal DA release, probably through the actions on presynaptic DA receptors (so-called “autoreceptors”) on the dopaminergic terminals in the striatum (72a, 124, 185).

In the nigrostriatal system, and perhaps in other central CA projection systems as well, complex local transmitter interactions are probably important modulatory mechanisms that allow local regulation of the CA neurons within the innervated target.

We thank Siv Carlson and Agneta Persson for their invaluable help in the preparation of this manuscript. Our research reviewed in this chapter was supported by Swedish Medical Research Council Grant 04X-4493 and National Institutes of Health Grant NS-06701.

VIEWED AS COMPONENTS OF BRAIN STEM RETICULAR

2. ADER, J.-P., P. ROOM, F. POSTEMA, AND J. KORF. Bilaterally diverging axon collaterals and contralateral projections from rat locus coeruleus neurons, demonstrated by fluorescent retrograde double labeling and norepinephrine metabolism. J. Neural Transm. 49: 207-218, 1980.

3. AGHAJANIAN, G. K., AND B. s. BUNNEY. Dopamine “autoreceptors”: pharmacological characterization by microionto- phoretic single cell recording studies. Naunyn-Schmiedeberg’s


Arch. Pharmacol. 297: 1-7, 1977. 4. AGID, Y. , P. GUYENET, J. GLOWINSKI, J. C. BEAUJOUAN, AND

F. JAVOY. Inhibitory influence of the nigrostriatal dopamine system on the striatal cholinergic neurons in the rat. Brain Res. 86: 488-492, 1975.

~ ~ . A G I D , Y., F. JAVOY, AND J. GLOWINSKI. Hyperactivity of remaining dopaminergic neurones after partial destruction of the nigro-striatal dopaminergic system in the rat. Nature London New Biol. 245: 150-151, 1973.

5. AJIKA, K., AND T . HOKFELT. Ultrastructural identification of catecholamine neurones in the hypothalamic periventricular- arcuate nucleus-median eminence complex with special reference to quantitative aspects. Brain Res. 57: 97-117, 1973.

6. AKAGI, K., A N D E. W. POWELL. Differential projection of habenular nuclei. J . Comp. Neurol. 132: 264-274, 1968.

7. ALBANESE, A,, AND M. BENTIVOGLIO. The organization of dopaminergic and non-dopaminergic mesencephalo-cortical neurons in the rat. Brain Res. 238: 421-425, 1982.

7a.ALBANESE, A,, AND D. MINCIACCHI. Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. J. Comp. Neurol. 216: 406-420, 1983.

8. AMARAL, D. G., AND H. M. SINNAMON. The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog. Neu- robiol. 9: 147-196, 1977.

9. ANDEN, N.-E., A. CARLSSON, A. DAHLSTROM, K. FUXE, N.A. HILLARP, A N D K. LARSSON. Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci. 3: 523-530, 1964.

10. ANDEN, N.-E., A. DAHLSTROM, K. FUXE, AND K. LARSSON. Mapping out of catecholamine and 5-hydroxytryptamine neurons innervating the telencephalon and diencephalon. Life Sci. 4: 1275-1279,1965.

11. ANDEN, N.-E., A. DAHLSTROM, K. FUXE, K. LARSSON, L. OLSON, AND U. UNGERSTEDT. Ascending monoamine neurons to the telencephalon and diencephalon. Acta Physiol. Scand. 67: 313-326, 1966.

12. ANDEN, N.-E., K. FUXE, B. HAMBERGER, AND T . HOKFELT. A quantitative study on the nigro-striatal dopamine neuron system in the rat. Acta Physiol. Scand. 67: 306-312, 1966.

13. ANDEN, N.-E., K. FUXE, A N D U. UNGERSTEDT. Monoamine pathways to the cerebellum and cerebral cortex. Experientia 23: 838-842, 1967.

14. ANDERSEN, H., &. BRAESTRUP, AND A. RANDRUP. Apamor- phine-induced stereotyped biting in the tortoise in relation to dopaminergic mechanisms. Brain Behau. Euol. 11: 365-373, 1975.

15. ANDRADE, R., AND G. K. AGHAJANIAN. Single cell activity in the noradrenergic A-5 region: responses to drugs and peripheral manipulations of blood pressure. Brain Res. 242: 125-135, 1982.

15a.ARLUISON, M., Y . AGID, AND F. JAVOY. Dopaminergic nerve endings in the neostriatum of the rat. I. Identification hy intracerebral injections of 5-hydroxydopamine. Neuroscience 3: 657-673, 1978.

16. ARNOLD, P. S., R. J . RACINE, A N D R. A. WISE. Effects of atropine, reserpine, 6-hydroxydopamine and handling on seizure development in the rat. Exp. Neural. 4 0 457-470, 1973.

16a.ARvIDsSoN, J., I. JURNA, AND G. STEG. Striatal and spinal lesions eliminating reserpine and physostigmine rigidity. Life Sci. 6: 2017-2020, 1967.

17. ASSAF, S. Y., A N D J. J . MILLER. Excitatory action of the mesolimbic dopamine system on septa1 neurones. Brain Res. 129: 353-360, 1977.

18. ASTON-JONES, G., AND F. E. BLOOM. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats an- ticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1: 876-886, 1981.

19. ASTON-JONES, G., AND F. E. BLOOM. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J . Neurosci. 1: 887-890, 1981.

lga.AZMITIA, E. c . , A. M. BUCHAN, AND J. H. WILLIAMS. Collat- eral sprouting of hippocampal 5-HT axons: structural and functional restoration. Nature London 274: 374-376, 1978.

lgb.BARBEAU, A. Biology of the striatum. In: Biology of Brain Dysfunction, edited by G. E. Gaull. New York: Plenum, 1983, vol. 2, p. 333-350.

20. BASBAUM, A. I., AND H. L. FIELDS. The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: further studies on the anatomy of pain modulation. J. Comp. Neurol. 187: 513-532, 1979.

21. BATTISTA, A., K. FUXE, M. GOLDSTEIN, AND M. OGAWA. Mapping of central monoamine neurons in the monkey. Ex- perientia 28: 688-690, 1972.

22. BAUMGARTEN, H. G. Biogenic monoamines in the cyclostome and lower vertebrate brain. Prog. Histochem. Cytochem. 4: 1- 90, 1972.

23. BAUMGARTEN, H. G., A. BJORKLUND, A. F. HOLSTEIN, AND A. NOBIN. Organization and ultrastructural identification of the catecholamine nerve terminals in the neural lobe and pars intermedia of the rat pituitary. Z. Zellforsch. Mikrosk. Anat. 126: 483-517, 1972.

24. BAUMGARTEN, H. G., AND H. BRAAK. Catecholamine im Hy- pothalamus von Goldfisch (Carassius auratus). 2. Zellforsch. Mikrosk. Anat. 80: 246-263, 1967.

25. BAUMCARTEN, H. G., AND H. BRAAK. Catecholamine im Ge- hirn der Eidechse (Lacerta uiridis und Lacerta muralis). 2. Zellforsch. Mikrosk. Anat. 86: 574-602, 1968.

26. BEAUDET, A,, AND L. DESCARRIES. The monoamine innervation of rat cerebral cortex: synaptic and nonsynaptic axon terminals. Neuroscience 3: 851-860, 1978.

27. BECKSTEAD, R. M. Convergent thalamic and mesencephalic projections to the anterior medial cortex in the rat. J . Comp. Neurol. 166: 403-416, 1976.

28. BECKSTEAD, R. M. Afferent connections of the entorhinal area in the rat as demonstrated by retrograde cell-labeling with horseradish peroxidase. Brain Res. 152: 249-264, 1978.

29. BECKSTEAD, R. M. Convergent prefrontal and nigral projections to the striatum of the rat. Neurosci. Lett. 12: 59-64, 1979.

29a.BECKSTEAD. R. M. A reciprocal axonal connection between the subthalamic nucleus and the neostriatum in the cat. Brain Res. 275: 137-142, 1983.

30. BECKSTEAD, R. M., V. B. DOMESICK, AND W. J. H. NAUTA. Efferent connections of the substantia nigra and ventral tegmental area in the rat. Bruin Res. 175: 191-217, 1979.

31. BEDARD, P., L. LACHORELLE, A. PARENT, AND L. J. POIRIER. The nigrostriatal pathway: a correlative study based on neuroanatomical and neurochemical criteria in the cat and the monkey. Exp. Neurol. 25: 365-377, 1969.

31a.BEEBE, B. K., K. MBLLGARD, A. BJORKLUND, AND u. STE- NEVI. Ultrastructural evidence of synaptogenesis in the adult rat dentate gyrus from brain stem implants. Brain Res. 167:

%lb.BENFREY, M., AND A. J. AGUAYO. Extensive elongation of axons from rat brain into peripheral nerve grafts. Nature

32. BERGER, B., J. NGUYEN-LEGROS, AND A. M. THIERRY. Dem- onstration of horseradish peroxidase and fluorescent catecholamines in the same neuron. Neurosci. Lett. 9: 297-302, 1978.

33. BERGER, B., J. P. TASSIN, B. BLANC, M. A. MOYNE, AND A. M. THIERRY. Histochemical confirmation for dopaminergic innervation of the rat cerebral cortex after destruction of the noradrenergic ascending pathways. Brain Res. 81: 332-337, 1974.

34. BERGER, B., A. M. THIERRY, J. P. TASSIN, AND M. A. MOYNE. Dopaminergic innervation of the rat prefrontal cortex: a fluorescence histochemical study. Brain Res. 106: 133-145, 1976.

35. BERK, M. L., AND J. A. FINKELSTEIN. Afferent projections to the preoptic area and hypothalamic regions in the rat brain. Neuroscience 6: 1601-1624, 1981.

36. BERTLER, A,, B. FALCK, C. G. GOTTFRIES, L. LJUNGGREN, A N D E. ROSENGREN. Some observations on adrenergic connections between mesencephalon and cerebral hemispheres.

391-395, 1978.

London 296: 150-152, 1982.


Acta Pharmacol. Toxicol. 21: 283-289, 1964. 36a.BERTLER, A., AND E. ROSENGREN. Occurrence and distribu-

tion of catecholamines in brain. Acta Physiol. Scand. 47: 3507 361, 1959.

37. BIGL, V., N. J . WOOLF, AND L. L. BUTCHER. Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis. Brain Res. Bull. 8:

38. BISCHOFF, S., B. SCATTON, AND J . KORF. Biochemical evidence for a transmitter role of dopamine in the rat hippocampus. Brain Res. 165: 161-165, 1979.

38a.Bls~oP, G. A., H. T. CHANG, AND S. T. KITAI. Morphological and physiological properties of neostriatum neurons: an intracellular horseradish peroxidase study in the rat. Neuroscience 7: 179-191, 1982.

39. BJORKLUND, A. Organization of catecholamine neurons involved in endocrine functions. In: Biologie cellulaire des pro- cessus neurosecretoires hypothalamiques, edited by J. D. Vin- cent and C. Kordon. Paris: CNRS, 1978, no. 280, p. 81-100.

E. ROSENGREN. Recovery of brain noradrenaline after 5,7- dihydroxytryptamine-induced axonal lesions in the rat. Cell Tissue Res. 161: 145-155, 1975.

40. BJORKLUND, A., I. DIVAC, AND 0. LINDVALL. Regional distribution of catecholamines in monkey cerebral cortex, evidence for a dopaminergic innervation of the primate prefrontal cortex. Neurosci. Lett. 7: 115-119, 1978.

AND S. D. IVERSEN. Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 199: 307-333, 1980.

41. BJORKLUND, A., B. FALCK, F. HROMEK, C. OWMAN, AND K. A. WEST. Identification and terminal distribution of the tubero-hypophyseal monoamine fibre systems in the rat by means of stereotaxic and microspectrofluorimetric techniques. Brain Res. 17: 1-23, 1970.

42. BJORKLUND, A., B. FALCK, A. NOBIN, AND u. STENEVI. Or- ganization of the dopamine and noradrenaline innervations of the median eminence-pituitary region in the rat. In: Neurose- cretion-The Final Neuroendocrine Pathway, edited by F. Knowles and L. Vollrath. New York: Springer-Verlag, 1974, p. 209-222. (6th Int. Symp. Neurosecretion, London, 1973.)

SVENDGAARD. Re-establishment of functional connections by regenerating central adrenergic and cholinergic axons. Nature London 253: 446-448, 1975.

Development and growth of axonal sprouts from noradrenaline and 5-hydroxtryptamine neurones in the rat spinal cord. Brain Res. 31: 21-33, 1971.

43. BJORKLUND, A., AND 0. LINDVALL. Dopamine in dendrites of substantia nigra neurons: suggestions for a role in dendritic terminals. Brain Res. 83: 531-537, 1975.

43a.BJORKLUND, A,, AND 0. LINDVALL. Regeneration of normal terminal innervation patterns by central noradrenergic neurons after 5,7-dihydroxytryptamine-induced axotomy in the rat. Brain Res. 171: 271-293, 1979.

43b.BJORKLUND, A,, AND 0. LINDVALL. Dopamine-containing systems in the CNS. In: Handbook of Chemical Neuroanatomy. Classical Transmitters in the CNS, edited by A. Bjorklund and T . Hokfelt. Amsterdam: Elsevier, 1984, vol. 2, pt. 1, p. 55-122.

44. BJORKLUND, A,, 0. LINDVALL, AND A. NOBIN. Evidence of an incertohypothalamic dopamine neurone system in the rat. Brain Res. 89: 29-42, 1975.

45. BJ~RKLUND, A., R. Y. MOORE, A. NOBIN, AND U. STENEVI. The organization of tubero-hypophyseal and reticulo-infundibular catecholamine neuron systems in the rat brain. Brain Res. 51: 171-191, 1973.

46. BJ~RKLUND, A,, AND A. NOBIN. Fluorescence histochemical and microspectrofluorometric mapping of dopamine and nor-

727-749,1982.

%a.BJORKLUND, A,, H. G. BAUMGARTEN, L. LACHENMAYER, AND

40a.BJORKLUND, A., s. B. DUNNETT, u. STENEVI, M. E. LEWIS,

42a.BJi)RKLIJND, A,, B. JOHANSSON, U. STENEVI, AND N.-A.

42b.BJbRKLUND, A., R. KATZMAN, u. STENEVI, AND K. A. WEST.

adrenaline cell groups in the rat diencephalon. Brain Res. 51:

47. BJORKLUND, A., M. SEGAL, AND u. STENEVI. Functional reinnervation of rat hippocampus by locus coeruleus implants. Brain Res. 170 409-426, 1979.

48. BJ~RKLUND, A., AND G. SKAGERBERG. Evidence for a major spinal cord projection from the diencephalic A l l dopamine cell group in the rat using transmitter-specific fluorescent retrograde tracing. Brain Res. 177: 170-175, 1979.

49. BJORKLUND, A., A N D G. SKAGERBERG. Descending monoaminergic projections to the spinal cord. In: Brain Stem Control of Spinal Mechanisms, edited by B. H. Sjolund and A. Bjork- lund. Amsterdam: Elsevier, 1982, p. 55-88. (Fernstrom Found. Ser., vol. 1.)

4%.BJORKLUND, A,, AND u. STENEVI. Growth of central catecholamine neurones into smooth muscle grafts in the rat mesencephalon. Brain Res. 31: 1-20, 1971.

49b.BJORKLUND, A., AND u. STENEVI. Reconstruction of brain circuitries by neural transplants. Trends Neurosci. 2: 301-306, 1979.

4%.BJORKLUND, A,, AND U. STENEVI. Regeneration of monoaminergic and cholinergic neurons in the mammalian central nervous system. Physiol. Reu. 59: 62-100, 1979.

~~~.BJORKLUND, A., AND u. STENEVI. Intracerebral neural implants: neuronal replacement and reconstruction of damaged circuitries. Annu. Reu. Neurosci. 7: 279-308, 1984.

50. BJORKLUND, A., U. STENEVI, S. B. DUNNETT, AND S. D. IVERSEN. Functional reactivation of the deafferented neostriatum by nigral transplants. Nature London 289: 497-499,1981.

50a.BJORKLUND, A., U. STENEVI, R. H. SCHMIDT, s. B. DUNNETT, AND F. H. GAGE. Intracerebral grafting of neuronal cell sus- pensions. 11. Survival and growth of nigral cells implanted in different brain sites. Acta Physiol. Scand. Suppl. 522: 9-18, 1983.

51. BLACKSTAD, T. W., K. FUXE, AND T. HOKFELT. Noradrena- line nerve terminals in the hippocampal region of the rat and the guinea pig. 2. Zellforsch. Mikrosk. Anat. 78: 463-473, 1967.

52. BLESSING, w . w . , AND J. P. CHALMERS. Direct projection of catecholamine (presumably dopamine)-containing neurons from hypothalamus to spinal cord. Neurosci. Lett. 11: 35-40, 1979.

53. BLESSING, W. W., P. FROST, AND J. B. FURNESS. Catechola- mine cell groups of the cat medulla oblongata. Brain Res. 192:

54. BLESSING, W. W., <J. B. FURNESS, M. COSTA, M. J . WEST, AND J . P. CHALMERS. Projection of ventrolateral medullary (Al) catecholamine neurons toward nucleus tractus solitarii. Cell Tissue Res. 220: 27-40, 1981.

55. BLESSING, W. W., A. K. GOODCHILD, R. A. L. DAMPNEY, AND J. P. CHALMERS. Cell groups in the lower brain stem of the rabbit projecting to the spinal cord, with special reference to catecholamine-containing neurons. Brain Res. 221: 35-55, 1981.

56. BLESSING, W. W., C. B. JAEGER, D. A. RUGGIERO, AND D. J . REIS. Hypothalamic projections of medullary catecholamine neurons in the rabbit: a combined catecholamine fluorescence and HRP transport study. Brain Res. Bull. 9: 279-286, 1982.

57. BLOOM, F. E. A discussion of control of brain serotonin and norepinephrine by specific neural systems. In: Advances in Pharmacology, edited by S. Garattini and P. A. Shore. New York: Academic, 1968, vol. 6A, p. 207-209.

58. BLOOM, F. E., AND E. L. F. BATTENBERG. A rapid, simple and more sensitive method for the demonstration of central catecholamine-containing neurons and axons by glyoxylic acid induced fluorescence. 11. A detailed description of methodology. J. Histochem. Cytochem. 24: 561-571, 1976.

59. BLOOM, F. E., B. J. HOFFER, AND G. R. SIGGINS. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. I. Localization of the fibers and their synapses. Brain Res. 25: 501-521, 1971.

59a.Bo~AM, J. P., J . F. POWELL, s. TOTTERDELL, AND A. D. SMITH. The proportion of neurons in the rat neostriatum that

193-205,1973.

69-75, 1980.


project to the substantia nigra demonstrated using horseradish peroxidase conjugated with wheatgerm agglutinin. Brain Res. 220 339-343, 1981.

60. BRAAK, H. Biogene Amine im Gehirn vom Frosch (Rana esculenta). Z. Zellforsch. Mikrosk. Anat. 106: 269-308, 1970.

61. BRAAK, H. On the pars cerebellaris loci coerulei within the cerebellum of man. Cell Tissue Res. 160: 279-282, 1975.

62. BRODIE, B. B., AND E. COSTA. Some current views on brain monoamines. Psychopharmacol. Seru. Cent. Bull. 2: 1-25,1962.

63. BROWN, L. L., M. H. MAKMAN, L. I. WOLFSON, B. DVORKIN, C. WARNER, AND R. KATZMAN. A direct role of dopamine in the rat subthalamic nucleus and an adjacent intrapeduncular area. Science 206: 1416-1418,1979,

64. BROWN, L. L., AND L. I. WOLFSON. A dopamine-sensitive striatal efferent system mapped with ['4C]deoxyglucose in the rat. Brain Res. 261: 213-229, 1983.

64a.BRowN, M. C., R. L. HOLLAND, AND W. G. HOPKINS. Motor nerve sprouting. Annu. Rev. Neurosci. 4: 17-42, 1981.

65. BROWN, R. M., A. M. CRANE, AND P. S. GOLDMAN. Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates. Brain Res. 168: 133-150, 1979.

66. BROWN, R. M., A N D P. s. GOLDMAN. Catecholamines in neocortex of rhesus monkeys: regional distribution and ontogenetic development. Brain Res. 124: 576-580, 1977.

67. BROWNSTEIN, M. J., M. PALKOVITS, M. L. TAPPAZ, J. M. SAAVEDRA, A N D J . S. KIZER. Effect of surgical isolation of the hypothalamus on its neurotransmitter content. Brain Res. 117: 287-295, 1976.

67a.BRu~N, G. W. Neurotransmitters in Huntington's chorea-a clinician's view. In: Progress in Brain Research. Chemical Transmission in the Brain, edited by R. M. Buijs, P. Pevbt, and D. F. Swaab. Amsterdam: Elsevier, 1982, vol. 55, p. 445- 464.

67b.Bui~s, R. M., M. GEFFARD, c . W. POOL, AND M. D. HOORNE- MAN. The dopaminergic innervation of the supraoptic and paraventricular nucleus. A light and electron microscopical study. Brain Res. 323: 65-72, 1984.

68. BUNNEY, B. S., J. R. WALTERS, R. H. ROTH, AND G. AGHA- JANIAN. Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J. Pharmacol. Exp. Ther. 185: 560-571, 1973.

69. BURGI, S., AND V. M. BUCHER. Markhaltige Faseruerbindun- gen im Hirnstamm der Katze. Berlin: Springer-Verlag, 1960.

amine metabolism during bicuculline-induced epileptic seizures in the rat. Brain Res. 157: 295-302, 1978.

72. CALLAGHAN, D. A., AND W. S. SCHWARK. Involvement of catecholamines in kindled amygdaloid convulsions in the rat. Neuropharmacology 18: 541-545, 1979.

72a.CARLSSON, A. Dopaminergic autoreceptors. In: Chemical Took in Catecholamine Research, edited by 0. Almgren, A. Carlsson, and J. Engel. Amsterdam: North-Holland, 1975, vol. 2, p. 219- 225.

73. CARLSSON, A., B. FALCK, K. FUXE, A N D N.-A. HILLARP. Cellular localization of monoamines in the spinal cord. Act0 Physiol. Scand. 60: 112-119, 1963.

74. CARLSSON, A,, B. FALCK, AND N.-A. HILLARP. Cellular localization of brain monoamines. Acta Physiol. Scand. Suppl. 196:

75. CARLSSON, A., T. HOLMIN, M. LINDQUIST, AND B. K. SIESJO. Effect of hypercapnia and hypocapnia on tryptophan and tyrosine hydroxylation in rat brain. Acta Physiol. Scand. 99:

75a.CARPENTER, M. B., R. R. BATTON 111, s. c. CARLETON, AND J. T . KELLER. Interconnections and organization of pallidal and subthalamic nucleus neurons in the monkey. J. Comp. Neurol. 197: 579-603, 1981.

75b.CARPENTER, M. B., s. c. CARLETON, J. T. KELLER, AND P. CONTE. Connections of the subthalamic nucleus in the monkey. Brain Res. 224: 12-29, 1981.

71. CALDERINI, G., A. CARLSSON, AND C.-H. NORDSTROM. Mono-

1-27,1962.

503-509,1977.

75c.CARPENTER, M. B., AND N. L. STROMINGER. Efferent fiber projections of the subthalamic nucleus in the rhesus monkey. A comparison of the efferent projections of the subthalamic nucleus, substantia nigra and globus pallidus. Am. J. Anat. 121: 47-72, 1967.

Analysis of choreoid hyperkinesia in the rhesus monkey. Sur- gical and pharmacological analysis of hyperkinesia resulting from lesions of the subthalamic nucleus of Luys. J. Comp. Neurol. 92: 293-331, 1950.

76. CARTER, D. A,, AND H. c. FIBIGER. Ascending projections of presumed dopamine-containing neurons in the ventral tegmentum of the rat as demonstrated by horseradish peroxidase. Neuroscience 2: 569-576, 1977.

77. CEDARBAUM, J. M., AND G . K. AGHAJANIAN. Activation of locus coemleus neurons by peripheral stimuli: modulation by a collateral inhibitory mechanism. Life Sci. 23: 1383-1392, 1978.

77a.CEDARBAUM, J. M., AND G. K. AGHAJANIAN. Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J. Comp. Neurol. 178: 1-16, 1978.

77b.CHAN-PALAY, v., L. ZABORSZKY, c. KOHLER, M. GOLDSTEIN, AND S. L. PALAY. Distribution of tyrosine hydroxylase-immunoreactive neurons in the hypothalamus of rats. J. Comp. Neurol. 227: 467-496, 1984.

78. CHERAMY, A,, V. LEVIEL, AND J . GLOWINSKI. Dendritic release of dopamine in the substantia nigra. AVature London 289: 537-542, 1981.

79. CHERAMY, A,, A. NIEOULLON, R. MICHELOT, AND J. GLOW- INSKI. Effects of intranigral application of dopamine and substance P on the in vivo release of newly synthesized I3H]- dopamine in the ipsilateral caudate nucleus of the cat. Neu- rosci. Lett. 4: 105-109, 1977.

79a.CHESSELET, M.-F., AND T. D. REISINE. Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei. J . Neurosci. 3: 232-236, 1983.

80. CHIODO, L. A,, S. M. ANTELMAN, A. R. CAGGIULA, AND C. G. LINEBERRY. Sensory stimuli alter the discharge rate of dopamine (DA) neurons: evidence for two functional types of DA cells in the substantia nigra. Brain Res. 189: 544-549, 1980.

81. CHU, N.-S., A N D F. E. BLOOM. The catecholamine-containing neurons in the cat dorsolateral pontine tegmentum: distribution of the cell bodies and some axonal projections. Brain Res. 66: 1-21, 1974.

82. CLARK, T. K. The locus coeruleus in behavior regulation: evidence for behavior-specific versus general involvement. Be- hau. Neural Biol. 25: 271-300, 1979.

83. CLAVIER, R. M. Afferent projections to the self-stimulation regions of the dorsal pons, including the locus coeruleus, in the rat as demonstrated by the horseradish peroxidase technique. Brain Res. Bull. 4: 497-504, 1979.

84. COLLIER, T. J., AND A. ROUTTENBERG. Entorhinal cortex: catecholamine fluorescence and Nissl staining of identical sections. SOC. Neurosci. Abstr. 2: 43, 1976.

85. COMMISSIONG, J. W. Evidence that the noradrenergic coeru- lospinal projection decussates a t the spinal level. Brain Res.

86. COMMISSIONG, J. w. Spinal monoaminergic systems: an aspect of somatic motor function. Federation Proc. 40: 2771- 2777, 1981.

87. COMMISSIONG, J. w., c . L. GALL[, AND N. 1%. NEFF. Differ- entiation of dopaminergic and noradrenergic neurons in rat spinal cord. J. Neurochem. 30: 1095-1099, 1978.

88. COMMISSIONG, J. W., S. GENTLEMAN, AND N. H. NEFF. Spinal cord dopaminergic neurons: evidence for an uncrossed nigrospinal pathway. Neuropharmacology 18 565-568, 1979.

89. COMMISSIONG, J. w., s. 0. HELLSTROM, AND N. H. NEFF. A new projection from locus coeruleus to the spinal ventral columns: histochemical and biochemical evidence. Brain Res.

90. COMMISSIONG, J. w . , AND N. H. NEFF. Current status of

75d.CARPENTER, M. B., J. R. WHITTIER, AND F. A. METTLER.

212: 145-151, 1981.

148: 207-213, 1978.


dopamine in the mammalian spinal cord. Biochem. Pharmacol.

91. CONRAD, L. C. A., AND D. W. PFAFF. Autoradiographic tracing of nucleus accumbens efferents in the rat. Brain Res. 113: 589- 596, 1976.

92. COOLS, A. R., AND J. VAN DEN BERCKEN. Cerebral organization of behavior and neostriatal function. In: Psychobiology of the Striatum, edited by A. R. Cools, A. H. M. Lohmann, and <J. H. L. van den Bercken. Amsterdam: Elsevier/North-Hol- land, 1977, p. 119-140.

93. CORCORAN, M. E., H. C. FIBIGER, J . A. MCCAUGHRAN, AND ,J. A. WADA. Potentiation of amygdaloid kindling and Metra- zol-induced seizures by 6-hydroxydopamine in rats. Exp. Neu- rol. 45: 118-133, 1974.

94. CORCORAN, M. E., AND S. T. MASON. Role of forebrain catecholamines in amygdaloid kindling. Brain Res. 190 473- 484,1980.

95. COSTA, E., AND N. H. NEFF. Isotopic and non-isotopic measurements of the rate of catecholamine biosynthesis. In: Bio- chemistry and Pharmacology of the Basal Ganglia, edited by E. Costa, L. J. Cotb, and M. D. Yahr. New York: Raven, 1966, p.

%a.COTMAN, c. w., AND G. s. LYNCH. Reactive synaptogenesis in the adult nervous system. In: Neuronal Recognition, edited by S. H. Barondes. London: Chapman & Hall, 1976, p. 69- 108.

96. CROW, T. J. Catecholamine-containing neurons and electrical self-stimulation. 2. A theoretical interpretation and some psy- chiatric implications. Psychol. Med. 3: 66-73, 1973.

97. CRUTCHER, K. A., AND A. 0. HUMBERTSON, JR. The organization of monoamine neurons within the brainstem of the North American opossum (Didelphis virginiana). J. Comp. Neurol. 179: 195-222, 1978.

98. CUELLO, A. C., A. s. HORN, A. v. P. MACKAY, AND L. L. IVERSEN. Catecholamines in the median eminence: new evidence for a major noradrenergic input. Nature London 243: 465-467, 1973.

99. CUELLO, A. C., A N D G. PAXINOS. Evidence for a long Leu- enkephalin striopallidal pathway in rat brain. Nature London

100. DAHLGREN, N., 0. LINDVALL, T. SAKABE, U. STENEVI, AND R. K. SIESJO. Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system. Brain Res. 209: 11-23, 1981.

101. DAHLSTROM, A. The Intraneuronal Distribution of Noradren- aline and the Transport and Life-Span of Amine Storage Granules in the Sympathetic Adrenergic Neuron. Stockholm: Karolinska Inst., 1966. MD thesis.

102. DAHLSTROM, A,, AND K. FUXE. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. Suppl. 232: 1-55, 1964.

103. DAHLSTROM, A,, AND K. FUXE. Evidence for the existence of monoamine neurons in the central nervous system. 11. Exper- imentally induced changes in the intraneuronal amine levels of bulbospinal neuron systems. Acta Physiol. Scand. Suppl. 247: 1-36, 1965,

104. DAHLSTROM, A., K. FUXE, L. OLSON, AND U. UNGERSTEDT. On the distribution and possible function of monoamine nerve terminals in the olfactory bulb of the rabbit. Life Sci. 4: 2071- 2074, 1965.

105. DAILEY, J. W., H. D. BATTARBEE, AND P. C. JOBE. Enzyme activities in the central nervous system of the epilepsy-prone rat. Brain Res. 231: 225-230, 1982.

106. DAY, T. A., W. BLESSING, AND J. 0. WILLOUGHBY. Noradre- nergic and dopaminergic projections to the medial preoptic area of the rat. A combined horseradish peroxidase/catecholamine fluorescence study. Brain Res. 193: 543-548, 1980.

107. DE LA TORRE, J . C. Local cerebral blood flow following stimulation of locus coeruleus in monkeys and rats. In: Neu- rogenic Control of the Brain Circulation, edited by C. Owman

28: 1569-1573, 1979.

141-155.

271: 178-180,1978.

and L. Edvinsson. Oxford, UK: Pergamon, 1977, p. 443-454. (Wenner-Gren Center Int. Symp. Ser., vol. 30.)

108. DEL FIACCO, M., G. PAXINOS, AND A. C. CUELLO. Neostriatal enkephalin-immunoreactive neurons project to the globus pallidus. Brain Res. 231: 1-17, 1982.

108a,DELONG, M. R., AND A. P. GEORGOPOULOS. Motor functions of the basal ganglia. In: Handbook of Physiology. The Nervous System. Motor Control, edited by V. Brooks. Bethesda, MD: Am. Physiol. SOC., 1981, sect. 1, vol. 11, pt. 2, chapt. 21, p. 1017-1061.

109. DEMIRJIAN, C., R. GROSSMAN, R. MEYER, AND R. KATZMAN. The catecholamine pontine cellular groups locus coeruleus, A4, subcoeruleus in the primate Cebus apella. Brain Res. 115: 395-411, 1976.

110. DENIAU, J. M., G. CHEVALIER, AND J. FEGER. Electrophysio- logical study of the nigro-tectal pathway in the rat. Neurosci. Lett. 1 0 215-220,1978,

111. DENIAU, J . M., J. FEGER, AND C. LEGUYADER. Striatal evoked inhibition of identified nigro-thalamic neurons. Brain Res. 104: 152-156, 1976.

Evidence for branched subthalamic nucleus projections to substantia nigra, entopeduncular nucleus and globus pallidus. Neurosci. Lett. 9: 117-121, 1978.

112. DENIAU, J. M., A. M. THIERRY, AND J. FEGER. Electrophysi- ological identification of mesencephalic ventromedial tegmental (VMT) neurons projecting to the frontal cortex, septum and nucleus accumbens. Brain Res. 189: 315-326, 1980.

113. DE OLMOS, J., H. HARDY, AND L. HEIMER. The afferent connections of the main and the accessory olfactory bulb formations in the rat: an experimental HRP-study. J. Comp. Neurol. 181: 213-244, 1978.

113a.DESCARRIES, L., 0. BOSLER, F. BERTHELET, AND M. H. DES ROSIERS. Dopaminergic nerve endings visualized by high- resolution autoradiography in adult rat neostriatum. Nature London 284: 620-622,1980.

113b.DESCARRIES, L., 0. ROSLER, F. BERTHELET, AND M. H. DES ROSIERS. Innervation dopaminergique du neostriatum: nou- velle possibilitb d’investigation radioautographique. J. Physiol. Paris 77: 53-61, 1981.

114. DESCARRIES, L., AND G. SAUCIER. Disappearance of the locus coeruleus in the rat after intraventricular 6-hydroxydopamine. Brain Res. 37: 310-316, 1972.

115. DI CHIARA, G., M. MORELLI, A. IMPERATO, AND M. L. P O R - CEDDU. Substantia nigra as an efferent station for dopaminergic behavioural syndromes arising in the striatum. In: Apomorphine and Other Dopaminomimetics-Basic Pharma- cology, edited by G. L. Gessa and G. U. Corsini. New York: Raven, 1981, vol. 1, p. 41-64.

116. DI CHIARA, G., M. MORELLI, A. IMPERATO, AND M. L. POR- CEDDU. A re-evaluation of the role of superior colliculus in turning behaviour. Brain Res. 237: 61-77, 1982.

117. DIVAC, I. Neostriatum and functions of prefrontal cortex. Acta Neurobiol. Exp. 32: 461-477, 1972.

SINGHAM. Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons to the neocortex in three species. J. Comp. Neurol. 180 59-72, 1978.

119. DIVAC, I., F. FONNUM, AND J. STORM-MATHISEN. High affn- ity uptake of glutamate in terminals of corticostriatal axons. Nature London 266: 377-378, 1977.

SINGHAM. Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons to the neocortex in three species (Abstract). Exp. Brain Res. 23: 58, 1975.

121. DIVAC, I., H. J. MARKOWITSCH, AND M. PRITZEL. Behavioral and anatomical consequences of small intrastriatal injections of kainic acid in the rat. Brain Res. 151: 523-532, 1978.

12la.D1v~C, I., AND R. G. E. OBERG. Current conceptions of neostriatal functions: history and evaluation. In: The Neostriatum,

Illa.DENIAU, J. M., c . HAMMOND, G. CHEVALIER, AND J. FEGER.

118. DIVAC, I., A. BJORKLUND, 0. LINDVALL, AND R. E. PAS-

120. DIVAC, I., 0. LINDVALL, A. BJORKLUND, AND R. E. PAS-


edited by I. Divac and R. G. E. Oberg. Oxford, UK: Pergamon,

122. DOMESICK, V. B., R. M. BECKSTEAD, AND W. J . H. NAUTA. Some ascending and descending projections of the substantia nigra and ventral tegmental area in the rat. Soc. Neurosci. Abstr. 6: 61, 1976.

123. DOURISH, C. T., A N D R. S. G. JONES. Dopamine agonist- induced restoration of drinking in response to hypertonic saline in adipsic dopamine denervated rats. Brain Res. Bull. 8:

124. DRAY, A. The striatum and substantia nigra: a commentary on their relationship. Neuroscience 4: 1407-1439, 1979.

125. DRAY, A. The physiology and pharmacology of mammalian basal ganglia. Prog. Neurobiol. 14: 221-335, 1980.

126. DRAY, A., T . J. GONYE, A N D N. R. OAKLEY. Effects of a- flupenthixol on dopamine and 5-hydroxytryptamine responses of substantia nigra neurones. Neuropharmacology 15: 793-796, 1976.

27. DuBE, L., AND A. PARENT. The monoamine-containing neurons in avian brain. I. A study of the brain stem of the chicken (Gallus domesticus) by means of fluorescence and acetylcholinesterase histochemistry. J . Comp. Neurol. 196: 695-708, 1981.

27a.DUNNETT, s. B. Functional Organization of the Neostriatum. Cambridge, UK: Cambridge Univ., 1981. PhD thesis.

28. DUNNETT, S. B., AND A. BJORKLUND. Conditioned turning in rats: dopaminergic involvement in the initiation of movement rather than the movement itself. Neurosci. Lett. 41: 173-178, 1983.

128a.DUNNETT, s. B., A. BJORKLUND, AND u. STENEVI. Dopamine- rich transplants in experimental parkinsonism. Trends Neu- rosci. 6: 266-270, 1983.

129. DUNNETT, S. B., A. BJORKLUND, U. STENEVI, A N D s. D. IVERSEN. CNS transplantation: structural and functional recovery from brain damage. In: Progress in Brain Research. Chemical Transmission in the Brain, edited by R. M. Buijs, P. Pkvet, and D. F. Swaab. Amsterdam: Elsevier, 1982, vol. 55, p.

1979, p. 215-230.

375-379, 1982.

431-443. 129a.DUNNETT, s. B., F. H. GAGE, A. BJORKLUND, u . STENEVI,

W. C. LOW, A N D S. D. IVERSEN. Hippocampal deafferentation: transplant-derived reinnervation and functional recovery. Scand. J. Physiol. Suppl. 1: 104-111, 1982.

130. DUNNETT, S. B., AND s. D. IVERSEN. Regulatory impairments following selective kainic acid lesions of the neostriatum. Behau. Brain. Res. 1: 497-506, 1980.

131. DUNNETT, s. B., AND s. D. IVERSEN. Learning impairments following selective kainic acid-induced lesions within the neostriatum of rats. Behau. Brain Res. 2: 189-209, 1981.

13la.EDDs. M. W. Collateral nerve regeneration. Q. Reu. Biol. 28: 260-276, 1953.

MAN. Are brain vessels innervated also by central (non-sympathetic) adrenergic neurones? Brain Res. 63: 496-499, 1973.

133. EDWARDS, B. E. The deep cell layers of the superior colliculus: their reticular characteristics and structural organization. In: The Reticular Formation Reuisited, edited by J. A. Hobson and M. A. B. Brazier. New York: Raven, 1980, p. 193-205.

134. EHINGER, B. Adrenergic nerves to the eye and to related structures in man and in the cynomolgus monkey. Inuest. Ophthalmol. 5: 42-52, 1966.

135. EHINGER, B. Functional role of dopamine in the retina. In: Progress in Retinal Research, edited by N. N. Osborne and G. Chader. Oxford, UK: Pergamon, 1983, vol. 2, p. 213-232.

136. ELAM, M., T . YAO, P. THOREN, A N D T . H. SVENSSON. Hy- percapnia and hypoxia: chemoreceptor-mediated control of locus coeruleus neurons and splanchnic, sympathetic nerves. Brain Res. 222: 373-381, 1981.

137. EMSON, P. C., A. BJORKLUND, 0. LINDVALL, AND G. PAXINOS. Contributions of different afferent pathways to the catechol- arnine and 5-hydroxytryptamine-innervation of the amygdala: a neurochemical and histochemical study. Neuroscience 4: 1347-1357,1979.

132. EDVINSSON, L., M. LINDVALL, K. c . NIELSEN, AND c . OW-

138. EMSON, P. C., AND G. F. KOOB. The origin and distribution of dopamine-containing afferents to the rat frontal cortex. Brain Res. 142: 249-267, 1978.

139. ENGEL, J., JR., AND N. s. SHARPLESS. Long-lasting depletion of dopamine in the rat amygdala induced by kindling stimulation. Brain Res. 136: 381-386, 1977.

140. FAHN, S. Regional distribution studies of GABA and other putative neurotransmitters and their enzymes. In: GABA in Neruous System Function, edited by E. Roberts, T . N. Chase, and D. B. Tower. New York: Raven, 1976, p. 169-186.

141. FAIERS, A. A,, AND G. J. MOGENSON. Electrophysiological identification of neurons in the locus coeruleus. Exp. Neurol. 53: 254-266, 1976.

142. FALCK, B., L. LJUNGGREN, AND L. NORDGREN. Diencephalic catecholamines in chick and pigeon. Life Sci. 8: 889-893, 1969.

143. FALLON, J. H., D. A. KOZIELL, AND R. Y. MOORE. Catechol- amine innervation of the basal forebrain. II. Amygdala, suprarhinal cortex and entorhinal cortex. J. Comp. Neurol. 180:

144. FALLON, J . H., AND s. E. LOUGHLIN. Monoamine innervation of the forebrain: collateralization. Brain Res. Bull. 9 295-307, 1982.

145. FALLON, J . H., A N D R. Y. MOORE. Catecholamine innervation of the basal forebrain. III. Olfactory bulb, anterior olfactory nuclei, olfactory tubercle and piriform cortex. J . Cump. Neurol. 180: 533-544, 1978.

46. FALLON, J . H., AND R. Y. MOORE. Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J. Comp. Neu- rol. 180 545-580, 1978.

47. FALLON, J. H., J. N. RILEY, A N D R. Y. MOORE. Substantia nigra dopamine neurons: separate populations project to neostriatum and allocortex. Neurosci. Lett. 7: 157-162, 1978.

48. FALLON, J. H., J . N. RILEY, J. C. SIPE, A N D R. Y. MOORE. The islands of Calleja: organization and connections. J . Comp. Neurol. 181: 375-396, 1978.

149. FASS, B., A N D L. L. BUTCHER. Evidence for a crossed nigrostriatal pathway in rats. Neurosci. Lett. 22: 109-113, 1981.

150. FELTEN, D. L., A. LATIES, A N D M. CARPENTER. Monoamine- containing cell bodies in the squirrel monkey brain. Am. J. Anat. 139: 153-166, 1974.

151. FELTEN, D. L., A N D d. R. SLADEK, JR. Monoamine distribution in primate brain. V. Monoaminergic nuclei: anatomy, pathways, and local organization. Brain Res. Bull. 9: 253-254,1982.

152. FERRENDELLI, J. A,, A. c. BLANK, AND R. A. GROSS. Rela- tionships between seizure activity and cyclic nucleotide levels in brain. Brain Res. 200: 93-103, 1980.

153. FERRENDELLI, J. A,, AND D. A. KINSCHERF. cyclic nucleotides in epileptic brain: effects of pentylenetetrazol on regional cyclic AMP and cyclic GMP levels in vivo. Epilepsia 18: 525- 530, 1977.

154. FIBIGER, H. C. The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Res.

155. FIBIGER, H. C., R. c . PUDRITZ, P. L. MCGEER, AND E. G. MCGEER. Axonal transport in nigrostriatal and nigrothalamic neurons: effects of medial forebrain bundle lesions and 6- hydroxydopamine. J. Neurochem. 19: 1697-1708, 1972.

156. FINK, J. S., AND G. P. SMITH. Mesolimbicortical dopamine terminal fields are necessary for normal locomotor and inves- tigatory exploration in rats. Brain Res. 199: 359-384, 1980.

157. FLEETWOOD-WALKER, S. M., A N D J . H. COOTE. The contribution of brain stem catecholamine cell groups to the innervation of the sympathetic lateral cell column. Brain Res. 205:

158. FLEETWOOD-WALKER, S. M., A N D J . H. COOTE. Contribution of noradrenaline-, dopamine- and adrenaline-containing axons to the innervation of different regions of the spinal cord of the cat. Brain Res. 206: 95-106, 1981.

159. FOLBERGROVA, J. cyclic 3’,5’-adenosine monophosphate in mouse cerebral cortex during homocysteine convulsions and

509-532, 1978.

R ~ u . 4: 327-388, 1982.

141-155, 1981.


their prevention by sodium phenobarbital. Brain Res. 92: 165- 169, 1975.

160. FOLBERGROVA, J., M. INGVAR, AND B. K. SIESJO. Metabolic changes in cerebral cortex, hippocampus, and cerebellum during sustained bicuculline-induced seizures. J. Neurochem. 37:

161. FONNUM, F., AND J. STORM-MATHISEN. Localization of GA- BAergic neurons in the CNS. In: Handbook of Psychophar- macology. Chemical Pathways in the Brain, edited by L. L. Iversen, S. D. Iverson, and S. H. Snyder. New York: Plenum,

162. FOOTE, S., G . ASTON-JONES, AND F. E. BLOOM. Impulse activity of locus coeruleus neurons in awake rats and squirrel monkeys is a function of sensory stimulation and arousal. Proc. Natl. Acad. Sci. USA 77: 3033-3037, 1980.

163. FOOTE, S., AND F. E. BLOOM. Activity of norepinephrine- containing locus coeruleus neurons in the unanesthetized squirrel monkey. In: Catecholamines: Basic and Clinical Fron- tiers, edited by E. Usdin, I. Kopin, and J. Barchas. New York: Pergamon, 1979, p. 625-627.

163a.FOOTE, s. L., F. E. BLOOM, AND G . ASTON-JONES. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol. Reu. 63: 844-914, 1983.

164. FORSSBERG, H., AND S. GRILLNER. The locomotion of the acute spinal cat injected with clonidine i.v. Brain Res. 50: 184- 186,1973.

165. FREEDMAN, R., B. HOFFER, D. WOODWARD, AND D. PURO. Interaction of norepinephrine with cerebellar activity evoked by mossy and climbing fibers. E5p. Neurol. 55: 269-288, 1977.

166. FREEDMAN, R., D. A. TAYLOR, A. SEIGER, L. OLSON, AND B. J. HOFFER. Seizures and related epileptiform activity in hippocampus transplanted to the anterior chamber of the eye: modulation by cholinergic and adrenergic input. Ann. Neurol. 6 281-295,1979.

67. FREMBERG, M., T. VAN VEEN, AND H. G . HARTWIG. Formal- dehyde-induced fluorescence in the telencephalon and diencephalon of the eel (Anguilla anguilla L.). A fluorescence- microscopic and microspectrofluorometric investigation with special reference to the innervation of the pituitary. Cell Tissue Res. 176: 1-22, 1977.

67a.FREUND, T. F., J. P. BOLAM, A. BJORKLUND, u. STENEVI, s. B. DUNNETT, AND A. D. SMITH. Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: a tyrosine hydroxylase immunocytochemical study. J . Neurosci. In press.

167b.FREUND, T . F., J. F. POWELL, AND A. D. SMITH. Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience 13: 1189-1215, 1984.

167c.FUNG, Y. K., AND R. D. SCHWARZ. An in vivo method for testing drugs that influence striatal dopaminergic functions. E’harmacol. Biochem. Behau. 19: 231-234, 1983.

168. FUXE, K. Cellular localization of monoamines in the median eminence and infundibular stem of some mammals. 2. Zell- forsch Mikrosk. Anat. 61: 710-724, 1964.

169. FUXE, K. Evidence for the existence of monoamine neurons in the central nervous system. IV. Distribution of monoamine nerve terminals in the central nervous system. Acta Physiool. Scand. Suppl. 247: 39-85, 1965.

169a.Fux~, K., M. GOLDSTEIN, AND A. LJUNGDAHL. Antiparkin- sonian drugs that influence striatal dopaminergic functions. Life Sci. 9 811-824, 1970.

170. FUXE, K., AND T. HOKFELT. Further evidence for the existence of tubero-infundibular dopamine neurons. Acta Physiol. Scand. 66: 245-246, 1966.

171. FUXE, K., AND T. HOKFELT. Catecholamines in the hypothalamus and the pituitary gland. In: Frontiers in Neuroendocri- nology, edited by W. F. Ganong and L. Martini. Oxford, UK: Oxford Univ. Press, 1969, p. 47-96.

172. FUXE, K., T . H-OKFELT, 0. JOHANSSON, G . JONSSON, P. LIDBRINK, AND A. LJUNGDAHL. The origin of the dopamine

1228-1238, 1981.

1978, VOI. 9, p. 357-401.

nerve terminals in limbic and frontal cortex. Evidence for mesocortico dopamine neurons. Brain Res. 82: 349-355, 1974.

173. FUXE, K., T. HOKFELT, AND u. UNGERSTEDT. Distribution of monoamines in the mammalian central nervous system by histochemical studies. In: Metabolism of Amines in the Brain, edited by G. Hooper. London: Macmillan, 1969, p. 10-22.

174. FUXE, K., T. HOKFELT, AND u. UNGERSTEDT. Morphological and functional aspects of central monoamine neurons. Int. Rev. Neurobiol. 13: 93-126, 1970.

175. FUXE, K., AND L. LJUNGGREN. Cellular localization of monoamines in the upper brain stem of the pigeon. J. Comp. Neurol.

176. GAGE, F. H., A. BJORKLUND, AND U. STENEVI. Local regulation of compensatory noradrenergic hyperactivity in the partially denervated hippocampus. Nature London 303: 819-821, 1983.

176a.GnGE, F. H., A. BJORKLUND, AND U. STENEVI. Reinnervation of the partially deafferented hippocampus by compensatory collateral sprouting from spared cholinergic and noradrenergic afferents. Brain Res. 268: 27-37, 1983.

176b.GAGE, F. H., A. BJORKLUND, u. STENEVI, AND s. B. DUN- NETT. Functional correlates of compensatory collateral sprouting by aminergic and cholinergic afferents in the hippocampal formation. Brain Res. 268: 39-47, 1983.

177. GALE, K. , J . S. HONG, AND A. GUIDOTTI. Presence of substance P and GABA in separate striatonigral neurons. Brain Res. 136: 371-375, 1977.

178. GARCIA-RILL, E., R. D. SKINNER, M. B. JACKSON, AND M. M. SMITH. Connections of the mesencephalic locomotor region (MLR). I. Substantia nigra afferents. Brain Res. Bull. 10: 57- 62, 1983.

179. GARCIA-RILL, E., R. D. SKINNER, S. A. GILMORE, AND R. OwrNGs. Connections of the mesencephalic locomotor region (MLR). 11. Afferents and efferents. Brain Res. Bull. 10: 63-71, 1983.

180. GARLAND, J. C., AND G. J. MOGENSON. An electrophysiological study of convergence of entopeduncular and lateral preoptic inputs on lateral habenular neurons projecting to the midbrain. Brain Res. 263: 33-41, 1983.

181. GARVER, D. L., AND J. R. SLADEK, JR. Monoamine distribution in primate brain. I. Catecholamine-containing perikarya in the brain stem of Macaca speciosa. J . Comp. Neurol. 159: 289-305, 1975.

18la.GEFFARD, M., R. M. BUIJS, P. SEGUELA, c. w. POOL, AND M. LE MOAL. First demonstration of highly specific and sensitive antibodies against dopamine. Brain Res. 294: 161- 165, 1984.

182. GEFFEN, L. B., T. M. JESSELL, A. C. CUELLO, AND L. L. IVERSEN. Release of dopamine from dendrites in rat substantia nigra. Nature London 260 258, 1976.

182a.GERFEN, c. R. The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Na- ture London 311: 461-464,1984.

183. GERFEN, C. R., AND R. M. CLAVIER. Neural inputs to the prefrontal agranular insular cortex in the rat: horseradish peroxidase study. Brain Res. Bull. 4: 347-353, 1979.

183a .G1~~D, G . M., T. H. JOH, V. M. PICKEL, AND D. J. REIS. Biochemical and immunocytochemical evidences for collateral sprouting in mesolimbic dopaminergic neurons in rat brain. Soc. Neurosci. Abstr. 6: 813, 1976.

184. GIRGIS, M. Kindling as model for limbic epilepsy. Neuroscience

185. GLOWINSKI, J., M. F. GIORGUIEFF, AND A. CHERAMY. Regu- latory processes involved in the control of the activity of nigrostriatal dopaminergic neurons. In: The Reticular Forma- tion Reuisited, edited by J . A. Hobson and M. A. B. Brazier. New York: Raven, 1980, p. 285-301.

185a.GODDARD, G. v., D. c. MCINTYRE, AND c. LEECH. A perma- nent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 2 5 295-330, 1969.

185b.GOLDMAN, P. s., AND w. J . NAUTA. An intricately patterned

125: 355-382, 1965.

6 1695-1706,1981.


prefronto-caudate projection in the rhesus monkey. J . Comp. Neurol. 172: 369-386, 1977.

186. GOLDMAN-RAKIC, P. S. Cytoarchitectonic heterogeneity of the primate neostriatum: subdivision into island and matrix cellular compartments. J. Comp. Neurol. 205: 398-413, 1982.

187. GRACE, A. A., AND B. S. BUNNEY. Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons. Eur. J. Pharmacol. 59: 211-218, 1979.

187a.GRAYBIEL, A. M., AND C. W. RAGSDALE, JR. Histochemically distinct compartments in the neostriatum of human being, monkey and cat demonstrated by the acetylthiocholinesterase staining method. Proc. Natl. Acad. Sci. USA 75: 5723-5726, 1978.

188. GRAYBIEL, A. M., AND C. W. RAGSDALE, JR. Fiber connections of the basal ganglia. In: Progress in Brain Research. Deuelop- ment and Chemical Specificity of Neurons, edited by M. Cuenod, G. W. Kreutzberg, and F. E. Bloom. Amsterdam: Elsevier, 1979, vol. 51, p. 239-283.

188a.GRAyeIE~, A. M., AND C. W. RAGSDALE, JR. Biochemical anatomy of the striatum. In: Chemical Neuroanatomy, edited by P. C. Emson. New York: Raven, 1983, p. 427-504.

188b.GRAYBIEL, A. M., C. W. RAGSDALE, JR., E. s. YONEOKA, AND R. P. ELDE. An immunohistochemical study of enkephalins and other neuropeptides in the striatum of the cat with evidence that the opiate peptides are arranged to form mosaic patterns in register with the striosomal compartments visible by acetylcholinesterase staining. Neuroscience 6 377-397, 1981.

189. GRILLNER, S. Supraspinal and segmental control of static and dynamic y-motoneurones in the cat. Acta Physiol. Scand.

190. GRILLNER, S. Locomotion in the spinal cat. In: Advances in Behavioral Biology. Control of Posture and Locomotion, edited by R. B. Stein, K. G. Pearson, S. R. Smith, and J. B. Redord. New York: Plenum, 1973, vol. 7, p. 515-535.

191. GRILLNER, S. On the neural control of movement-a comparison of different basic rhythmic behaviors. In: Function of Neural Systems, edited by G. S. Stent. Berlin: Dahlem Kon- ferenzen, 1977, p. 197-224.

192. GRILLNER, S. Brain stem control of motor pattern and locomotion. Neurosci. Res. Program Bull. 18: 58-62, 1980.

193. GRILLNER, S. Control of locomotion in bipeds, tetrapods, and fish. In: Handbook of Physiology. The Nervous System. Motor Control, edited by V. Brooks. Bethesda, MD: Am Physiol. Soc., 1981, sect. 1, vol. 11, pt. 2, chapt. 26, p. 1179-1236.

194. GRILLNER, S., AND M. L. SHIK. On the descending control of the lumbosacral spinal cord from the “mesencephalic locomotor region.” Acta Physiol. Scand. 87: 320-333, 1973.

195. GROENEWEGEN, H. J., N. E. H. M. BECKER, AND A. H. M. LOHMAN. Subcortical afferents of the nucleus accumbens septi in the cat, studied with retrograde axonal transport of horseradish peroxidase and bisbenzimid. Neuroscience 5: 1903-1916, 1980.

196. GROENEWEGEN, H. J., AND W. J. H. NAUTA. Afferent and efferent connections of the mediodorsal thalamic nucleus in the rat (Abstract). Neurosci. Lett. Suppl. 1 0 S217-S218, 1982.

197. GROENEWEGEN, H. J., P. ROOM, M. P. WITTER, AND A. H. M. LOHMAN. Cortical afferents of the nucleus accumbens in the cat, studied with anterograde and retrograde transport techniques. Neuroscience 7: 977-995, 1982.

198. GROSS, R. A., AND J. A. FERRENDELLI. Effects of reserpine, propranolol, and aminophylline on seizure activity and CNS cyclic nucleotides. Ann. Neurol. 6: 296-301, 1979.

198a.GROvES, P. M. Synaptic endings and their postsynaptic targets in neostriatum: synaptic specializations revealed from analysis of serial sections. Proc. Natl. Acad. Sci. USA 7 7 6926-6929, 1980.

199. GROVES, P. M. A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement. Brain Res. Rev. 5: 109-132, 1983.

SUppl. 327: 1-34, 1969.

200. GROVES, P. M., c . J. WILSON, s. J. YOUNG, A N D G. V. REBEC. Self-inhibition by dopaminergic neurons. Science 190: 522- 529, 1975.

201. GRZANNA, R., A N D M. E. MOLLIVER. The locus coeruleus in the rat: an immunocytochemical delineation. Neuroscience 5: 21-40, 1980.

202. GUDELSKY, G. A,, L. ANNUNZIATO, AND K. E. MOORE. Local- ization of the site of the haloperidol-induced, prolactin-mediated increase of dopamine turnover in the median eminence: studies in rats with complete hypothalamic deafferentations. J. Neural Transm. 42: 181-192,1978.

203. GUEVARA-AGUILAR, R., L. P. SOLANO-FLORES, Q . A. DON- ATTI-ALBARRAN, AND H. U. AGUILAR-BATURONI. Differential projections from locus coeruleus to olfactory bulb and olfactory tubercle: an HRP study. Brain Res. Bull, 8: 71.1-719, 1982.

204. GUPTA, K. C., G.-M. MOOLENAAR, AND J. A. HOLLOWAY. The nucleus locus coeruleus afferent connections (Abstract). Fed- eration Proc. 36: 385, 1977.

205. GUYENET, P. G. The coeruleospinal noradrenergic neurons: anatomical and electrophysiological studies in the rat. Brain Res. 189: 121-133, 1980.

206. GUYENET, P. G., A N D G. K. AGHAJANIAN. Antidromic identification of dopaminergic and other output neurons of the rat substantia nigra. Brain Res. 150: 69-84, 1978.

207. GUYENET, P. G., AND J. K. CRANE. Non-dopaminergic nigrostriatal pathway. Brain Res. 213: 291-305, 1981.

208. HALASZ, N., A. LJUNGDAHL,T. HOKFELT, 0. JOHANSSON, M. GOLDSTEIN, D. PARK, AND P. BIBERFELD. Transmitter histochemistry of the rat olfactory bulb. I. Immunohistochemical localization of monoamine synthesizing enzymes. Support for intrabulbar, periglomerular dopamine neurons. Brain Res. 126:

209. HARIK, S. I., R. BUSTO, AND E. MARTINEZ. Norepinephrine regulation of cerebral glycogen utilization during seizures and ischemia. J . Neurosci. 2: 409-414, 1982.

210. HARIK, S. I., V. K. SHARMA, J. R. WETHERBEE, R. H. WAR- REN, A N D S. P. BANERJEE. Adrenergic receptors of cerebral microvessels. Eur. J . Pharmacol. 61: 207-208, 1980.

211. HARTMAN, B. K., D. ZIDE, A N D S. UDENFRIEND. The use of dopamine-8-hydroxylase as a marker for the central noradrenergic nervous system in rat brain. Proc. Natl. Acad. Sci. USA 69: 2722-2726, 1972.

212. HATTORI, T., H. C. FIBIGER, A N D P. L. MCGEER. Demonstra- tion of a pallido-nigral projection innervating dopaminergic neurons. J . Comp. Neurol. 162: 487-504, 1975.

212a.HATTOR1, T., H. C. FIBIGER, P. L. MCGEER, AND L. MALER. Analysis of the fine structure of the dopaminergic nigrostriatal projection by electron microscopic autoradiography. Exp. Neu- rol. 41: 599-611, 1973.

213. HATTORI, T., V. K. SINGH, E. G. MCGEER, A N D P. L. MC- GEER. Immunohistochemical localization of choline acetyltransferase containing neostriatal neurons and their relationship with dopaminergic synapses. Brain RFS. 102: 164-173, 1976.

214. HEDREEN, J . C. Terminal degeneration demonstrated by the Fink-Heimer method following lateral ventricular injection of 6-hydroxydopamine. Brain Res. Bull. 5: 425-436, 1980.

215. HEDREEN, J. C., A N D J. P. CHALMERS. Neuronal degeneration in rat brain induced by 6-hydroxydopamine: a histological and biochemical study. Brain Res. 47: 1-36, 1972.

215a.HEFT1, F., E. MELAMED, AND R. J. WURTMAN. Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res. 195: 123-127, 1980.

Ventral striatum and ventral pallidum. Components of the motor system? Trends Neurosci. 5: 83-87, 1982.

217. HEIMER, L., AND R. D. WILSON. The subcortical projections of the allocortex: similarities in the neural associations of the hippocampus, the piriform cortex, and the neocortex. In: Golgi Centennial Symposium: Perspectives in Neurobiology, edited by M. Santini. New York: Raven, 1975, p. 177-193.

455-474, 1977.

216. HEIMER, L., R. c . SWITZER 111, AND G. W. VAN HOESEN.


218. HELLER, A., AND R. Y. MOORE. Effect of central nervous system lesions on brain monoamines in the rat. J. Pharmacol. Exp. Ther. 150: 1-9, 1965.

219. HELLER, A., AND R. Y. MOORE. Control of brain serotonin and norepinephrine by specific neural systems. In: Advances in Pharmacology, edited by S. Garattini and P. A. Shore. New York: Academic, 1968, vol. 6A, p. 191-206.

220. HERBST, T. J., M. E. RAICHLE, AND J. A. FERRENDELLI. p- Adrenergic regulation of adenosine 3’,5’-monophosphate concentration in brain microvessels. Science 204: 330-332, 1979.

221. HERKENHAM, M., AND W. J. H. NAUTA. Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem. J. Comp. Neurol. 173: 123-146, 1977.

222. HERKENHAM, M., AND W. J. H. NAUTA. Efferent connections of the habenular nuclei in the rat. J. Comp. Neurol. 187: 19- 48, 1979.

222a.HERKENHAM, M., AND c . B. PERT. Mosaic distribution of opiate receptors, parafascicular projections and acetylcholinesterase in rat striatum. Nature London 291: 415-418, 1981.

222b.HERRL1NG, P. L., AND c. D. HULL. Iontophoretically applied dopamine depolarizes and hyperpolarizes the membrane of cat caudate neurons. Brain Res. 192: 441-462, 1980.

222c.HIRATA, K., c. Y. YIM, AND G. J. MOGENSON. Excitatory input from sensory motor cortex to neostriatum and its modification by conditioning stimulation of the substantia nigra. Brain Res. 321: 1-8, 1984.

223. HOKFELT, T. In vitro studies on central and peripheral monoamine neurons at the ultrastructural level. Z. Zellforsch. Mik- rosk. Anat. 91: 1-74, 1968.

223a.H6KFELT, T. Possible site of action of dopamine in the hypothalamic pituitary control. Acta Physiol. Scand. 89: 606-608, 1973.

224. HOKFELT, T., A N D K. FUXE. Cerebellar monoamine nerve terminals, a new type of afferent fiber to the cortex cerebelli. Exp. Brain Res. 9: 63-72, 1969.

225. HOKFELT, T., K. FUXE, M. GOLDSTEIN, AND 0. JOHANSSON. Immunohistochemical evidence for the existence of adrenaline neurons in the rat brain. Brain Res. 66: 235-251, 1974.

226. HOKFELT, T., K. FUXE, 0. JOHANSSON, AND A. LJUNGDAHL. Pharmacohistochemical evidence of the existence of dopamine nerve terminals in the limbic cortex. Eur. J. Phurmacol. 25:

227. HOKFELT, T., N. HALASZ, A. LJUNGDAHL, 0. JOHANSSON, M. GOLDSTEIN, AND D. PARK. Histochemical support for a dopaminergic mechanism in the dendrites of certain periglomerular cells in the rat olfactory bulb. Neurosci. Lett. 1: 85-90, 1975.

228. HOKFELT, T., 0. JOHANSSON, K. FUXE, M. GOLDSTEIN, AND D. PARK. Immunohistochemical studies on the localization and distribution of monoamine neuron systems in the rat brain. I. Tyrosine hydroxylase in the mes- and diencephalon. Med. Biol. 54: 427-453, 1976.

229. HOKFELT, T., 0. JOHANSSON, K. FUXE, M. GOLDSTEIN, AND D. PARK. Immunohistochemical studies on the localization and distribution of monoamine neuron systems in the rat brain. 11. Tyrosine hydroxylase in the telencephalon. Med. Biol. 55: 21-40, 1977.

230. HOKFELT, T., A. LJUNGDAHL, K. FUXE, AND 0. JOHANSSON. Dopamine nerve terminals in the rat limbic cortex: aspects of the dopamine hypothesis of schizophrenia. Science 184 177- 179, 1974.

230a.HOKFELT, T., R. MARTENSSON, A. BJ~RKLUND, S. KLEINAU, AND M. GOLDSTEIN. Distributional maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In: Handbook of Chemical Neuroanatomy. Classical Transmitters in the CNS, edited by A. Bjorklund and T. Hokfelt. Amsterdam: Elsevier,

231. HOKFELT, T., 0. PHILLIPSON, AND M. GOLDSTEIN. Evidence for a dopaminergic pathway in the rat descending from the A l l cell group to the spinal cord. Acta Physiol. Scand. 107:

108-112,1974.

1984, V O ~ . 2, pt. 1, p. 277-379.

393-395, 1979. 232. HOKFELT, T., AND u. UNGERSTEDT. Electron and fluorescence

microscopical studies on the nucleus caudatus putamen of the rat after unilateral lesions of ascending nigroneostriatal dopamine neurons. Acta Physiol. Scand. 7 6 415-426, 1969.

233. HONC, J . S., H.-Y. T. YANG, G. RACAGNI, AND E. COSTA. Projections of substance P containing neurons from neostriatum to substantia nigra. Brain Res. 1 2 2 541-544, 1977.

234. HUBBARD, J. E., AND V. DICARLO. Fluorescence histochemistry of monoamine-containing cell bodies in the brain stem of the squirrel monkey (Saimiri sciureus). 11. Catecholamine- containing groups. J. Comp. Neurol. 153: 369-384, 1974.

235. IGARASHI, S., M. SASA, AND S. TAKAORI. Convergence of sensory input from tooth pulp, optic chiasm and sciatic nerve onto locus coeruleus neurons in the rat. Neurosci. Lett. 12: 189-194,1979.

236. IGARASHI, S., M. SASA, AND S. TAKAORI. Feedback loop between locus coeruleus and spinal trigeminal nucleus neurons responding to tooth pulp stimulation in the rat. Brain Res. Bull. 4: 75-84, 1979.

237. INGVAR, M., 0. LINDVALL, J. FOLBERGROVA, AND B. K. S I E S J ~ . Influence of lesions of the noradrenergic locus coeruleus system on the cerebral metabolic response to bicuculline- induced seizures. Brain Res. 264: 225-231, 1983.

238. ISHIKAWA, K., T. OTT, AND J. L. MCGAUGH. Evidence for dopamine as a transmitter in dorsal hippocampus. Brain Res.

238a.JACKSON, A,, AND A. R. CROSSMAN. Subthalamic nucleus efferent projection to the cerebral cortex. Neuroscience 6: 2367-2377, 1981.

238b.JACKSON, A,, AND A. R. CROSSMAN. Subthalamic projection to nucleus tegmenti pedunculopontinus in the rat. Neurosci. Lett. 22: 17-22, 1981.

238c.JACKSON, A., AND A. R. CROSSMAN. Nucleus tegmenti pedunculopontinus: efferent connections with special reference to the basal ganglia, studied in the rat by anterograde and retrograde transport of horseradish peroxidase. Neuroscience 10:

238d.JACKSON, E. A., AND P. H. KELLY. Nigral dopaminergic mechanisms in drug-induced circling. Brain Res. Bull. 11: 605- 611,1983.

238e.JACKsON, E. A., AND P. H. KELLY. Role of nigral dopamine in amphetamine-induced locomotor activity. Brain Res. 278:

239. JACOBOWITZ, D. M. Effects of 6-hydroxydopa. In: Frontiers in Catecholamine Research, edited by E. Usdin and S. Snyder. Oxford, UK: Pergamon, 1973, p. 729-739.

240. JACOBOWITZ, D. M., AND P. D. MACLEAN. A brainstem atlas of catecholaminergic neurons and serotonergic perikarya in a pygmy primate (Cebuella pygmaea). J. Comp. Neurol. 177: 397- 416,1978.

241. JAHR, E., AND R. A. NICOLL. Noradrenergic modulation of dendrodenritic inhibition in the olfactory bulb. Nature London

242. JAMES, T. A,, AND M. S. STARR. Behavioural and biochemical effects of substance P injected into the substantia nigra of the rat. J. Pharm. Pharmacol. 29: 181-182, 1977.

242a.JAMES, T. A,, AND M. s. STARR. Effects of substance P injected into the substantia nigra. Br. J. Pharmacol. 65: 423-429,1979.

243. JANKOWSKA, E., M. G. M. JUKES, S. LUND, AND A. LUND- BERG. The effect of DOPA on the spinal cord. 5. Reciprocal organization of pathways transmitting effects from the flexor afferents. Acta Physiol. Scand. 7 0 369-388, 1967.

244. JANKOWSKA, E., M. G. M. JUKES, S. LUND, AND A. LUND- BERG. The effect of DOPA on the spinal cord. 6. Half-centre organization of interneurons transmitting effects from the flexor reflex afferents. Acta Physiol. Scand. 7 0 389-402, 1967.

245. JAVOY, F., AND J. GLOWINSKI. Dynamic characteristics of the “functional compartment” of dopamine in dopaminergic terminals of the rat striatum. J. Neurochern. 18: 1305-1311,1971,

246. JESSEL, T. M., P. c . EMSON, G. PAXINOS, AND A. C. CUELLO.

232: 222-226, 1982.

725-765,1983.

366-369, 1983.

297: 227-229,1982.


Topographic projections of substance P and GABA pathways in the striato- and pallido-nigral system: a biochemical and immunohistochemical study. Brain Res. 152: 487-498, 1978.

DAILEY. Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy-prone rat. Epilepsia

247a.Jo~NELs, B., G. STEG, AND U. UNGERSTEDT. A method for mechanographical recording of muscle tone in the rat. The effect of some antiparkinsonian drugs on rigidity induced by reserpine. Brain Res. 140: 177-181, 1978.

MOORE. Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons. Brain Res. 127: 1-21, 1977.

249. JONES, B. E., AND R. Y. MOORE. Catecholamine-containing neurons of the nucleus locus coeruleus in the cat. J . Comp. Neurol. 157: 43-52, 1974.

250. JONES, B. E., AND R. Y. MOORE. Ascending projections of the locus coeruleus in the rat. 11. Autoradiographic study. Brain Res. 127: 23-53, 1977.

251. JONES, G., M. SEGAL, S. FOOTE, A N D F. E. BLOOM. Locus coeruleus neurons in freely moving rats exhibit pronounced alterations of firing rate during sensory stimulation and stages of the sleep-wake cycle. In: Catecholamines: Basic and Clinical Frontiers, edited by E. Usdin, I. Kopin, and J. Barchas. New York: Pergamon, 1979, p. 643-645.

252. JONSSON, G., K. FUXE, AND T. HOKFELT. On the catecholamine innervation of the hypothalamus, with special reference to the median eminence. Brain Res. 40: 271-281, 1972.

253. JOUVET, M. The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle. Ergeb. Physiol. 64: 166-307, 1972.

254. J U O R I O , A. V. The distribution of catecholamines in the by- pothalamus and other brain areas of some lower vertebrates. J. Neurochem. 20: 641-645, 1973.

254a.Juo~10, A. V., AND M. VOGT. Monoamines and their metab- olites in the avian brain. J . Physiol. London 189: 489-518, 1967.

255. JURASKA, J . M., C. J. WILSON, A N D P. M. GROVES. The substantia nigra of the rat: a Golgi study. J. Comp. Neurol. 172: 586-594, 1977.

255a.K~~1L, K. Patch-like termination of thalamic fibers in the putamen of the rhesus monkey: an autoradiographic study. Brain Res. 140: 333-339, 1978.

256. KANAZAWA, I. , P. c . EMSON, AND A. c . CUELLO. Evidence for the existence of substance P-containing fibres in striato-nigral and pallido-nigral pathways in rat brain. Brain Res. 119: 447- 453, 1977.

256a.KANAZAWA, I. , G. R. MARSHALL, AND J. S. KELLY. Afferents to the rat subtantia nigra studied with horseradish peroxidase, with special reference to fibres from the subthalamic nucleus. Brain Res. 115: 485-491, 1976.

257. KAROUM, F., J . W. COMMISSIONG, N. F. NEFF, AND R. J. WYATT. Biochemical evidence for uncrossed and crossed locus coeruleus projections to the spinal cord. Brain Res. 196: 237- 241, 1980.

257a.KATAYAMA, Y., Y. UENO, T . TSUKIYAMA, AND T . TSUBOK- AWA. Long lasting suppression of firing of cortical neurons and decrease in cortical blood flow following train pulse stimulation of the locus coeruleus in the cat. Brain Res. 216: 173- 179, 1981.

K. A. WEST. Evidence for regenerative axon sprouting of central catecholamine neurons in the rat mesencephalon following electrolytic lesions. Brain Res. 25: 579-596, 1971.

258. KELLEY, A. E., AND V. B. DOMESICK. The distribution of the projection from the hippocampal formation to the nucleus accumbens in the rat: an anterograde- and retrograde-horseradish peroxidase study. Neuroscience 7: 2321-2335, 1982.

259. KELLEY, A. E., V. B. DOMESICK, AND W. J. H. NAUTA. The

247. JOBE, P. c., H. E. LAIRD 11, K. H. KO, T. RAY, AND J . W.

23: 359-366, 1982.

248. JONES, B. E., A. E. HALARIS, M. MCILLHANY, AND R. Y.

257b.KATZMAN, R., A. BJORKLUND, c. OWMAN, u . STENEVI, AND

amygdalostriatal projection in the rat-an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7: 615-630, 1982.

260. KELLY, P. A. T. GABAergic Activity Influencing Cerebral Function in the Rat. Glasgow: Univ. of Glasgow, 1982. PhD thesis.

261. KELLY, P. H. Drug-induced motor behaviour. In: Handbook of Psychopharmacology. Drugs, Neurotransmitters, and Behavior, edited by L. L. Iversen, S. D. Iversen, and S. H. Snyder. New York: Plenum, 1977, vol. 8, p. 295-331.

262. KELLY, P. H., AND K. E. MOORE. Mesolimbic dopaminergic neurones in the rotational model of nigrostxiatal function. Nature London 263: 695-696, 1976.

263. KELLY, P. H., P. w. SEVIOUR, AND s. D. IVERSEN. Amphet- amine and apomorphine responses in the rat following 6- OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res. 94: 507-522, 1975.

264. KEMP, J . M., A N D T . P. S. POWELL. The site of termination of afferent fibres in the caudate nucleus. Philos. Trans. R. SOC. London Ser. B 262: 413-427, 1971.

264a.KEM~, J. M., AND T . P. S. POWELL. The connexions of the striatum and globus pallidus: synthesis and speculation. Phi- 10s. Trans. R. SOC. London Ser. B 262: 441-457, 1971.

265. KETY, S. S. The biogenic amines in the central nervous system: their possible roles in arousal, emotion and learning. In: The Neurosciences, edited by F. 0. Schmitt. New York: Rockefeller Univ. Press, 1970, p. 324-336.

266. KEVERNE, E. B., AND c. DE LA RIVA. Pheromones in mice: reciprocal interaction between the nose and brain. Nature

267. KIM, J.-s., R. HASSLER, P. HAUG, AND K.-S. PAIK. Effect of frontal cortex ablation on striatal glutamic acid level in rat. Brain Res. 132: 370-374, 1977.

267a.KIM, R., K. NAKANO, A. JAYARAMAN, AND M. B. CARPENTER. Projections of the globus pallidus and adjacent structures: an autoradiographic study in the monkey. J. Comp. Neurol. 169:

268. KIMURA, H., P. MCGEER, AND J.-H. PENG. Choline acetyltransferase-containing neurons in the rat brain. In: Handbook of Chemical Neuroanatomy. Classical Transmitters and Trans- mitter Receptors in the CNS, edited by A. Bjorklund and T. Hokfelt. Amsterdam: Elsevier, 1984, vol. 3, pt. 2, p. 51-67.

269. KIMURA, H., P. L. MCGEER, J. H. P E N G , AND E. G. MCGEER. The central cholinergic system studied by choline acetyltransferase immunohistochemistry in the cat. J. Comp. Neurol. 200:

270. KITAI, S. T. Electrophysiology of the corpus striatum and brain stem integrating systems. In: Handbook of Physiology. The Nervous System. Motor Control, edited by V. Brooks. Bethesda, MD: Am. Physiol. Soc., 1981, sect. 1, vol. 11, pt. 2, chapt. 20, p. 997-1015.

271. KIZER, J. S., M. PALKOVITS, AND M. J. BROWNSTEIN. The projections of the AS, A9 and A10 dopaminergic cell bodies: evidence for a nigral-hypothalamic-median eminence dopaminergic pathway. Brain Res. 108: 363-370, 1976.

27la.KLAWANS, H. L., R. RUBOVlTs, B. C. PATEL, AND w . J. WEINER. Cholinergic and anticholinergic influence on amphetamine-induced stereotyped behavior. J. Neurol. Sci. 17:

London 296: 148-150, 1982.

263-289, 1976.

151-201, 1981.

303-308,1972. 272. KOBAYASHI, H., T. MAORET, M. FERRANTE, P. SPANO, AND

M. TRABUCCHI. Subtypes of 8-adrenergic receptors in rat cerebral microvessels. Brain Res. 220: 194-198, 1981.

273. KOBAYASHI, R. M., M. PALKOVITS, I. J. KOPIN, AND D. M. JACOBOWITZ. Biochemical mapping of noradrenergic nerves arising from the rat locus coeruleus. Brain. Res. 77: 269-279, 1974.

273a.Kocs1s, J . D., M. SUGIMORI, AND S.T. KITAI. Convergence of excitatory synaptic inputs to caudate spiny neurons. Brain Res. 124: 403-413, 1976.

274. KORF, J. The role of dopamine containing dendrites in the substantia nigra. In: Neurotransmission and Disturbed Behau-


ior, edited by H. M. van Praag and J. Bruinvels. Utrecht, The Netherlands: Bohn, Scheltema, & Holkema, 1976, p. 96-102.

275. KORF, J., M. ZIELEMAN, AND B. H. C. WESTERINK. Dopamine release in substantia nigra? Nature London 260: 257-258,1976.

275a.KOSOFSKY, B. E., M. E. MOLLIVER, J. H. MORRISON, AND S. L. FOOTE. The serotonin and norepinephrine innervation of primary visual cortex in the cynomolgus monkey (Macaca fascicularis). J . Comp. Neurol. 239 168-178, 1984.

2 7 5 b . K o z ~ o w s ~ 1 , M. R., S. SAWYER, AND J. F. MARSHALL. Behav- ioral effects and supersensitivity following nigral dopamine receptor stimulation. Nature London 287: 52-54, 1980.

276. KRAYNIAK, P. F., R. c. MEIBACH, AND A. SIEGEL. A projection from the entorhinal cortex to the nucleus accumbens in the rat. Brain Res. 209: 427-431, 1981.

277. KRISTT, D. A., M. S. SHIRLEY, AND E. KASPER. Monoamin- ergic synapses in infant mouse neocortex: comparison of cortical fields in seizure-prone and resistant mice. Neuroscience 5: 883-891,1980,

278. KROMER, L. F., AND R. Y. MOORE. Cochlear nucleus innervation by central norepinephrine neurons in the rat. Brain Res. 118 531-537, 1976.

279. KROMER, L. F., AND R. Y. MOORE. Norepinephrine innervation of the cochlear nuclei by locus coeruleus neurons in the rat. Anat. Embryol. 1 5 8 227-244, 1980.

279a.KROMER, L. F., AND R. Y. MOORE. A study of the organization of the locus coeruleus projections to the lateral geniculate nuclei in the albino rat. Neuroscience 5: 255-271, 1980.

279b.KUNZLE, H. Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. Brain Res. 88 195-210, 1975.

280. KUYPERS, H. G. J. M., AND A. M. HUISMAN. The new anatomy of the descending brain pathways. In: Brain Stem Control of Spinal Mechanisms, edited by B. H. Sjolund and A. Bjorklund. Amsterdam: Elsevier, 1982, p. 29-54. (Fernstrom Found. Ser., vol. 1.)

281. KUYPERS, H. G. J. M., J. KIEVIT, AND A. C. GROEN-KLEVANT. Retrograde axonal transport of horseradish peroxidase in rat’s forebrain. Brain Res. 67: 211-218, 1974.

282. KUYPERS, H. G. J. M., AND V. A. MAISKY. Retrograde axonal transport of horseradish peroxidase from spinal cord to brain stem cell groups in the cat. Neurosci. Lett. 1: 9-14, 1975.

283. LAI, F. M., s. UDENFRIEND, AND s. SPECTOR. Presence of norepinephrine and related enzymes in isolated brain microvessels. Proc. Natl. Acad. Sci. USA 72: 4622-4625, 1975.

284. LANDIS, s., w. J. SHOEMAKER, F. E. BLOOM, AND M. SCHLUMPF. Catecholamines in mutant mouse cerebellum. Flu- orescence microscopic and chemical studies. Brain Res. 93:

285. LAPIERRE, Y., A. BEAUDET, N. DEMIANCZUK, A N D L. DESCAR- HIES. Noradrenergic axon terminals in the cerebral cortex of the rat. 11. Quantitative data revealed by light and electron microscope radioautography of the frontal cortex. Brain Res. 63: 175-182, 1973.

285a.I>ARSEN, K. D., AND R. L. MCBRIDE. The organization of feline ent,opeduncular nucleus projections: anatomical studies. J. Comp. Neurol. 184: 293-308, 1979.

286. LAURENT, J.-P., R. CESPUGLIO, A N D M. JOUVET. Delimitation des voies ascendantes de l’activite ponto-geniculo-occipitale chez le chat. Brain Res. 65: 29-52, 1974.

287. LEE, L. A., A. R. CROSSMAN, AND P. SLATER. The neurological basis of striatally induced head-turning in the rat: the effects of lesions in putative output pathways. Neuroscience 5: 73-79, 1980.

288. LEGER, L., L. WIKLUND, L. DESCARRIES, AND M. PERSSON. Description of an indolaminergic cell component in the cat locus coeruleus: a fluorescence histochemical and radioauto- graphic study. Brain Res. 168: 43-56, 1979.

288a.LEHMANN, J., AND s. z. LANCER. The striatal cholinergic interneuron: synaptic target of dopaminergic terminals? Neu- roscience 10: 1105-1120, 1983.

289. LEVITT, P., AND R. Y. MOORE. Noradrenaline neuron inner-

253-266,1975.

vation of the neocortex in the rat. Brain Res. 139: 219-231, 1978.

290. LEVITT, P., AND R. Y. MOORE. Origin and organization of brainstem catecholamine innervation in the rat. J. Comp. Neurol. 186: 505-528, 1979.

cific distribution of catecholamine afferents in primate cerebral cortex: a fluorescence histochemical analysis. J. Comp. Neurol. 227: 23-36, 1984.

291. LIBET, B., C. A. GLEASON, E. W. WRIGHT, JR., AND B. FEINSTEIN. Suppression of an epileptiform type of electro- cortical activity in the rat by stimulation in the vicinity of locus coeruleus. Epilepsia 18: 451-462, 1977.

292. LICHTENSTEIGER, W. Katecholaminhaltige Neurone in der neuroendokrinen Sf euerung. Prog. Histochem. Cytochem. 1:

293. LIDBRINK, P., AND G. JONSSON. Noradrenaline nerve terminals in the cerebral cortex: effects on noradrenaline uptake and storage following axonal lesion with 6-hydroxydopamine. J. Neurochem. 22: 617-626, 1974.

294. LINDVALL, M., J. CERVOS-NAVARRO, L. EDVINSSON, C. Ow- MAN, AND u. STENEVI. Non-sympathetic perivascular nerves in the brain: origin and mode of innervation studied by fluorescence and electron microscopy combined with stereotaxic lesions and sympathectomy. In: Blood Flow and Metabolism in the Brain, edited by A. M. Harper, W. B. Jennett, J. D. Miller, and J. 0. Rowan. Edinburgh: Churchill Livingstone, 1975, p.

295. LINDVALL, 0. Mesencephalic dopaminergic afferents to the lateral septa1 nucleus of the rat. Brain Res. 87: 89-95, 1975.

296. LINDVALL, O., AND A. BJORKLUND. The glyoxylic acid fluorescence histochemical method: a detailed account of the methodology for the visualization of central catecholamine neurons. Histochemistry 39: 97-127, 1974.

297. LINDVALL, O., AND A. BJORKLUND. The organization of the ascending catecholamine neuron systems in the rat brain as revealed by the glyoxylic acid fluorescence method. Acta Phys- iol. Scand. Suppl. 412: 1-48, 1974.

298. LINDVALL, o., AND A. BJORKLUND. Anatomy of the dopaminergic neuron systems in the rat brain. In: Advances in Bio- chemical Psychopharmacology. Dopamine, edited by P. J. Rob- erts, G. N. Woodruff, and L. L. Iversen. New York: Raven,

299. LINDVALL, O., AND A. BJORKLUND. Organization of catecholamine neurons in the rat central nervous system. In: Handbook of Psychopharmacology. Chemical Pathways in the Brain, edited by L. L. Iversen, S. D. Iversen, and S. H. Snyder. Plenum, 1978, vol. 9, p. 139-231.

300. LINDVALL, o., AND A. BJORKLUND. Dopaminergic innervation of the globus pallidus by collaterals from the nigrostriatal pathway. Brain Res. 172: 169-173, 1979.

301. LINDVALL, o., A. BJORKLUND, AND I. DIVAC. Organization of mesencephalic dopamine neurons projecting to neocortex and septum. Advances in Biochemical Psychopharmacology. Non- striatal Dopaminergic Neurons, edited by E. Costa and G. L. Gessa. New York: Raven, 1977, vol. 16, p. 39-46.

302. LINDVALL, o., A. BJORKLUND, AND I. DIVAC. Organization of catecholamine neurons projecting to the frontal cortex in the rat. Brain Res. 142: 1-24, 1978.

303. LINDVALL, o., A. BJORKLUND, R. Y. MOORE, AND U. STE- NEVI. Mesencephalic dopamine neurons projecting to neocortex. Brain Res. 81: 325-331, 1974.

304. LINDVALL, O., A. BJORKLUND, A. NOBIN, AND U. STENEVI. The adrenergic innervation of the rat thalamus as revealed by the glyoxylic acid fluorescence method. J. Comp. Neurol. 154:

305. LINDVALL, o., A. BJORKLUND, AND G. SKAGERBERG. Selective histochemical demonstration of dopamine terminal systems in rat di- and telencephalon: new evidence for a dopaminergic innervation of hypothalamic neurosecretory nuclei. Brain Res. 306: 19-30, 1984.

290a.LEVITT, P., P. RAKIC, AND P. GOLDMAN-RAKIC. Region-spe-

185-276,1970.

1.7-1.9.

1978, V O ~ . 19, p. 1-23.

317-348,1974.


305a.LINDVALL, o., AND u. STENEVI. Dopamine and noradrenaline neurons projecting to the septa1 area in the rat. Cell Tissue Res. 190: 383-407, 1978.

306. LJUNGBERG, T., AND u . ~NGERSTEDT. Reinstatement of eat- ing by dopamine agonists in aphagic dopamine denervated rats. Physiol. Behau. 16: 277-283, 1976.

307. LJUNGDAHL, A., T. HOKFELT, M. GOLDSTEIN, AND D. PARK. Retrograde peroxidase tracing of neurons combined with transmitter histochemistry. Brain Res. 84: 313-319, 1975.

308. LJUNGDAHL, A., T . HOKFELT, AND G. NILSSON. Distribution of substance P-like immunoreactivity in the central nervous system of the rat. I. Cell bodies and nerve terminals. Neuro- science 3: 861-943, 1978.

308a.LLINAS, R., s. A. GREENFIELD, AND H. JAHNSEN. Electro- physiology of pars compacta cells in the in vitro substantia nigra-a possible mechanism for dendritic release. Brain Res.

309. LOEWY, A. D., S. MCKELLAR, AND C. B. SAPER. Direct projections from the A5 catecholamine cell group to the intermediolateral cell column. Brain Res. 174: 309-314, 1979.

310. LOEWY, A. D., J . H. WALLACH, AND S. MCKELLAR. Efferent connections of the ventral medulla oblongata in the rat. Brain Res. Reu. 3: 63-80, 1981.

311. LOFSTROM, A., G. JONSSON, AND K. FUXE. Microfluorometric quantitation of catecholamine fluorescence in rat median eminence. I. Aspects on the distribution of dopamine and noradrenaline nerve terminals. J . Histochem. Cytochem. 24: 415- 429, 1976.

312. LOIZOLJ, L. A. Projections of the nucleus locus coeruleus in the albino rat. Brain Res. 15: 563-566, 1969.

312a.LOUGHLIN, s. E., AND J. H. FALLON. Mesostriatal projections from ventral tegmentum and dorsal raphe: cells project ipsilaterally or contralaterally but not bilaterally. Neurosci. Lett. 32: 11-16,1982,

313. LOUGHLIN, S. E., AND J. H. FALLON. Dopaminergic and nondopaminergic projections to amygdala from substantia nigra and ventral tegmental area. Brain Res. 262: 334-338, 1983.

313a.LOUGHLIN, s. E., AND J. H. FALLON. Substantia nigra and ventral tegmental area projections to cortex: topography and collateralization. Neuroscience 11: 425-435, 1984.

314. LOUGHLIN, s. E., S. L. FOOTE, AND J. H. FALLON. Locus coeruleus projections to cortex: topography, morphology, and collateralization. Brain Res. Bull. 9: 287-294, 1982.

315. Lou, R., D. A. KOZIELL, J. D. LINDSAY, AND R. Y. MOORE. Noradrenergic innervation of the adult rat hippocampal formation. J. Comp. Neurol. 189: 699-710, 1980.

316. LUITEN, P. G. M., F. KUIPERS, AND H. SCHUITMAKER. Orga- nization of diencephalic and brainstem afferent projections to the lateral septum in the rat. Neurosci. Lett. 3 0 211-216,1982.

317. LUST, W. D., N. D. GOLDBERG, AND J. v. PASSONNEAU. cyclic nucleotides in murine brain: the temporal relationship of changes induced in adenosine 3’,5’-monophosphate and guanosine 3’,5’-monophosphate following maximal electroshock or decapitation. J. Neurochem. 26: 5-10, 1976.

318. MADISON, D. V., AND R. A. NICOLL. Noradrenaline blocks accommodation of pyramidal cell discharge in the hippocampus. Nature London 299: 636-638,1982.

319. MAEDA, T., c . PIN, D. SALVERT, M. LIGIER, AND M. JOUVET. Les neurones contenant des catecholamines du tegmentum pontique et leurs voies de projection chez le chat. Brain Res.

320. MAEDA, T., AND N. SHIMIZU. Projections ascendantes du locus coeruleus et dautres neurones aminergiques pontiques au ni- veau du prosencephale du rat. Brain Res. 36: 19-35, 1972.

321. MAGNUSSON, T. Effect of chronic transection on dopamine, noradrenaline and 5-hydroxytryptamine in the rat spinal cord. Naunyn-Schmiedeberg‘s Arch. Pharmacol. 278: 13-22, 1973.

322. MALMFORS, T. Evidence of adrenergic neurons with synaptic terminals in the retina of rats demonstrated with fluorescence and electron microscopy. Acta Physiol. Scand. 58: 99-100, 1963.

323. MARCHAND, E. R., J. N. RILEY, AND R. Y. MOORE. Interpe-

294 127-132, 1984.

57: 119-152, 1973.

duncular nucleus afferents in the rat. Brain Res. 193: 339-352, 1980.

323a.MARCHAND, J. E., AND N. HAGINO. Afferents to the periaqueductal gray in the rat. A horseradish peroxidase study. Neuroscience 9: 95-106, 1983.

324. MARKOWITSCH, H. J., A N D E. IRLE. Widespread cortical projections of the ventral tegmental area and of other brain stem structures in the cat. Exp. Brain Res. 41: 233-246, 1981.

325. MARSDEN, C. D. The mysterious motor function of the basal ganglia: the Robert Wartenberg Lecture. Neurology 32: 514- 539, 1982.

326. MARSHALL, J. F., AND R. GOTTHELF. Sensory inattention in rats with 6-hydroxydopamine-induced degeneration of ascending dopamine neurons: apomorphine-induced reversal of defi- cits. Exp. Neurol. 65: 389-411, 1979.

327. MARSHALL, J . F., AND P. TEITELBAUM. New considerations in the neuropsychology of motivated behaviours. In: Handbook of Psychopharmacology. Animal Psychopharmacology, edited by L. L. Iversen, S. D. Iversen, and S. H. Snyder. New York: Plenum, 1977, vol. 7, p. 201-229.

328. MARSHALL, J. F., AND U. UNGERSTEDT. Apomorphine-induced restoration of drinking to thirst challenges in 6-hydroxydopamine-treated rats. Physiol. Behau. 17: 817-822, 1976.

329. MASON, S. T. Noradrenaline and behaviour. Trends Neurosci. 2: 82-84, 1979.

330. MASON, S. T. Noradrenaline in the brain: progress in theories of behavioural function. Prog. Neurobiol. 16: 263-303, 1981.

330a.MASON, S. T. Catecholamines and Behauiour. Cambridge, UK: Cambridge Univ. Press, 1984.

331. MASON, S. T., AND M. E. CORCORAN. Catecholamines and convulsions. Brain Res. 170: 497-507, 1979.

332. MASON, S. T., A N D H. c . FIBIGER. Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase. J. Comp. Neurol. 187: 703-724, 1979.

333. MASON, S. T., AND S. D. IVERSEN. Theories of the dorsal bundle extinction effect. Brain Res. Reu. 1: 107-137, 1979.

333a.MCBRIDE, R. L., AND K. D. LARSEN. Projections of the feline globus pallidus. Brain Res. 189: 3-14, 1980.

334. MCCULLOCH, J., AND P. A. T. KELLY. Alterations in local cerebral glucose utilization in specific thalamic nuclei following apomorphine. J . Cereb. Blood Flow Metab. 1: 133-136, 1981.

335. MCCULLOCH, J., H. E. SAVAKI, M. C. MCCULLOCH, J . JEHLE, AND L. SOKOLOFF. The distribution of alterations in energy metabolism in the rat brain produced by apomorphine. Brain Res. 243: 67-80, 1982.

336. MCCULLOCH, J., H. E. SAVAKI, AND L. SOKOLOFF. Influence of dopaminergic systems on the lateral habenular nucleus of the rat. Brain Res. 194: 117-124, 1980.

337. MCGEER, E. G., P. L. MCGEER, S. DARSHAN, D. S. GREWAAL, AND V. K. SINGH. Striatal cholinergic interneurons and their relation to dopaminergic nerve endings. J. Pharmacol. 6: 143- 152, 1975.

338. MCGEER, P. L., T. HATTORI, V. K. SINGH, AND E. G. Mc- GEER. Cholinergic systems in extrapyramidal function. In: The Basal Ganglia, edited by M. D. Yahr. New York: Raven,

339. MCGEER, P. L., AND E. G. MCGEER. Evidence for glutamic acid decarboxylase-containing interneurons in the neostriatum. Brain Res. 91: 331-335, 1975.

340. MCGEER, P. L., E. G. MCGEER, A N D T . HATTORI. Biochemical interactions in the basal ganglia. In: Progress in Brain Re- search. Development and Chemical Specificity of Neurons, edited by M. Cuenod, G. W. Kreutzberg, and F. E. Bloom. Amsterdam: Elsevier, 1979, vol. 51, p. 285-301.

340a.MCGEER, P. L., E. G. MCGEER, U. SCHERER, AND K. SINGH. A glutamatergic corticostriatal path? Brain Res. 128: 369-373, 1977.

341. MCGEER, P. L., E. G. MCGEER, A N D J. S. S U Z U K t . Aging and extrapyramidal function. Arch. Neurol. 34: 33-35, 1977.

342. MCINTYRE, D. C. Amygdala kindling in rats: facilitation after

1976, p. 213-226.


local amygdala norepinephrine depletion with B-hydroxydopamine. Exp. Neurol. 6 9 395-407, 1980.

343. MCINTYRE, D. C., AND N. EDSON. Facilitation of amygdala kindling after norepinephrine depletion with B-hydroxydopamine in rats. Exp. Neurol. 74: 748-757, 1981.

344. MCINTYRE, D. C., M. SAARI, AND B. A. PAPPAS. Potentiation of amygdala kindling in adult or infant rats by injections of 6- hydroxydopamine. Exp. Neurol. 63: 527-544, 1979.

345. MCKELLAR, s., AND A. D. LOEWY. Spinal projections of norepinephrine-containing neurons in the rat. SOC. Neurosci. Abstr. 5: 344, 1979.

346. MCKELLAR, S., A N D A. D. LOEWY. Organization of some brain stem afferents to the paraventricular nucleus of the hypothalamus in the rat. Brain Res. 217: 351-357, 1981.

347. MCKELLAR, S., AND A. D. LOEWY. Efferent projections of the A1 catecholamine cell group in the rat: an autoradiographic study. Bruin Res. 241: 11-29, 1982.

348. MCNAUGHTON, N., AND s. T. MASON. The neuropsychology and neuropharmacology of the dorsal ascending noradrenergic bundle-a review. Prog. Neurobiol. 14: 157-219, 1979.

349. MEIBACH, R. c . , A N D R. KATZMAN. Catecholaminergic innervation of the subthalamic nucleus: evidence for a rostra1 con- tinuation of the A9 (substantia nigra) dopaminergic cell group. Brain Res. 173: 364-368, 1979.

350. MEIBACH, R. c . , AND R. KATZMAN. Origin, course and termination of dopaminergic substantia nigra neurons projecting to the amygdaloid complex in the cat. Neuroscience 6: 2159-2171, 1981.

350a.MOGENSON, G. J., L. w. SWANSON, AND M. WU. Neural projections from nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area: an anatomical and electrophysiological investigation in the rat. J. Neurosci. 3: 189-202, 1983.

350b.MoGE~sON, G. J., AND M. A. NIELSEN. Evidence that an accumbens to subpallidal GABAergic projection contributes to locomotor activity. Brain Res. Bull. 11: 309-314,1983.

Q~OC.MONAKOW, K. H., K. AKERT, AND H. KUNZLE. Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey. Exp. Brain Res. 33: 395-403, 1978.

350d.Moo~ EDLEY, S., AND A. M. GRAYBIEL. The afferent and efferent connections of the feline nucleus tegmenti pedunculopontinus, pars compacta. J . Comp. Neurol. 217: 187-215, 1983.

351. MOORE, R. Y. Brain lesions and amine metabolism. Int. Reo. Neurobiol. 13: 67-91, 1970.

352. MOORE, R. Y. Telencephalic distribution of terminals of brainstem norepinephrine neurons. In: Frontiers in Catecholamine Research, edited by E. Usdin and S. H. Snyder. Oxford, UK: Pergamon, 1973, p. 767-769.

353. MOORE, R. Y. Monoamine neurons innervating the hippocampal formation and septum: organization and response to injury. In: The Hippocampus. Structure and Development, edited by R. L. Isaacson and K. H. Pribam. New York Plenum, 1975, vol. 1, p. 215-237.

354. MOORE, R. Y. Catecholamine innervation of the basal forebrain. 1. The septal area. J. Comp. Neurol. 177: 665-684, 1978.

355. MOORE, R. Y., R. K. BHATNAGAR, AND A. HELLER. Anatom- ical and chemical studies of a nigro-neostriatal projection in the cat. Bruin Res. 30: 119-135, 1971.

355a.MOORE, R. Y., A. BJ~RKLUND, AND u . STENEVI. Plastic changes in the adrenergic innervation of the rat septal area in response to denervation. Brain Res. 33: 13-35, 1971.

356. MOORE, R. Y., AND F. E. BLOOM. Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu. Rev. Neurosci. 1: 129-169, 1978.

357. MOORE, R. Y., AND F. E. BLOOM. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu. Rev. Neurosci. 2: 113- 168,1979.

358. MOORE, R. Y., AND A. HELLER. Monoamine levels and neuronal degeneration in rat brain following lateral hypothalamic

lesions. J. Pharmucol. Exp. Ther. 156: 12-23, 1967. 359. MOORE, S. D., AND P. G. GUYENET. An electrophysiological

study of the forebrain projection of nucleus commissuralis: preliminary identification of presumed A2 catecholaminergic neurons. Brain Res. 263: 211-222, 1983.

360. MORGAN, W. W., AND R. D. HUFFMAN. Effect of catecholaminergic and serotoninergic neurotoxins on locomotor responses in cat (Abstract). Anat. Rec. 196: 129A-l30A, 1980.

361. MORRISON, J. H., S. L. FOOTE, M. E. MOLLIVER, F. E. BLOOM, AND H. G. W. LIDOV. Noradrenergic and serotonergic fibers innervate complementary layers in monkey primary visual cortex: an immunohistochemical study. Proc. Nutl. Acad. Sci. USA 7 9 2401-2405, 1982.

362. MORRISON, J. H., S. L. FOOTE, D. O'CONNOR, A N D F. E. BLOOM. Laminar, tangential and regional organization of the noradrenergic innervation of monkey cortex: dopamine-@-hydroxylase immunohistochemistry. Brain Res. Bull. 9: 309-319, 1982.

363. MORRISON, J. H., R. GRZANNA, M. E. MOLLIVER, AND J. T. COYLE. The distribution and orientation of noradrenergic fibers in neocortex of the rat: an immunofluorescence study. J . Comp. Neurol. 181: 17-40, 1978.

364. MORRISON, J. H., M. E. MOLLIVER, A N D R. GRZANNA. Nor- adrenergic innervation of cerebral cortex: widespread effects of local cortical lesions. Science 205: 313-316, 1979.

365. MORRISON, J. H., M. E. MOLLIVER, R. GRZANNA, AND J. T. COYLE. Noradrenergic innervation patterns in three regions of medial cortex: an immunofluorescence characterization. Brain Res. Bull. 4: 849-857, 1979.

366. MORRISON, J. H., M. E. MOLLIVER, R. GRZANNA, AND J. T. COYLE. The intra-cortical trajectory of the coeruleo-cortical projection in the rat: a tangentially organized cortical afferent. Neuroscience 6: 139-158, 1981.

367. MORUZZI, G., AND H. w. MAGOUN. Brain stem reticular formation and activation of the E. E. G. Electroencephalogr. Clin. Neurophysiol. 1: 455-473, 1949.

368. MOUCHET, P., B. GUERIN, AND C. FEUERSTEIN. Dissociate destruction of noradrenaline and dopamine descending projections in the thoracic spinal cord of the rat. Life Sci. 30: 373- 381, 1981.

369. MROZ, E. A,, M. J. BROWNSTEIN, AND S. E. LEEMAN. Evi- dence for substance P in the striato-nigral tract. Brain Res.

370. MUGNAINI, E., AND A.-L. DAHL. Mode of distribution of aminergic fibers in the cerebellar cortex of the chicken. J. Comp. Neurol. 162: 417-432, 1975.

371. NAGAI, T., K. SATOH, K. IMAMOTO, AND T. MAEDA. Divergent projections of catecholamine neurons of the locus coeruleus as revealed by fluorescent retrograde double labeling technique. Neurosci. Lett. 23: 117-123, 1981.

372. NAGATSU, I., s. INAGAKI, Y. KONDO, N. KARASAWA, AND T. NAGATSU. Immunofluorescent studies on the localization of tyrosine hydroxylase and dopamine-@-hydroxylase in the mes- , di- , and telencephalon of the rat using unperfused fresh frozen sections. Acta Histochem. Cytochem. 12: 20-37, 1979.

372a.NAGY, J. L., D. A. CARTER, J. LEHMANN, AND H. C. FIBIGER. Evidence for a GABA-containing projection from the entopeduncular nucleus to the lateral habenula in the rat. Brain Res.

373. NAGY, J. L., T. LEE, P. SEEMAN, AND H. c. FIBIGER. Direct evidence for presynaptic and postsynaptic dopamine receptors in brain. Nature London 274: 278-281, 1978.

374. NAKAI, Y., AND s. TAKAORI. Influence of norepinephrine- containing neurons derived from the locus coeruleus on lateral geniculate neuronal activities of cats. Brain Res. 71: 47-60, 1974.

375. NAKAMURA, S. Some electrophysiological properties of neurones of rat locus coeruleus. J. Physiol. London 267: 641-658, 1977.

376. NATHANSON, J. A. Cerebral microvessels contain a &adrenergic receptor. Life Sci. 26: 1793-1799, 1980.

377. NATHANSON, J. A., AND G. H. GLASER. Identification of @-

125: 305-311, 1977.

145: 360-364,1978.


adrenergic-sensitive adenylate cyclase in intracranial blood vessels. Nature London 278: 567-569, 1979.

377a.NAUTA, H. J . W. Projections of the pallidal complex: an autoradiographic study in the cat. Neuroscience 4: 1853-1873, 1979.

377b.NAUTA, H. J . w . , A N D M. COLE. Efferent projections of the subthalamic nucleus: an autoradiographic study in monkey and cat. J . Comp. Neurol. 180: 1-16, 1978.

378. NAUTA, H. J. W., M. B. PRITZ, A N D R. J. LASEK. Afferents to the rat caudoputamen studied with horseradish peroxidase: an evaluation of a retrograde neuroanatomical research method. Brain Rex 67: 219-238, 1974.

379. NAUTA, W. J. H., AND V. B. DOMESICK. The anatomy of the extrapyramidal system. In: Dopaminergic Ergot Deriuatiues and Motor Functions, edited by K. Fuxe and D. B. Calne. New York: Pergamon, 1979, p. 3-22. (Wenner-Gren Cent. Int. Symp. Ser., vol. 31.)

380. NAUTA, W. J. H., A N D H. G. J . M. KUYPERS. Some ascending pathways in the brain stem reticular formation. In: Reticular Formation of the Brain, edited by H. H. Jasper, L. D. Proctor, R. S. Knighton, W. C. Noshay, and R. T. Costello. Boston, MA: Little, Brown, 1958, p. 3-30. (Henry Ford Hosp. Int. Symp. 7.)

381. NAUTA, W. J . H., G. P. SMITH, R. L. M. FAULL, AND V. B. DOMESICK. Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience 3: 385-401, 1978.

38“. NEWMAN, R., AND s. s. WINANS. An experimental study of the ventral striatum of the golden hamster. I. Neuronal connections of the nucleus accumbens. J. Comp. Neurol. 191: 167- 192, 1980.

383. NEWMAN, R., AND S. S. WINANS. An experimental study of the ventral striatum of the golden hamster. 11. Neuronal connections of the olfactory tubercle. J . Comp. Neurol. 191: 193- 212, 1980.

?A4. NIEOULLON, A., A. CHERAMY, A N D J. GLOWINSKI. Release of dopamine in vivo from cat substantia nigra. Nature London 266: 375-377, 1977.

385. NIEOULLON, A,, A. CHERAMY, AND J. GLOWINSKI. Release of dopamine from terminals and dendrites of the two nigrostriatal dopaminergic pathways in response to unilateral sensory stimuli in the cat. Nature London 269: 340-342, 1977.

386. NIEOULLON, A., A. CHERAMY, AND J . GLOWINSKI. Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra in the cat. Brain Res. 145: 69-84, 1978.

387. NIEOULLON, A., A. C H E R A M Y , AND J . GLOWINSKI. Release of dopamine in both caudate nuclei and both substantia nigrae in response to unilateral stimulation of cerebellar nuclei in the cat. Brain Res. 148: 143-152, 1978.

388. NIEOULLON, A,, A. CHERAMY, v. LEVIEL, AND J. GLOWINSKI. Effects of the unilateral nigral application of dopaminergic drugs on the in vivo release of dopamine in the two caudate nuclei of the cat. Eur. J . Pharmacol. 53: 289-296, 1979.

389. NOBIN, A,, A N D A. BJORKLUND. Topography of the monoamine neuron systems in the human brain as revealed in fetuses. Acta Physiol. Scand. Suppl. 388 1-40, 1973.

389a.NoMU~A, s., N. MIZUNO, AND T. SUGIMOTO. Direct projections from the pedunculopontine tegmental nucleus to the subthalamic nucleus in the cat. Brain Res. 196: 223-227, 1980.

390. NORBERG, K., B. SCATTON, A N D J. KORF. Amphetamine- induced increase in rat cerebral blood flow: apparent lack of catecholamine involvement. Brain Res. 149: 165-174, 1978.

390a.NORNES, H., A. BJORKLUND, A N D u. STENEVI. Reinnervation of the denervated adult spinal cord of rats by intraspinal transplants of embryonic brain stem neurons. Cell Tissue Res. 230: 15-35, 1983.

391. NYBACK, H. Regional disappearance of catecholamines formed from “C-tyrosine in rat brain. Effect of synthesis inhibitors and chlorpromazine. Acta Pharmacol. Toxicol. 30: 375-390, 1971.

39la.NYGREN, L.-G., AND L. OLSON. On spinal noradrenaline receptor supersensitivity: correlation between nerve terminal densities and flexor reflexes various times after intracisternal 6-hydroxydopamine. Brain Res. 116: 455-470, 1976.

392. NYGREN, L.-G., AND L. OLSON. A new major projection from locus coeruleus: the main source of noradrenergic nerve terminals in the ventral and dorsal columns of t.he spinal cord. Brain Res. 132: 85-93, 1977.

393. NYGREN, L.-G., AND L. OLSON. Intracisternal neurotoxins and monoamine neurons innervating the spinal cord: acute and chronic effects on cell and axon counts and nerve terminal densities. Histochemistry 52: 281-306, 1977.

394. @HI, J., AND K. SHIMIZU. Occurrence of dopamine-containing neurons in the midbrain raphe nuclei of the rat. Neurosci. Lett. 8 317-320, 1978.

Analysis of the time course of changes in hippocampal acetylcholinesterase and choline acetyltransferase activities after various septa1 lesions in the rat: return of enzymatic activity after extensive medioventral lesions. Neuroscitince 2: 641-648, 1977.

395. OLSON, L., A N D K. FUXE. On the projections from the locus coeruleus noradrenaline neurons: the cerebellar innervation. Brain Res. 28: 165-171, 1971.

396. OLSON, L., AND K. FUXE. Further mapping out of central noradrenaline neuron systems: projections of the “subcoeruleus” area. Brain Res. 43: 289-295, 1972.

396a.O~soN, L., A. SEIGER, AND K. FUXE. Heterogeneity of striatal and limbic dopamine innervation: highly fluorescent islands in developing and adult rats. Brain Res. 44: 283-288, 1972.

397. OTTERSEN, 0. P. Afferent connections to the amygdaloid complex of the rat with some observations in the cat. 111. Afferents from the lower brain stem. J . Comp. Neurol. 202:

398. OTTERSEN, 0. P., AND Y. BEN-ARI. Pontine and mesencephalic afferents to the central nucleus of the amygdala of the rat. Neurosci. Lett. 8 329-334, 1978.

399. OWMAN, C., L. EDVINSSON, A N D J . E. HARDEBO. Amine mechanisms and contractile properties of the cerebral micro- vascular endothelium. In: Vascular Neuroeffector Mechanisms, edited by J. A. Bevan, T. Godfraind, R. A. Maxwell, and P. M. Vanhoutte. New York: Raven, 1980, p. 277-290.

400. PALKOVITS, M., M. BROWNSTEIN, J. M. SAAVEDRA, A N D J. AXELROD. Norepinephrine and dopamine content of hypothalamic nuclei of the rat. Brain Res. 77: 137-149, 1974.

401. PALKOVITS, M., w . DEJONG, P. ZANDBERG, D. H. G. VER- STEEG, J. VAN DER GUGTEN, AND C. LERANTH. Central hypertension and nucleus tractus solitarii catecholamines after surgical lesions in the medulla oblongata of the rat. Brain Res. 127: 307-312,1977,

402. PALKOVITS, M., M. FEKETE, G . B. MAKARA, AND J . P. HER- MAN. Total and partial hypothalamic deafferentations for topographical identification of catecholaminergic innervations of certain preoptic and hypothalamic nuclei. Brain Res. 127: 127-136, 1977.

403. PALKOVITS, M., A N D D. M. JACOBOWITZ. Topographic atlas of catecholamine and acetylcholinesterase-containing neurons in the rat brain. 11. Hindbrain (mesencephalon, rhombenceph- alon). J. Comp. Neurol. 1 5 7 29-42, 1974.

404. PALKOVITS, M., C. LERANTH, L. ZABORSZKY, AND M. J. BROWNSTEIN. Electron microscopic evidence of direct neuronal connections from the lower brain stem to the median eminence. Brain Res. 136: 339-344, 1977.

405. PALKOVITS, M., A N D L. ZABORSZKY. Neuroanatomy of central cardiovascular control. Nucleus tractus solitarius: afferent and efferent neuronal connections in relation to the baroreceptor reflex arc. In: Progress in Brain Research. Hypertension and Brain Mechanisms, edited by W. De Jong, A. P. Provoost, and A. P. Shapiro. Amsterdam: Elsevier, 1977, vol. 47, p. 9-34.

406. PALKOVITS, M., L. ZABORSZKY, A. FEMINGER, E. MEZEY, M. I. K. FEKETE, J . P. HERMAN, B. KANYICSKA, AND D. SZABO.

394a.ODERFELD-NOWAK, B., A. POEMPSKA, AND J. ODERFELD.

335-356,1981.


Noradrenergic innervation of the rat hypothalamus: experimental biochemical and electron microscopic studies. Brain Res. 191: 161-171, 1980.

407. PALMER, G. C. Beta adrenergic receptors mediate adenylate cyclase responses in rat cerebral capillaries. Neuropharmacol-

408. PARENT, A. Demonstration of a catecholaminergic pathway from the midbrain to the strio-amygdaloid complex in the turtle (Chrysemys picta). J . Anat. 114: 379-387, 1973.

409. PARENT, A. Distribution of monoamine-containing nerve terminals in the brain of the painted turtle, Chrysemys picta. J . Comp. Neurol. 148: 153-166, 1973.

410. PARENT, A. Distribution of monoamine-containing neurons in the brain stem of the frog, Rana temporaria. J . Morphol. 139:

411. PARENT, A. The monoaminergic innervation of the telencephalon of the frog, Rana pipiens. Brain Res. 99: 35-47, 1975.

412. PARENT, A. Striatal afferent connections in the turtle (Chry- semys picta) as revealed by retrograde axonal transport of horseradish peroxidase. Brain Res. 1 0 8 25-36, 1976.

413. PARENT, A. Monoaminergic systems of the brain. In: Biology of the Reptilia, edited by C. Gans, R. G. Northcutt, and P. Ulinski. London: Academic, 1979, p. 247-285.

413a.PARENT, A., D. POCTRAS, AND L. DUBE. Comparative anatomy of central monoaminergic systems. In: Handbook of Chemical Neuroanutomy edited by A. Bjorklund and T. Hokfelt. Am- sterdam: Elsevier, 1984, vol. 2, 1984, p. 409-439.

414. PARENT, A., L. DUBE, M. R. BRADFORD, JR., AND R. G. NORTHCUTT. The organization of monoamine-containing neurons in the brain of the sunfish (Lepomis gibbosus) as revealed by fluorescence microscopy. J. Comp. Neurol. 182: 495-516, 1978.

415. PARENT, A,, S. GRAVEL, AND R. BOUCHER. The origin of forebrain afferents to the habenula in rat, cat and monkey. Brain Res. Bull. 6: 23-38, 1981.

416. PARENT, A., AND G. NORTHCUTT. The monoamine-containing neurons in the brain of the garfish, Lepisosteus osseus. Brain Res. Bull. 9: 189-204, 1982.

417. PARENT, A,, AND L. J. POIRIER. Occurrence and distribution of monoamine-containing neurons in the brain of the painted turtle, Chrysemys picta. J . Anat. 110 81-89, 1971.

418. PARENT, A., AND D. POITRAS. The origin and distribution of catecholaminergic axon terminals in the cerebral cortex of the turtle (Chrysemys picta). Brain Res. 78: 345-358, 1974.

418a.PARK, M. R., J . W. LIGHTHALL, AND s. T. KITAI. Recurrent inhibition in the rat neostriatum. Brain Res. 194: 359-369, 1980.

419. PASQUIER, D. A., M. A. GOLD, AND D. M. JACOBOWITZ. Noradrenergic perikarya (A5-A7, subcoeruleus) projections to the rat cerebellum. Brain Res. 1 9 6 270-275, 1980.

420. PASQUIER, D. A., AND F. REINOSO-SUAREZ. The topographic organization of hypothalamic and brain stem projections to the hippocampus. Brain Res. Bull. 3: 373-389, 1978.

421. PEARSON, J., M. GOLDSTEIN, K. MARKEY, AND L. BRANDEIS. Human brainstem catecholamine neuronal anatomy as indicated by immunocytochemistry with antibodies to tyrosine hydroxylase. Neuroscience 8 3-22, 1983.

421a.PERT, C. B., M. J. KUHAR, AND s. H. SNYDER. Autoradi- ographic localization of the opiate receptor in rat brain. Life Sci. 1 6 1849-1854, 1975.

422. PERSSON, M., AND L. WIKLUND. Scattered catecholaminergic cells in the dorsolateral tegmentum caudal to locus coeruleus in cat. Neurosci. Lett. 23: 275-280, 1981.

423. PHILLIPSON, 0. T. The cytoarchitecture of the interfascicular nucleus and ventral tegmental area of Tsai in the rat. J. Comp. Neurol. 187: 85-98, 1979.

424. PHILLIPSON, 0. T. Afferent projections to the ventral tegmental area of Tsai and interfascicular nucleus: a horseradish peroxidase study in the rat. J. Comp. Neurol. 187: 117-144, 1979.

425. PHILLIPSON, 0. T., P. C. EMSON, A. S. HORN, AND T. JES-

Ogy 19: 17-23, 1980.

67-78, 1973.

SELL. Evidence concerning the anatomical location of the dopamine stimulated adenylate cyclase in the substantia nigra. Brain Res. 136: 45-58, 1977.

426. PHILLIPSON, 0. T., AND A. C. GRIFFITH. The neurons of origin for the mesohabenular dopamine pathway. Brain Res. 197:

427. PHILLIPSON, 0. T., AND C. J . PYCOCK. Dopamine neurones of the ventral tegmentum project to both medial and lateral habenula. Exp. Brain Res. 45: 89-94, 1982.

427a.PICKEL, V. M., S. c . BECKLEY, T. H. JOH, AND D. J. REIS. Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 225: 373-385,1981.

427b.PICKEL, V. M., H. KREBS, AND F. E. BLOOM. Proliferation of norepinephrine-containing axons in rat cerebellar cortex after peduncle lesions. Brain Res. 59: 169-179, 1973.

428. PICKEL, V. M., M. SEGAL, AND F. E. BLOOM. A radiographic study of the efferent pathways of the nucleus locus coeruleus. J . Comp. Neurol. 1 5 5 15-42, 1974.

429. PICKEL, V. M., L. A. SPECHT, K. K. SUMAL, T. H. JOH, D. J . REIS, AND A. HERVONEN. Immunocytochemical localization of tyrosine hydroxylase in the human fetal nervous system. J. Comp. Neurol. 194: 465-474, 1980.

430. PICKEL, V. M., K. K. SUMAL, S. C. BECKLEY, R. J. MILLER, AND D. J. REIS. Immunocytochemical localization of enkephalin in the neostriatum of rat brain: a light and electron microscopic study. J. Comp. Neurol. 189: 721-740, 1980.

431. POIRIER, L. J., AND T. L. SOURKES. Influence of the substantia nigra on the catecholamine content of the striatum. Brain 88:

432. PORRINO, L. J., AND P. S. GOLDMAN-RAKIC. Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP. J. Comp. Neurol. 205: 63-76, 1982.

433. PRASADA RAO, P. D., AND H. G. HARTWIG. Monoaminergic tracts of the diencephalon and innervation of the pars intermedia in Rana temporaria. Cell Tissue Res. 15: 1-26, 1974.

434. PYCOCK, C., AND C. D. MARSDEN. The rotating rodent: a two component system? Eur. J. Pharmacol. 47: 167-175, 1978.

434a.PYCOCK, C., J. MILSON, D. TARSY, AND C. D. MARSDEN. The effect of manipulation of cholinergic mechanisms on turning behavior in mice with unilateral destruction of the nigrostriatal dopaminergic system. Neuropharmacology 17: 175-183, 1978.

435. RACAGNI, G., F. BRUNO, F. CATTABENI, A. MAGGI, A. M. DI GIULIO, M. PARENTI, A N D A. GROPPETTI. Interactions among dopamine, acetylcholine, and GABA in the nigro-striatal system. In: Interactions Between Putative Neurotransmitters in the Brain, edited by S. Garattini, J. F. Pujol, and R. Samanin. New York: Raven, 1978, p. 61-71.

435a.RAGSDALE, c. w . , AND A. M. GRAYBIEL. The fronto-striatal projection in the cat and monkey and its relationship to inhomogeneities established by acetylcholinesterase histochemistry. Brain Res. 208 259-266, 1981.

436. RAICHLE, M. E., B. K. HARTMAN, J . 0. EICHLING, AND L. G. SHARPE. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc. Natl. Acad. Sci. USA 72:

437. RAMM, P. The locus coeruleus, catecholamines, and REM sleep: a critical review. Behau. Neural. Biol. 2 5 415-448, 1979.

437a.R~MoN Y CAJAL, S. Histologie du systeme nerueux de l’homme et uertebres. Madrid CSIC, Inst. R a m h y Cajal, 1955, vol. 2, p. 275-278.

438. RANDRUP, A., AND I. MUNKVAD. Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologica 11: 300-310, 1967.

439. RANDRUP, A., AND I. MUNKVAD. Biochemical, anatomical and psychological investigations of stereotyped behaviour induced by amphetamines. In: International Symposium on Amphet- amines and Related Compounds: Proceedings, edited by E. Costa and G. Garattini. New York: Raven, 1970, p. 695-713.

440. REUBI, J. C., AND M. CUENOD. Glutamate release in vitro

213-218, 1980.

181-192,1965.

3726-3730, 1975.


from corticostriatal terminals. Brain Res. 176: 185-188, 1979. 441. REUBI, J. C., L. L. IVERSEN, AND T . M. JESSELL. Dopamine

selectively increases 3H-GABA release from slices of rat substantia nigra in vitro. Nature London 268: 652-654, 1977.

44la.RICARD0, J . A. Efferent connections of the subthalamic region in the rat. I. The subthalamic nucleus of Luys. Brain Res. 202:

442. RICARDO, J. A., A N D E. T. KOH. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 153: 1-26, 1978.

443. RILEY, J. N., AND R. Y. MOORE. Diencephalic and brainstem afferents to the hippocampal formation of the rat. Brain Res.

443a.RINvIK, E., I. GROFOVA, c . HAMMOND, J. FEGER, AND J. M. DENIAU. A study of the afferent connections to the subthalamic nucleus in the monkey and the cat using the HRP technique. In: Advances in Neurology. The Extrapyramidal System and Its Disorders, edited by L. J. Poirier, T. L. Sourkes, and P. B6dard. New York: Raven, 1979, vol. 24, p. 53-70.

444. ROBBINS, T . W., A N D B. J. EVERITT. Functional studies of the central catecholamines. Int. Reu. Neurobiol. 23: 303-366, 1982.

445. ROGAWSKI, M. A., AND G. K. AGHAJANIAN. Modulation of lateral geniculate neurone excitability by noradrenaline mi- croiontophoresis or locus coeruleus stimulation. Nature Lon- don 287: 731-734, 1980.

~ ~ ~ ~ . R o L L s , E. T., S. J . THORPE, M. BOYTIM, I. SZABO, AND D. I. PERRETT. Responses of striatal neurons in the behaving monkey. 3. Effects of iontophoretically applied dopamine on normal responsiveness. Neuroscience 12: 1201-1212, 1984.

446. ROOM, P., F. POSTEMA, AND J. KORF. Divergent axon collaterals of rat locus coeruleus neurons: demonstration by a fluorescent double labeling technique. Brain Res. 221: 219-230, 1981.

447. Ross, R. A,, A N D D. J . REIS. Effects of lesions of locus coeruleus on regional distribution of dopamine-(3-hydroxylase activity in rat brain. Brain Res. 73: 161-166, 1974.

448. ROSVOLD, H. E. The frontal lobe system: cortical-subcortical interrelationships. Acta Neurobiol. Exp. 32: 439-460, 1972.

449. ROWLANDS, G. J., AND P. J. ROBERTS. Specific calcium- dependent release of endogenous glutamate from rat striatum is reduced by destruction of the corticostriatal tract. Exp. Brain Res. 39: 239-240, 1980.

450. ROYCE, G. d. Autoradiographic evidence for a discontinuous projection to the caudate nucleus from the centromedian nucleus in the cat. Brain Res. 146: 145-150, 1978.

4 5 0 a . R o ~ c ~ . G. J. Cells of origin of subcortical afferents to the caudate nucleus: a horseradish peroxidase study in the cat. Brain Res. 153: 465-475, 1978.

451. RUFFIEUX, A,, AND w. SCHULTZ. Dopaminergic activation of reticulata neurones in the substantia nigra. Nature London 285: 240-241, 1980.

452. SAAVEDRA, J. M., P. E. SETLER, AND J. W. KEBABIAN. Bio- chemical changes accompanying unilateral 6-hydroxydopamine lesions in the rat substantia nigra. Brain Res. 151: 339- 352,1978.

453. SACHS, C., G. JONSSON, A N D K. FUXE. Mapping of central noradrenaline pathways with 6-hydroxy-dopa. Brain Res. 63:

454. SAKAI, K., D. SALVERT, M. TOURET, A N D M. JOUVET. Afferent connections of the nucleus raphe dorsalis in the cat as visualized by the horseradish peroxidase technique. Brain Res. 137:

257-271,1980,

Bull. 6: 437-444, 1981.

249-261, 1973.

11-35, 1977. 454a.SAKA1, K., M. TOURET, D. SALVERT, L. LEGER, AND M.

JOUVET. Afferent projections to the cat locus coeruleus as visualized by the horseradish peroxidase technique. Brain Res. 119: 21-41,1977.

455. SAKUMOTO, T., M. TOHYAMA, K. SATOH, Y. KIMOTO, T . KINUGASA, 0. TANIZAWA, K. KURACHI, AND N. SHIMIZU. Afferent fiber connections from lower brain stem to hypothalamus studied by the horseradish peroxidase method with spe-

cial reference to noradrenaline innervation. Erp. Brain Res.

456. SAPAWI, R. R., AND I. DIVAC. Absence of evidence for the nigro-cerebellar projection in the rat (Abstract). Neurosci. Lett. 3, Suppl.: S234, 1979.

456a.SAPER, c . B., AND A. D. LOEWY. Projections of the pedunculopontine tegmental nucleus in the r a t evidence for additional extrapyramidal circuitry. Brain Res. 252: 367-372, 1982.

457. SAR, M., W. E. STUMPF, R. J. MILLER, K.-J. CHANG, AND P. CUATRECASAS. Immunohistochemical localization of enkephalin in rat brain and spinal cord. J. Comp. Neurol. 182: 17-38, 1978.

458. SATO, M., AND T. NAKASHIMA. Kindling: secondary epileptogenesis, sleep and catecholamines. Can. J . Neurol. Sci. 2: 439- 446, 1975.

459. SATOH, K. The origin of reticulospinal fibers in the rat: a HRP study. J. Hirnforsch. 20: 313-332, 1979.

460. SATOH, K., M. TOHYAMA, K. YAMAMOTO, T . SAKUMOTO, A N D N. SHIMIZU. Noradrenaline innervation of the spinal cord studied by the horseradish peroxidase method combined with monoamine oxidase staining. Exp. Brain Res. 30, 175-186, 1977.

461. SATTIN, A. Increase in the content of adenosine 3’,5’-monophosphate in mouse forebrain during seizures and prevention of increase by methylxanthines. J. Neurochem. 18 1087-1096, 1971.

462. SAWCHENKO, P. E., A N D L. W. SWANSON. Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses. Science 214: 685-687, 1981.

463. SAWCHENKO, P. E., AND L. W. SWANSON. The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat. Brain Res. Rev. 4:

464. SCATTON, B., H. SIMON, M. LE MOAL, AND s. BISCHOFF. Origin of dopaminergic innervation of the rat hippocampal formation. Neurosci. Lett. 18 125-131, 1980.

464a.SCHEIBEL, M. E., AND A. B. SCHEIBEL. Structural substrates for integrative patterns in the brain stem reticular core. In: Reticular Formation of the Brain, edited by H. H. Jasper, L. D. Proctor, and R. T. Costello. Boston, MA: Little Brown, 1958, p. 31-55. (Henry Ford Hosp. Int. Symp., 7.)

465. SCHWAB, M. E., F. JAVOY-ACID, AND Y. AGID. Labeled wheat germ agglutinin (WGA) as a new, highly sensitive retrograde tracer in the rat brain hippocampal system. Brain Res. 152:

466. SEGAL, M., AND F. E. BLOOM. The action of norepinephrine in the rat hippocampus. IV. The effects of locus coeruleus stimulation on evoked hippocampal unit activity. Brain Res.

467. SEGAL, M., AND S. C. LANDIS. Afferents to the hippocampus of the rat studied with the method of retrograde transport of horseradish peroxidase. Bruin Res. 78: 1-15, 1974.

468. SEGAL, M., AND S. C. LANDIS. Afferents to the septa1 area of the rat studied with the method of retrograde axonal transport of horseradish peroxidase. Brain Res. 82: 263-268, 1974.

469. SEGAL, M., V. PICKEL, AND F. BLOOM. The projections of the nucleus locus coeruleus: an autoradiographic study. Life Sci.

470. SEIGER, A., A N D L. OLSON. Late prenatal ontogeny of central monoamine neurons in the rat: fluorescence histochemical observations. Z. Anat. Entwicklungsgesch. 140: 281-318, 1973.

471. SENBA, E., M. TOHYAMA, S. SHIOSAKA, H. TAKAGI, M. SAK- ANAKA, T . MATSUZAKI, Y. TAKAHASHI, AND N. SHIMIZU. Experimental and morphological studies of the noradrenaline innervations in the nucleus tractus spinalis nervi trigemini of the rat with special reference to their fine structures. Brain Res. 206: 39-50, 1981.

472. SHIK, M. L., AND G. N. ORLOVSKY. Neurophysiology of locomotor automatism. Physiol. Rev. 56: 465-501, 1976.

473. SHIMIZU, O., s. OHNISHI, M. TOHYAMA, AND T. MAEDA. Demonstration by degeneration silver method of the ascending

31: 81-94, 1978.

275-325,1982.

145-150, 1978.

107: 513-525,1976.

13: 817-821, 1973.


projection from the locus coeruleus. Exp. Brain Res. 21: 181- 192,1974.

474. SIGCINS, G. R., E. F. BATTENBERG, B.J. HOFFER, F. E. BLOOM, AND A. L. STEINER. Noradrenergic stimulation of cyclic adenosine monophosphate in rat Purkinje neurons: an immunocytochemical study. Science 179: 585-588, 1972.

475. SIGGINS, G. R., B. J . HOFFER, AND F. E. BLOOM. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. 111. Evidence for mediation of effects by 3’5’- adenosine monophosphate. Bruin Res. 25: 535-553,1971.

Cyclic adenosine monophosphate and norepinephrine: effects on transmembrane properties of cerebellar Purkinje cells. Sci- ence 171: 192-194, 1971.

477. SIMON, H., AND M. LE MOAL. Demonstration by the Fink- Heimer impregnating method of a ventral mesencephalic-locus coeruleus projection in the rat. Experientia 33: 614-616, 1977.

478. SIMON, H., M. LE MOAL, AND A. CALAS. Efferents and afferents of the ventral tegmental-A10 region studied after local injection of [3H]leucine and horseradish peroxidase. Brain Res. 1 7 8 17-40, 1979.

479. SIMON, H., M. LE MOAL, D. GALEY, AND €3. CARDO. Silver impregnation of dopaminergic systems after radiofrequency and 6-OHDA lesions of the rat ventral tegmentum. Brain Res.

480. SIMON, H., M. LE MOAL, L. STINUS, AND A. CALAS. Anatom- ical relationships between the ventral mesencephalic tegmentum-A10 region and the locus coeruleus as demonstrated by anterograde and retrograde tracing techniques. J. Neural Transm. 44: 77-86, 1979.

481. SIRKIN, D. W., A N D P. TEITELBAUM. The pontine reticular formation is part of the output pathway for amphetamine- and apomorphine-induced lateral head movements: evidence from experimental lesions in the rat. Brain Res. 260: 291-296,1983.

482. SKAGERBERG, G., A. BJ~RKLUND, 0. LINDVALL, AND R. H. SCHMIDT. Origin and termination of the diencephalo-spinal dopamine system in the rat. Brain Res. Bull. 9: 237-244, 1982.

482a.SKAGERBERG, G., AND 0. LINDVALL. Organization of diencephalic dopamine neurones projecting to the spinal cord in the rat. Brain Res. 342: 340-351, 1985.

483. SKAGERBERG, G., 0. LINDVALL, AND A. BJORKLUND. Origin, course and termination of the mesohabenular dopamine pathway in the rat. Brain Res. 307: 99-108, 1984.

483a.SMITH, G. c., AND G. FINK. Experimental studies on the origin of monoamine-containing fibres in the hypothalamo-hypophyseal complex of the rat. Brain Res. 43: 37-51, 1975.

484. SMOLEN, A. J., E. J. GLAZER, AND L. L. ROSS. Horseradish peroxidase histochemistry combined with glyoxylic acid-induced fluorescence used to identify brain stem catecholaminergic neurons which project to the chick thoracic spinal cord. Brain Res. 160: 353-357, 1979.

485. SOFRONIEW, M. V., F. ECKENSTEIN, H. THOENEN, AND A. C. CUELLO. Topography of choline acetyltransferase-containing neurons in the forebrain of the rat. Neurosci. Lett. 33: 7-12, 1982.

486. SOMOGYI, P., J. P. BOLAM, AND A. D. SMITH. Monosynaptic cortical input and local axon collaterals of identified striatonigral neurons. A light and electron microscopic study using the Golgi-peroxidase transport-degeneration procedure. J. Comp. Neurol. 195: 567-584,1981.

487. SOMOGYI, P., J. P. BOLAM, s. TOTTERDELL, AND A. D. SMITH. Monosynaptic input from the nucleus accumbens-ventral striatum region to retrogradely labelled nigrostriatal neurones. Bruin Res. 217: 245-263, 1981.

488. SOMOGYI, P., A. J. HODGSON, AND A. D. SMITH. An approach to tracing neuron networks in the cerebral cortex and basal ganglia. Combination of Golgi staining, retrograde transport of horseradish peroxidase and anterograde degeneration of synaptic boutons in the same material. Neuroscience 4: 1805- 1852, 1979.

489. SOMOGYI, P., J. V. PRIESTLEY, A. C. CUELLO, A. D. SMITH,

476. SIGGINS, G. R., A. P. OLIVER, B. J. HOFFER, AND F. E. BLOOM.

115: 215231,1976.

AND d. P. BOLAM. Synaptic connections of substance P- immunoreactive nerve terminals in the substantia nigra of the rat. Cell Tissue Rex 223: 469-486, 1982.

490. SOMOCYI, P., J. V. PRIESTLEY, A. C. CUELLO, A. D. SMITH, AND H. TAKAGI. Synaptic connections of enkephalin-immunoreactive nerve terminals in the neostriatum: a correlated light and electron microscopic study. J. Neurocytol. 11: 779- 807, 1982.

491. SPANO, P. F., M. TRABUCCHI, AND G. DI CHIARA. Localization of nigral dopamine-sensitive adenylate cyclase on neurons originating from the corpus striatum. Science 196: 1343-1345, 1977.

492. SPECIALE, S. G., W. R. CROWLEY, T. L. O’DONOHUE, AND D. M. JACOBOWITZ. Forebrain catecholamine projections of the A5 cell group. Bruin Res. 154: 128-133, 1978.

JORDAN. Effect of noradrenaline and 5-hydroxytryptamine depletion on locomotion in the cat. Brain Res. 185: 349-362, 1981.

493. STEIN, L. Self-stimulation of the brain and the central stim- ulant action of amphetamine. Federation Proc. 23: 836-850, 1964.

494. STEIN, P. S. G. Motor system, with specific reference to the control of locomotion. Annu. Reu. Neurosci. 1: 61-81, 1978.

495. STEINDLER, D. A. Locus coeruleus neurons have axons that branch to the forebrain and cerebellum. Brain Res. 223: 367- 373,1981.

496. STEINDLER, D. A., AND J. M. DENIAU. Anatomical evidence for collateral branching of substantia nigra neurons: a combined horseradish peroxidase and [3H]wheat germ agglutinin axonal transport study in the rat. Brain Res. 196: 228-236, 1980.

497. STENEVI, U., A. BJORKLUND, AND R. Y. MOORE. Growth of intact central adrenergic axons in the denervated lateral geniculate body. Exp. Neurol. 3 5 290-299, 1972.

498. STORM-MATHISEN, J., AND H. C. GULDBERG. 5-Hydroxytryp- tamine and noradrenaline in the hippocampal region: effect of transection of afferent pathways on endogenous levels, high affinity uptake and some transmitter-related enzymes. J. Neu- rochem. 22: 793-803, 1974.

stantia nigra pars reticulata neurons by the nucleus accumbens. Brain Res. Bull. 1: 259-263, 1983.

499. STRICKER, E. M., AND M. J. ZIGMOND. Recovery of function after damage to central catecholamine-containing neurons: a neurochemical model for the lateral hypothalamic syndrome. In: Progress in Psychobiology and Physiological Psychology, edited by J. M. Sprague and A. N. Epstein. New York Aca- demic, 1976, p. 121-188.

500. SUTHERLAND, R. J . The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci. Biobehau. Reu. 6: 1-13, 1982.

500a.SVENDGAARD, N.-A., A. BJORKLUND, AND u . STENEVI. Re- generative properties of central monoamine neurons. Adu. Anat. Embryol. Cell Biol. 51: 1-77, 1975.

501. SWANSON, L. W. The locus coeruleus: a cytoarchitectonic Golgi and immunohistochemical study in the albino rat. Brain Res. 1 1 0 39-56, 1976.

502. SWANSON, L. W. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res.

503. SWANSON, L. W., M. A. CONNELLY, AND B. K. HARTMAN. Ultrastructural evidence for central monoaminergic innervation of blood vessels in the paraventricular nucleus of the hypothalamus. Brain Res. 136: 166-173, 1977.

504. SWANSON, L. w., AND w. M. COWAN. A note on the connections and development of the nucleus accumbens. Brain Res. 92: 324-330, 1975.

505. SWANSON, L. w., AND W. M. COWAN. An autoradiographic study of the organization of the efferent connections of the

492a.STEEVES, J. D., B. J . SCHMIDT, B. J . SKOVGAARD, AND L. M.

498a.STRAHLENDORF, H. K., AND c. D. BARNES. Control of sub-

Bull. 9: 321-353, 1982.


hippocampal formation in the rat. J . Comp. Neurol. 172: 49- 84, 1977.

506. SWANSON, L. W., AND W. M. COWAN. The connections of the septa1 region in the rat. J . Comp. Neurol. 186: 621-656, 1979.

507. SWANSON, L. W., A N D B. K. HARTMAN. The central adrenergic system: an immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-p-hydroxylase as a marker. J. Comp. Neurol. 163: 467- 506, 1975.

ROBINSON. Evidence for a projection from the lateral preoptic area and substantia innominata to the mecencephalic locomotor region in the rat. Brain Res. 295: 161-178, 1984.

508. SWANSON, L. W., P. E. SAWCHENKO, A. BEROD, B. K. HART- M A N , K. B. HELLE, AND D. E. VANORDEN. An immunohistochemical study of the organization of catecholaminergic cells and terminal fields in the paraventricular and supraoptic nuclei of the hypothalamus. J. Comp. Neurol. 196: 271-285, 1981.

508a.SWERDLOW, N. R., L. W. SWANSON, AND G . F. KOOB. Sub- stantia innominata: critical link in the behavioral expression of mesolimbic dopamine stimulation in the rat. Neurosci. Lett.

509. SWITZER, R. C., 111, J. HILL, AND L. HEIMER. The globus pallidus and its rostroventral extension into the olfactory tubercle of the rat: a cyto- and chemoarchitectural study. Neuroscience 7: 1891-1904, 1982.

510. SZABO, J. Distribution of striatal afferents from the mesencephalon in the cat. Brain Res. 188 3-21, 1980.

51 1. SZENTAGOTHAI, J. The parvicellular neurosecretory system. In: Progress in Brain Research. Lectures on the Diencephalon, edited by W. Bargmann and J. P. Schadb. Amsterdam: Else- vier, 1964, vol. 5, p. 135-146.

511a.TA~AG1, H., P. SOMOGYI, J. SOMOGYI, AND A. D. SMITH. Fine structural studies on a type of somatostatin-immunoreactive neuron and its synaptic connections in the rat neostriatum: a correlated light and electron microscopic study. J . Comp. Neu- rol. 214: 1-16, 1983.

512. TAKAHASHI, Y., K. SATOH, T. SAKUMOTO, M. TOHYAMA, AND N. SHIMIZU. A major source of catecholamine terminals in the nucleus tractus solitarii. Brain Res. 172: 372-377, 1979.

513. TAKIGAWA, M., AND G. J. MOGENSON. A study of inputs to antidromically identified neurons of the locus coeruleus. Brain Res. 135: 217-230, 1977.

514. TANAKA, c. , M. ISHIKAWA, AND s. SHIMADA. Histochemical mapping of catecholaminergic neurons and their ascending fiber pathways in the rhesus monkey brain. Brain Res. Bull. 9:

515. TASSIN, J. P., A. CHERAMY, G. BLANC, A. M. THIERRY, AND J. GLOWINSKI. Topographical distribution of dopaminergic innervation and of dopaminergic receptors in the rat striatum. I. Microestimation of [3H]dopamine uptake and dopamine content in microdiscs. Brain Res. 107: 291-301, 1976.

516. TERLOU, M., AND R. E. PLOEMACHER. The distribution of monoamines in the tel- , di- and mesencephalon of Xenopus laeuis tadpoles, with special reference to the hypothalamo- hypophysial system. 2. Zellforsch. Mikrosk. Anat. 137: 521- 540,1973.

517. THIERRY, A. M., J. M. DENIAU, D. HERVE, AND G. CHEVALIER. Electrophysiological evidence for non-dopaminergic mesocortical and mesolimbic neurons in the rat. Brain Res. 201: 210- 214, 1980.

518. THIERRY, A. M., L. STINUS, G. BLANC, AND J. GLOWINSKI. Some evidence for the existence of dopaminergic neurons in the rat cortex. Brain Res. 50: 230-234, 1973.

519. TOHYAMA, M. Comparative anatomy of cerebellar catecholamine innervation from teleosts to mammals. J. Hirnforsch. 17: 43-60,1976.

520. TOHYAMA, M., T . MAEDA, J. HASHIMOTO, G. R. SHRESTHA, 0. TAMURA, AND N. SHIMIZU. Comparative anatomy of the locus coeruleus. I. Organization and ascending projections of the catecholamine-containing neurons in the pontine region

507a.SWANSON, L. w . , G. J. MOCENSON, c. R. GERFEN, A N D P.

5 0 19-24, 1984.

255-270,1982,

of the bird, Melopsittucus undulatus. J . Hirnforsch. 15: 319- 330, 1974.

S~O~.TOHYAMA, M., T . MAEDA, A N D N. SHIMIZU. Detailed noradrenaline pathways of locus coeruleus neuron to the cerebral cortex with use of 6-hydroxydopa. Brain Res. 79: 139-144, 1974.

521. TOHYAMA, M., T. MAEDA, AND N. SHIMIZU. Comparative anatomy of the locus coeruleus. 11. Organization and projection of the catecholamine-containing neurons in the upper rhomb- encephalon of the frog, RQIZU catesbiana. J . Hirnforsch. 16: 81- 89, 1975.

522. TORK, I., AND S. TURNER. Histochemical evidence for a catecholaminergic (presumably dopaminergic) projection from the ventral mesencephalic tegmentum to visual cortex in the cat. Neurosci. Lett. 24: 215-219, 1981.

523. TRIBOLLET, E., AND J. J. DREIFUSS. Localization of neurones projecting to the hypothalamic paraventricuIar nucleus area of the rat: a horseradish peroxidase study. Neuroscience 7:

524. TROTTIER, S., B. BERGER, P. CHAUVEL, J. DEDEK, AND M. GAY. Alterations of the cortical noradrenergic system in chronic cobalt epileptogenic foci in the rat: a histofluorescent and biochemical study. Neuroscience 6: 1069-1080, 1981.

524a.TSUKAMOT0, U., AND F. G. GILLINGHAM. Stereotaxic thala- motomy and L-dopa induced involuntary movement in parkinsonism. Neurol. Med. Chir. 13: 38-45, 1973.

524b.TSUKUHARA, N. Synaptic plasticity in the mammalian central nervous system. Annu. Reu. Neurosci. 4: 351-379, 1981.

525. UNGERSTEDT, U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Scand. Suppl. 367: 1- 48, 1971.

526. UNGERSTEDT, U. Brain dopamine neurons and behavior. In: The Neurosciences: Third Study Program, edited by F. 0. Schmidt and F. G. Worden. Cambridge, MA: MIT Press, 1974,

1315-1328,1981.

p. 695-703. 526b.UNGERSTEDT, u., T. LJUNGBERG, B. HOFFER, AND G. SIC-

GINS. Dopaminergic supersensitivity in the striatum. In: Ad- uances in Neurology. Dopaminergic Mechanisms, edited by D. B. Calne, T. N. Chase, and A. Barbeau. New York: Raven, 1975, vol. 9, p. 57-66.

527. USUNOFF, K. G., R. HASSLER, K. ROMANSKY, P. USUNOVA, AND A. WAGNER. The nigrostriatal projection in the cat. I. Silver impregnation study. J . Neurol. Sci. 2 8 265-288, 1976.

528. USUNOFF, K. G., K. V. ROMANSKY, D. P. IVANOV, AND Z. A. BLAGOV. Electron microscopic study of the projection of fun- dus striati (nucleus accumbens septi) to substantia nigra of the cat, with a note on the topographic distribution of striatonigral fibres. 2. R. Acad. Bulg. Sci. 32: 1125-1128, 1979.

529. VAN DEN BERCH, R. Phylogenese und Anatomie des Lobus limbicus. In: Limbisches System und Epilepsie, edited by F. Heppner. Bern: Huber, 1973, p. 27-51.

Biphasic and opposite effects of dopamine and apomorphine on endogenous GABA release in the rat substantia nigra. J. Neurochern. 34: 119-125, 1980.

530. VAN DER KOOY, D. The organization of the thalamic, nigral and raphe cells projecting to the medial vs lateral caudate- putamen in rat. A fluorescent retrograde double labeling study. Bruin Res. 169: 381-387, 1979.

531. VAN DER KooY, D., AND D. A. CARTER. The organization of the efferent projections and striatal afferents of the entopeduncular nucleus and adjacent areas in the rat. Brain Res. 211:

532. VAN DER KOOY, D., D. V. COSCINA, AND T. HATTORI. Is there a non-dopaminergic nigrostriatal pathway? Neuroscience 6:

5 3 2 a . V ~ ~ DER Koou, D., AND T. HATTORI. Single subthalamic nucleus neurons project to both the globus pallidus and substantia nigra in rat. J. Comp. Neurol. 192: 751-768, 1980.

532b.VAN DER KOOY, D., T. HATTORI, K. SHANNAK, AND 0. HORNYKIEWICZ. The pallido-subthalamic projection in rat: anatomical and biochemical studies. Brain Res. 204, 253-268,

529a.VAN DER HEYDEN, J. A. M., K. VENEMA, A N D J. KORF.

15-36, 1981.

345-357,1981.


1981. 533. VAN DER KOOY, D., AND R. A. WISE. Retrograde fluorescent

tracing of substantia nigra neurons combined with catecholamine histofluorescence. Brain Res. 183: 447-452, 1980.

534. VANDERMAELEN, c. P., AND G. K. AGHAJANIAN. Intracellular studies showing modulation of facial motoneurone excitability by serotonin. Nature London 287: 346-347, 1980.

535. VEENING, J. G., F. M. CORNELISSEN, AND P. A. J. M. LIEVEN. The topical organization of the afferents to the caudatoputamen of the rat. A horseradish peroxidase study. Neuroscience 5: 1253-1268,1980.

A N D K. B. HELLE. Morphological evidence for a dopaminergic terminal field in the hippocampal formation of young and adult rat. Neuroscience 1 4 1039-1052,1985.

536. VERSTEEG, D. H. G., J. VAN DER GUGTEN, W. DE JONG, AND M. PALKOVITS. Regional concentrations of noradrenaline and dopamine in rat brain. Brain Res. 113: 563-574,1976.

537. VIJAYASHANKAR, N., AND H. BRODY. A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging. J. Neuropathol. Exp. Neurol. 3 8 490-497, 1979.

538. VINCENT, S. R., T. HATTORI, AND E. G. MCGEER. The nigrotectal projection: a biochemical and ultrastructural characterization. Brain Res. 151: 159-164, 1978.

539. WALAAS, I. Biochemical evidence for overlapping neocortical and allocortical glutamate projections to the nucleus accumbens and rostra1 caudatoputamen in the rat brain. Neurosci- ence 6 399-405, 1981.

540. WALAAS, I., A N D F. FONNUM. The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions. Brain Res. 117: 325-336, 1979.

541. WALAAS, I., AND F. FONNUM. The effects of surgical and chemical lesions of neurotransmitter candidates in the nucleus accumbens of the rat. Neuroscience 4: 209-216, 1979.

542. WALAAS, I., AND F. FONNUM. Biochemical evidence for y- aminobutyrate containing fibers from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat. Neuroscience 5: 63-72, 1980.

543. WALAAS, I., A N D F. FONNUM. Biochemical evidence for glutamate as a transmitter in hippocampal efferents to the basal forebrain and hypothalamus in the rat brain. Neuroscience 5: 1691-1698,1980.

544. WAMSLEY, J . K., W. S. YOUNG 111, AND M. J. KUHAR. Im- munohistochemical localization of enkephalin in rat forebrain. Brain Res. 190 153-174, 1980.

545. WANG, R. Y. Dopaminergic neurons in the rat ventral tegmental area. 1. Identification and characterization. Brain Res. Reu. 3: 123-140, 1981.

546. WASSEF, M., A. BEROD, A N D C. SOTELO. Dopaminergic dendrites in the pars reticulata of the rat substantia nigra and their striatal input. Combined immunocytochemical localization of tyrosine hydroxylase and anterograde degeneration. Neuroscience 6: 2125-2139, 1981.

547. WASTERLAIN, C. G., AND E. CSISZAR. Cyclic nucleotide metabolism in mouse brain during seizures induced by bicuculline or dibutyryl cyclic guanosine monophosphate. Exp. Neurol. 70:

548. WASZCZAK, B. L., AND J . R. WALTERS. Dopamine modulation of the effects of gamma-aminobutyric acid on substantia nigra pars reticulata neurons. Science 220: 218-221, 1983.

WOODWARD. The distribution of neocortical projection neurons in the locus coeruleus. J. Comp. Neurol. 217: 418-431, 1983.

548b.WATLING, K. J. Transmitter candidates in the retina. Trends Pharmacol. Sci. 2: 244-247, 1981.

549. WEBSTER, K. E. Cortico-striate interrelations in the albino rat. J. Anat. 95: 532-544, 1961.

550. WEINER, R. I., tJ . E. SHRYNE, R. A. GORSKI, AND C. H.

535a.VERNEY, c . , M. BAULAC, B. BERGER, C . ALVAREZ, A. VIGNY,

260-268, 1980.

548a.WATERHOIJSE, B. D., c.-S. LIN, R. A. BURNE, AND D. J.

SAWYER. Changes in the catecholamine content of the rat hypothalamus following deafferentation. Endocrinology 90:

551. WELCH, K. M. A., AND J. A. HELPERN. Do serotonin and noradrenalin neurons project to cerebral capillaries? In: Cere- bral Blood Flow: Effect of Nerves and Neurotransmitters, edited by D. D. Heistad and M. L. Marcus. Amsterdam: Elsevier/ North-Holland, 1982, p. 551-555. (Dev. Neurosci. Ser., vol. 14.)

552. WELLER, K. L., AND D. A. SMITH. Afferent connections to the bed nucleus of the stria terminalis. Brain Res. 232: 255-270, 1982.

553. WESTLUND, K. N., R. M. BOWKER, M. G. ZIEGLER, AND J. D. COULTER. Noradrenergic projections to the spinal cord of the rat. Brain Res. 263: 15-31, 1983.

554. WHITE, S. R., AND R. S. NEUMAN. Facilitation of spinal motoneuron excitability by 5-hydroxytryptamine and noradrenaline. Brain Res. 188 119-127, 1980.

554a.WHITTIER, J . R. Ballism and subthalamic nucleus. Arch. Neu- rol. Psychiatry 58: 672-692, 1947.

555. WIEGAND, S. J., AND J . L. PRICE. Cells of origin of the afferent fibers to the median eminence in the rat. J . Comp. Neurol.

556. WIKLUND, L., L. LEGER, AND M. PERSSON. Monoamine cell distribution in the cat brain stem. A fluorescence histochemical study with quantification of indolaminergic and locus coeruleus cell groups. J. Comp. Neurol. 203: 613-647, 1981.

557. WILSON, C . J., P. M. GROVES, A N D E. FIFKOVA. Monoamin- ergic synapses, including dendro-dendritic synapses in the rat substantia nigra. Exp. Brain Res. 3 0 161-174, 1977.

558. WOODWARD, D. J., H. C. MOISES, B. D. WATERHOUSE, B. J . HOFFER, A N D R. FREEDMAN. Modulatory actions of norepinephrine in the central nervous system. Federation Proc. 38:

559. WOOLF, N. J., AND L. L. BUTCHER. Cholinergic neurons in the caudate-putamen complex proper are intrinsically organized: a combined Evans Blue and acetylcholinesterase analysis. Brain Res. Bull. 7: 487-507, 1981.

560. WUNSCHER, W., W. SCHROBER, AND L. WERNER. Architek- tonischerAt2a.s uon Hirnstamrn der Ratte. Leipzig: Hirzel, 1965.

561. WYSS, J . M., L. W. SWANSON, AND w. M. COWAN. A study of subcortical afferents to the hippocampal formation in the rat. Neuroscience 4: 463-476, 1979.

562. YAMAMOTO, B. K., AND C. R. FREED. The trained circling rat: a model for inducing unilateral caudate dopamine metabolism. Nature London 298: 467-468,1982.

563. YAMAMOTO, K., M. TOHYAMA, AND N. SHIMIZU. Comparative anatomy of the topography of catecholamine containing neuron system in the brain stem from birds to teleosts. J. Hirn- /orsch. 18: 229-240, 1977.

564. YIM, C. Y., AND G. J . MOGENSEN. Electrophysiological studies of neurons in the vental tegmental area of Tsai. Brain Res. 181: 301-313,1980,

564a.YIM, c. Y., AND G. J . MOGENSON. Response of nucleus accumbens neurons to amygdala stimulation and its modification by dopamine. Brain Res. 239: 401-415, 1982.

565. ZABORSZKY, L. Afferent connections of the medial basal hypothalamus. Adu. Anat. Embryol. Cell Bid. 69: 1-107, 1982.

566. ~ABORSZKY, L., M. J . BROWNSTEIN, AND M. PALKOVITS. Ascending projections to the hypothalamus and limbic nuclei from the dorsolateral pontine tegmentum: a biochemical and electron microscopic study. Actu Morphol. Acad. Sci. Hung. 25:

567. ~ABORSZKY, L., A. FEMINGER, AND M. PALKOVITS. Afferent brain stem connections of the central amygdaloid nucleus. Verh. Anat. Ges. 73: 117-1120, 1979.

568. ZEMLAN, F. P., L.-M. Kow, J. I. MORELL, AND D. W. PFAFF. Descending tracts of the lateral columns of the rat spinal cord a study using horseradish peroxidase and silver impregnation techniques. J. Anat. 1 2 8 489-512, 1979.

867-873, 1972.

192: 1-19, 1980.

2109-2116,1979,

175-188, 1977.

Documents

Comprehensive Physiology || Catecholaminergic Brain Stem Regulatory Systems