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D. Ganten and D. Pfaff (Eds.)
Neuroendocrinology o/Mood Coeditor
Contributors
L. F. Agnati, H. Agren, M. Aronsson, M. S. Bauer, G. P. Chrousos A.
Cintra, T. 1. Crow, M. A. Demitrack, M.1. Devlin, 1. N. Ferrier K.
Fuxe, P. W. Gold, R. N. Golden, 1.-A. Gustafsson A. Harfstrand, D.
S. Janowsky, K. Kalogeras, M. A. Kling B. Levant, P. Linkowski, D.
L. Loriaux, N. Matussek H.Y. Meltzer, 1. Mendlewicz, 1. F. Nash
Jr., C. B. Nemeroff R. M. Post, S. C. Risch, D. R. Rubinow, L.
Terenius L. Traskman-Bendz, B. T. Walsh, S. R. B. Weiss, H.
Whitfield P. C. Whybrow, F. A. Wiesel, M. Zoli
With 80 Figures
Editors
Dr. DETLEV OANTEN, M.D., Ph.D. Pharmakologisches Institut
Universitiit Heidelberg 1m Neuenheimer Feld 366 6900
Heidelberg/FRO
Dr. DONALD PFAFF, Ph.D. Rockefeller University York Avenue, and
66th Street New York, NY 10021jUSA
Coeditor
Karolinska Institute P.O. Box 60400 10401 Stockholm, Sweden
The picture on the cover has been taken from Nieuwenhuys R., Voogd
J., van Huijzen Chr.: The Human Central Nervous System. 2nd
Edition. Springer·Veriag Berlin Heidelberg New York 1981
ISBN-13: 978-3-642-72740-5
DOl: 10.1007/978-3-642-72738-2
e-ISBN-13: 978-3-642-72738-2
Library of Congress Cataloging in Publication Data.
Neuroendocrinology of mood. (Current topics in neuroendocrinology;
v. 8) Includes bibliographies and index. 1. Mood (psychology) -
Physiological aspects. 2. Neuroendocrinology. 3. Neurotransmitters.
4. Affective disorders - Physiological aspects. I. Ganten, D.
(Detlev), 1941-. II. PfatT, Donald W., 1939-. III. Fuxe, Kjell. IV.
Agnati,Luigi Francesco. V. Series. QP401.N37 1988 616.89'071
88-4897
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Table of Contents
Principles for the Hormone Regulation of Wiring Transmission and
Volume Transmission in the Central Nervous System By K. Fuxe, L. F.
Agnati, A. Harfstrand, A. Cintra, M. Aronsson, M. Zoli, and J.-A.
Gustafsson With 35 Figures . . . . . . . . . . . . . . . . 1
Clinical Studies with Corticotropin Releasing Hormone: Implications
for Hypothalamic-Pituitary-Adrenal Dysfunction in Depression and
Related Disorders By P. W. Gold, M.A. Kling, M.A. Demitrack, H.
Whitfield, K. Kalogeras, D. L. Loriaux, and G. P. Chrousos With 11
Figures . . . . . . . . . . . . . . . . . . . . 55
Biological Rhythms and Mood Disorders By J. Mendlewicz and P.
Linkowski With 3 Figures. . . . . . . . . . . . . . . . . . . . .
79
Recurrent Affective Disorders: Lessons from Limbic Kindling By R.
M. Post, S. R. B. Weiss, and D. R. Rubinow With 14 Figures . . . .
. . . . . . . . . . . . . . . . 91
The Mechanisms of Action of Antipsychotics and Antidepressant Drugs
By F.A. Wiesel and L. Traskman-Bendz. . . .. . ... 117
Catechohimines and Mood: Neuroendocrine Aspects By N. Matussek With
6 Figures. . . . . . . . . . . . . . . . . . 141
Serotonin and Mood: Neuroendocrine Aspects By H. Y. Meltzer and J.
F. Nash Jr.. . . . .
Cholinergic Mechanisms in Mood: Neuroendocrine Aspects
. 183
By D. S. Janowsky, R. N. Golden, and S. C. Risch . . . . .
211
The Psychobiology of Neurotensin By B. Levant and C. B. Nemeroff
With 6 Figures. . . . . . . . . . . . . . . . . . . . . 231
VI Table of Contents
Cholecystokinin and Mood By 1. N. Ferrier and T. J. Crow. . ...
263
Opioid Peptides and Mood: Neuroendocrine Aspects By H. Agren and L.
Terenius . . . . . . . . . . . 273
The Neuroendocrinology of Anorexia Nervosa By M.J. Devlin and B. T.
Walsh With 5 Figures. . . . . . . . . . . . . . . . . . . . .
291
Effects of Peripheral Thyroid Hormones on the Central Nervous
System: Relevance to Disorders of Mood By P. C. Whybrow and M. S.
Bauer. 309
Subject Index . . . . . . . . . . 329
Principles for the Hormone Regulation of Wiring Transmission and
Volume Transmission in the Central Nervous System * K. Fuxe 1, L.
F. Agnati 2, A. Harfstrand 1, A. Cintra 1, M. Aronsson 1
M. Zoli 2 and J .-A. Gustafsson 3
Contents
1 Introduction . 2 Humoral Modulation of Wiring Transmission . . .
7 3 Actions of Gonadal Steroids on Wiring Transmission 7
3.1 General Aspects . . . . . . . . . . . . . . 7 3.2 Studies on
Presynaptic Features of Monoamine Neurons. 10 3.3 Studies on
Monoamine Receptor Mechanisms . 12
4 Actions of Glucocorticoids on Wiring Transmission. . . . . 15 4.1
General Aspects . . . . . . . . . . . . . . . . . . 15 4.2
Morphometric and Microdensitometric Analysis of GR
Immunoreactivity
in the Central Nervous System . . . . . . . . . . . . 26 4.3
Studies on Presynaptic Features of Monoamine Neurons. 30 4.4
Studies on Monoamine Receptor Mechanisms . . 32
5 Actions of Thyroid Hormones on Wiring transmission. . . . 34 5.1
General Aspects . . . . . . . . . . . . . . . . . . 34 5.2 Studies
on Presynaptic Features of Monoamine Neurons . 35 5.3 Studies on
Monoamine Receptor Mechanisms 36
6 The Humoral Modulation of Volume Transmission 38 7 Aspects on the
Organization Principles of the CNS 38
7.1 Modules of Wiring Transmission . . . . . . 40 7.2 Modules of
Volume Transmission. . . . . . 41 7.3 Functional Aspects on the
Modular Organization 41
8 Summary 43 References. . . . . . . . . . . . . . . . . . . .
47
1 Introduction
We have recently suggested the existence in the central nervous
system of two types of electrochemical transmission, namely wiring
transmission (WT) and volume transmission (VT) (see Agnati et al.
1986a, b). The concepts are summarized in Tables 1 and 2. VT is a
humoral type of chemical transmission. However, it
* This work has been supported by a grant (04X-715) from the
Swedish Medical Research Council, a grant (MH25504) from the NIH, a
grant from the Wallenberg Foundation, and CNR-I, MDI grants
1 Department of Histology and Neurobiology, Karolinska Institute,
P.O. Box 60400, S-10401 Stockholm, Sweden
2 Department of Human Physiology, University of Modena, Modena,
Italy 3 Department of Medical Nutrition, Huddinge Hospital,
Huddinge, Sweden
Current Topics in Neuroendocrinology, Vol. 8 © Springer-Verlag
Berlin Heidelberg 1988
T ab
le 1
• TltAN.MI~ltCTl
DltECE~(lIl
/ / '//' / .L/"'/
-1 ~ ~ / ,~
_U.w;tIO ...
Fig. I. Integrative features of the chemical synapse. The multiple
transmission lines of the intramembrane receptor-receptor
interactions are illustrated. The local circuit is shown as an
electrometabolic unit
consists not only of humoral and paracrine signals, diffusing in
the extracellular fluid to reach the appropriate receptors, but
also of electrotonic signals, which also operate in the
extracellular fluid. In fact, the extracellular space of the brain
consti tutes a restricted microenvironment. Thus, ion fluxes
across cellular membranes can induce substantial changes in the ion
composition. These ionic fluctuations in the extracellular fluid
and the ionic fluxes from sources to sinks may represent
Hormones and Synaptic Transmission 5
7777G~==·=----![9777ZZ I REC£PTOA- RECEPTOR INTERACTION I
Fig. 2. The n-dimensional representation of synaptic
transmission
signals for communication between neural groups (Nicholson 1980).
In Table 1 the possible role of glia and neurons in WT and VT is
summarized. In VT the glial cells control the extracellular fluid
ion composition and the shaping of the extra cellular fluid
pathways (i.e., the communication channels between neural groups)
for signal diffusion as well as the release, uptake and metabolism
of humoral and paracrine signals. With regard to the function of
neurons in VT they represent the location of sources and sinks for
electrotonic signals and the sites of release and recognition of
humoral and paracrine signals. From a biochemical standpoint the
neurons control the sources and sinks of electrotonic signals and
are involved in the uptake, release and metabolism of humoral and
paracrine signals. When we focus our attention on chemical signals
in WT and VT it is possible to recognize some main differential
features. Thus, as seen in Table 2, the VT is characterized by low
speed and long-term action, a high degree of divergence and
plasticity and low safety of the transmission process. WT is the
classical type of transmission which is neuron-linked and operates
with high speed and safety and short-term actions, the divergency
and plasticity being low. It seems clear that the integrative
capability of the central and peripheral nervous system is
increased by the pres ence of VT, which is not submitted to
neuroanatomical constraints and may af fect the computing
charateristics of the neuronal networks.
In order to understand the actions of hormonal and paracrine
signals on WT it is important to emphasize that the synapse is now
regarded as a highly complex
6 K. Fuxe et al.
- - - - - - - - - 1- - - - - - - - - - .. - - -- --.
, '~ " e
PRESYNAPTIC I SIGNAL
.. z
i~ rJ 2!:! ;:: ...... 2" - rn .. if ffi ~~ ~ 02 a: a: .. " >-% %
Z IJ IJ o IJ
INTRACELLULAR
~ MACHINERY
~ FILTERING AND INTEGRATION OF SIGNALS
RESET OFTHE SENSITIVITY AND OF THE INTEGRATIVE FEATURES OF
RECOGNITION AND DECODING SYSTE MS FOR EXTRACELLULAR SIGNALS
Fig. 3. Possible interaction between volume transmission and wiring
transmission at membrane as well as at intracellular levels. At the
intracellular level different targets for the modulatory
interactions can be considered, such as rn
phosphorylation/dephosphorylation of the receptor complex; [2]
cyclic nucleotide cascades; [3] lipid composition and polarization
of the membrane
electrometabolic integrative unit (see Fig. 1). It consists of
multiple transmission lines (Agnati et al. 1983, 1984a; Fuxe et al.
1984a), which interact with one an other at the pre- and
postsynaptic membrane via intramembrane receptor-recep tor
interactions (Fuxe and Agnati 1985) and via postreceptor
intracellular signals. Furthermore, the ionic and metabolic
responses participate in the integrative ac tivity of the synaptic
membranes. In Fig. 2 the complexity of the integration is il
lustrated at the membrane level, where filtration and integration
signals take place. The intracytoplasmatic mechanisms control the
recognition sites and the decoding mechanisms in the membrane for
extracellular fluid signals, in this way, for example, resetting
sensitivity in the integrative capacity of the receptor mech
anisms. Hormonal and paracrine signals can directly modulate the
receptor charac teristics or the receptor-receptor interactions in
the membrane (Fig. 3). The intra cellular machinery and its short-
and long-term regulation of the receptor mech anisms is also
influenced, probably mainly via nuclear actions, at least as far as
steroid and thyroid hormones are concerned (see Fuxe et al. 1981
b). The electro tonic signals in the VT control the membrane
polarization, in this way influencing the opening and closure of
ionic channels. Changes in membrane polarization
Hormones and Synaptic Transmission 7
probably lead to allosteric changes in intramembrane proteins of
the receptor complex and ion pumps. In this way electrical
information can be transformed into chemical information. Thus, the
two languages of the brain, i.e. the electrical and chemical
signals, can be interconverted and the information coded into these
two languages effectively integrated.
The above concept on WT and VT makes it easier to understand how
mood can be affected by hormones such as steroid and thyroid
hormones. We have, for example, observed that glucocorticoid
receptor (Fuxe et al. 1985d) immunoreac tivity exist in very large
numbers of nerve cells all over the cortical hemispheres (archi-,
paleo- and neocortex), with predominant nuclear location. Thus, WT
in the cortical areas of the brain controlling mood can be
massively influenced by these hormones, which represent important
signals in VT. Furthermore, these hormones also influence VT on the
cortical networks subserving mood, since they can, by direct
nuclear actions, regulate the synthesis and release of paracrine
sig nals such as peptides from the cortical nerve cells to reach
distant receptor pop ulations in the cerebral cortex (see Fuxe
etal. 1985 a; Agnati et al. 1986b). Finally, in the frame of VT we
can surmise that psychoactive drugs, even if they work on the
wiring transmission (e.g. at synaptic level) reach their targets
according to a VT mode. This gives further evidence that that
endogenous signals may also effect WT by diffusing in the
extracellular fluid of the brain. Mood control can be con sidered
as the concerted result of a large number of endogenous and
exogenous signals affecting the networks subserving mood via
actions on WT and VT.
2 Humoral Modulation of Wiring Transmission
Firstly, it must be considered that there exists a blood-brain
barrier, so that the central nervous system will not receive a
number of peripheral signals. However, there also exist chemical
and physical "windows" through which the brain re ceives and
delivers lipophobic messages. Chemical windows consist of fa
cilitated transport, active transports etc. The physical windows
are represented by brain areas devoid of the blood-brain barrier,
such as the area postrema, the me dian eminence and the subfomical
organ. Also the neuronal inputs represent a part of the physical
window (see Fig. 4).
3 Actions of Gonadal Steroids on Wiring Transmission
3.1 General Aspects
By means of auto radiographic and steroid receptor binding
techniques nerve cells concentrating steroid sex hormone have been
demonstrated in the central nervous system and been found to be
concentrated in the limbic forebrain, the medial pre optic area
and the hypothalamus, especially the medial part (see Cottingham
and
8 K. Fuxe et al.
CSF
CNS (VT and WT)
PNS (VT and WT)
Fig. 4. Schematic illustration of interac tions between central
nervous system (CNS), peripheral nervous system (PNS) and endocrine
organs via volume trans mission (VI) and wiring transmission (WI).
The role of circumventricular or gans (CVOs) as "physical" windows
for blood signals not passing the blood-brain barrier is indicated
(e.g., peptide hor mones). CSF, cerebrospinal fluid
Pfaff 1986; Stumpf 1968; Stumpf and Sar 1975b,c, 1978, 1981; Sar
and Stumpf 1973, 1977). Recently, Cintra et al. (1986) have
demonstrated, by means of a rat monoclonal antibody directed
against the human estrogen receptor, purified from MCF-7 human
breast cancer cells, that estrogen receptor immunoreactive (IR)
nerve cells exist in the limbic forebrain areas, in the
hypothalamus and the preoptic area with the same distribution as
the estrogen-accumulating nerve cells (Figs. 5 and 6). Of
substantial interest was the observation that the estrogen re
ceptor immunoreactivity was exclusively present within the nuclei
and that no translocation of the IR material took place in the
cytoplasm following castration. These results strongly support the
importance of the genomic actions of es trogens, inducing changes
in the decoding of various types of proteins.
By means of combined autoradiography and immunohistochemistry it
has been possible to demonstrate the accumulation of steroid
hormones in transmit ter-identified neurons such as dopamine (DA),
noradrenaline (NA), vasopressin, p-endorphin, y-aminobutyric acid
(GABA) and somatotastin nerve cells (see Heritage et al. 1977;
Stumpf and Sar 1981; Wuttke et al. 1981). As pointed out
Fig.6. Camera lucida drawing of distribution of estrogen receptor
immunoreactivity pre sent in nuclei of nerve cells of the preoptic
area and adjacent regions in a coronal section of the normal male
rat brain. BSTL, bed nucleus striae terminalis, lateral part; BSTM,
bed nucleus striae terminalis, medial part;/, fornix; GP, globus
pallidus; HDB, nucleus of the horizontal limb of the diagonal band;
ICj, island of Calleja; LPO, lateral preoptic area; MPN, median
preoptic nucleus; MPO, medial preoptic area; ox, optic chiasm;
PVHap, paraventricular nucleus, anterior parvocellular part; PvPO,
periventricular preoptic nu cleus; sm, striae medullaris of the
thalamus; SO, supraoptic hypothalamic nucleus; Tu, ol factory
tubercle; VP, ventral pallidum; III V, third ventricle
Hormones and Synaptic Transmission 9
• ' . . '
'. "
" : .. ~.
.' , ."
.1 '
I.
·LJt '-, " I I .. I \ ' -ny, I \ 1\ " • , • I \ ~ I :.. \ I \ I ;'
I \ \ eSTM /"" \ GP \ I \ " • \
" ., "It ," :~. \
. I' •• ,....." ,; ~·,·H·..:P I. .. ..... "", .:.: ",'" ;r't/,.
,,01- ~ " • .;1
I·'·.···· 1"" .', .. ~., .. ~ ;"" .rr' :. I":: • :.~,:. . :,.."".""
. ,' VP . ~ .Ut. .. (sSTI~· ... ,'1.-.: ', \ f'J. :'1'" 'c' ......
~. ...... r . . . .. \
l~ •• ':S.4.., .'. .•. . \ 1'!~~;\" " " .; '-____ _ i'~'
.:::'iL';f'~ .:. : ./. '. '
t ,,4: l,: •• '.1" ,,: ., 0; • .... 1·.. "'MPH ht . { .... 'i
!:".,' " ' ~~.t-:. t~ It, " l u-~,I:.. .,/ ""ff- :. .... t.i'~· I
.' ,,' "'\ ... V ;. •.•. : .. I .
-l.~ . .cp'dj,hpO " ot
.I'!'---- .............. f Hoe ..
10 K. Fuxe et al.
by Cottingham and Pfaff (1986) sex steroid hormone-binding neurons
exhibit a high degree of interconnectedness. A network of steroid
hormone-binding neurons is created which allows the amplification
of steroid hormone actions and stability in the performance of the
hormone-dependent network, as well as appro priate channeling of
the inputs to this network (see Cottingham and Pfaff 1986). Thus,
these hormone-dependent networks can be influenced by sex steroid
hor mones in the medial hypothalamus, in the preoptic area and in
the limbic system, additionally enabling coordination of activity
in the networks controlling repro ductive behaviours and the
secretion of luteinizing hormone-releasing hormone (LHRH) and of
prolactin.
It should also be mentioned that regional levels of p-endorphin
immunoreac tivity and enkephalin immunoreactivity are altered in
the neuroendocrine areas of the hypothalamus and of the preoptic
area by estrogen treatment (see Dupont et al. 1981). It will be of
substantial interest to evaluate the possible presence of estrogen
immunoreactivity within these neurons of the mediobasal
hypothalamus and of the preoptic area.
In agreement with the importance of genomic actions of estrogen it
has been found that estrogens can regulate tyrosine hydroxylase
gene transcription in the arcuate nucleus of the rat hypothalamus
(Blum et al. 1985). Estrogens can also regulate proopiomelanocortin
(POMC) gene expression in the rat hypothalamus. A decrease has been
seen in POMC mRNA levels after estrogen treatment which is due at
least in part to a decrease in the synthesis ofPOMC mRNA (see
Roberts et al. 1985). As a matter of fact it seems likely that the
majority of sex steroid ac tions on the presynaptic properties of
transmitter-identified neurons, such as ef fects on synthesis
mechanisms and release mechanisms for neurotransmitters, e.g.
monoamines, and GABA are secondary to primary actions on the
decoding of the genome of the estrogen IR neurons of the brain (for
review, see McEwen et al. 1981).
3.2 Studies on Presynaptic Features of Monoamine Neurons
Estradiol-17 p, progesterone and androgens have all been found to
induce discrete changes in DA, NA and adrenaline (A) levels and
utilization in the hypothalamus and in the preoptic area in male
and female rats in various types of endocrine states (see Fuxe et
al. 1981 a; Andersson et al. 1981; Wuttke et al. 1981; Lofstrom and
Beckstrom 1981; Fuxe et al. 1977a). Estradiol-17P appears to
produce its central inhibitory feedback action on LHRH secretion at
least in part by a direct action on the hypothalamus, leading to an
activation of the lateral tuberoinfun dibular DA pathway, which in
tum, by axoaxonic influence and/or by effects on tanycytes, may
inhibit the secretion of LHRH from the median eminence (see Quimet
et al. 1984). This action ofestradiol-17P may be mediated partly by
an increase in the secretion of prolactin, which has the ability of
increasing DA turn over in the lateral palisade -zone of the
median eminence, where the LHRH and DA terminals interact (see Fuxe
et al. 1984 b). However, it must also be consid ered that estrogen
receptors are probably located in many of the DA nerve cell bodies
of the mediobasal hypothalamus (see Heritage et al. 1977) and that
es-
Hormones and Synaptic Transmission 11
trogen treatment of hypophysectomized and castrated animals leads
to a marked increase ofDA utilization in both the lateral and the
medial palisade zones of the median eminence (Fuxe et al. 1981
a).
The central facilitatory feedback action of estradiol-17 p on LHRH
secretion instead appears to involve an increase of NA utilization
in the medial preoptic area (see Fuxe et al. 1977a; Lofstrom and
Beckstrom 1981; Wuttke et al. 1981). It has been postulated that
this action of estrogen involves an inhibition of GABA interneurons
in the medial preoptic area (see Wuttke et al. 1981). Thus,
muscimol, when given intraventricularly, can reduce NA turnover in
the anterior hypothal amus (see Fuxe et al. 1979a).
Intraventricular injection of GABA also reduces NA turnover in the
medial preoptic area (see Wuttke et al. 1981). Thus, the cen tral
facilitatory feedback action of estrogen appears to involve
increased NA re lease in the medial preoptic area mediated at
least partly via an action on es trogen-sensitive GABAergic
neurons in this region, leading to a loss of presyn aptic
inhibition ofNA release (see Wuttke et al. 1981).
Evidence has also been obtained that androgenic steroids can
produce discrete change of DA and NA utilization in the
hypothalamus and preoptic area by ac tivation of androgenic
steroid receptors (see Andersson et al. 1981). Thus, evi dence was
obtained that the activity in noradrenergic mechanisms of the
preoptic area can be turned off by the androgenic steroid R1881,
while the inhibitory do paminergic mechanism in the median
eminence is turned on by this agent. As re ported above, similar
results have been obtained following treatment of castrated female
rats with estrogens such that estrogen produces its central
inhibitory feed back action on LHRH secretion.
The above results taken together indicate that sex steroids, by
means of changes in genetic transcription via their nuclear
actions, alter the formation of regulatory proteins controlling the
chemical transmission in the steroid target cells. By axoaxonic
contacts the steroid target cells in the local circuits of various
regions of hypothalamus and preoptic area will influence the
various DA and NA nerve terminal systems in a discrete way, as
observed in the above-mentioned ex periments (see Fuxe et al.
1979b).
However, estrogens not only influence catecholamine turnover in
regions where estrogen IR nerve cells exist but also influence DA
utilization in parts of the forebrain where few estrogen IR nerve
cells are found. In the hypophysecto mized and castrated female
rat it has, for example, been found that estradiol-17 p can
markedly reduce DA utilization in various parts of the striatum and
of the nucleus accumbens. These results may be induced by
activation of estrogen recep tors of neural groups within the
preoptic area and the hypothalamus which pro ject to the ascending
DA neurons and thus indirectly regulate DA utilization in the meso
striatal and meso limbic systems. These results clearly indicate
that es trogens can also modulate motor functions and mental
activities such as mood (see Fuxe et al. 1981 b). When discussing
the actions of estrogens on the striatal mechanisms, behavioural
and neurochemical studies have also indicated antido paminergic
actions, which may be mediated at least in part via the pituitary
gland through increases in the secretion of prolactin (see Euvrard
and Boissier 1981). Estrogens are known to alleviate extrapyramidal
symptoms such as hyperkinesias in patients receiving neuroleptic
drugs (see Bedard et al. 1981).
12 K. Fuxe et al.
Of special interest are our recent observations that steroid
hormones can in fluence the coexistence of peptides and monoamines
(Hokfelt et al. 1980) in the monoamine neurons (Fuxe et al. 1985
a), probably mainly via an influence on the synthesis of the
peptide comodulator (see Sect. 4.2. paragraph on glucocorticoid
receptors).
3.3 Studies on Monoamine Receptor Mechanisms
In a number of papers, estrogen, progesterone and other sex
steroids have been found to modulate the binding characteristics of
central oc- and fJ-adrenergic re ceptors (Fuxe et al. 1979b,c;
Wilkinson 1978; Wilkinson et al. 1979a,b, 1981). Our results have
demonstrated that the oc- and fJ-adrenergic receptors are sensitive
to combined treatment with estrogen and progesterone resulting in
the induction of sexual behaviour. The changes induced in the
binding characteristics are ligand and region specifIc. In
contrast, the gonadal steroids have been found to exert little
effect on opiate receptor binding parameters (see Wilkinson et al.
1981; for review see McEwen et aI1970). Estrogen treatment has also
been found to influ ence the 5-HTt receptors and D2 receptors in
the striatum. The effects of estrogen on striatal D2 receptors are
complex. It was found at an early stage that estrogen can produce
an increase in the number ofD2 receptors in striatal membranes (see
Bedard et al. 1981; Fuxe et al. 1979c). These biochemical signs of
DA receptor hypersensitivity may be related to the conversion of
estrogens to catecholes trogens and/or to reduced DA release (Fuxe
et al. 1981 a; Gordon 1985). How ever, the acute actions of
estradiol on DA receptors produce a direct desensitiza tion or an
uncoupling of the receptor-effector mechanisms, characterized by a
de crease in the proportion ofD2 receptors in the high-affinity
agonist state (Gordon 1985).
It seems likely that most of the effects of estrogen and
progesterone treatment on monoamine receptors in steroid
receptor-rich areas of the brain are produced via actions on the
estrogen and progesterone receptors present in these areas. The
activation of the steroid receptors may in turn produce changes in
genetic tran scription which can affect various aspects of
biochemical signals regulating monoamine and other types of
receptors (see Agnati et al. 1981; McEwen et al. 1981). This
hyothesis is supported by the ability of in vivo estrogen
administra tion to produce sustained and delayed increases in the
receptor density values of transmitter receptors in regions where
estrogen receptor immunoreactivity exists. Nongenomic actions of
sex steroids are probably also involved, however, since changes in
the binding characteristics of monoamine receptors can also be dem
onstrated in membrane preparations upon in vitro addition of the
steroid. This may be the case in the above-mentioned estrogenic
modulation of striatal DA re ceptor sensitivity. Membrane actions
have also been demonstrated in a number of electrophysiological and
biochemical experiments (see Baulieu 1981; Moss and Dudley 1985).
Thus, within seconds estradiol-17oc-butyric acid inhibits the
firing rate of nerve cells applied directly to the membrane of
these cells (Carette et al. 1979). These estrogen derivatives
cannot cross the cell membrane. Furthermore, progesterone on the
surface of maturing Xenopus laevis oocytes promotes oocyte
C H
E M
IC A
N -4
C O
E X
IS T
E N
C E
GENETIC TRANSCRIPTION
GENETIC TRANSCRIPTION
Fig.8. Schematic illustration of the possible interrelationships
between catecholamine (Rc.J and estrogen (RE) receptors in target
nerve cells. LAC, low-affinity component; HAC, high-affinity
component
meiosis without entering the cell (see Baulieu 1981). Also,
progesterone has re cently been found in vitro to activate LHRH
and DA nerve terminals by a non genomic mechanism (Ramirez 1985).
These effects, however, appear to be medi ated via the metabolite
pregnenolone, which has shown to exhibit highly potent activation
of DA terminals in the hypothalamus and in the striatum. It was
sug gested that membrane actions of steroids may lead to changes
in the transduction mechanisms, resulting in changes in adenylate
cyclase and phospholipase C activ ity. In this way a chain of
events may be started, leading finally to the release of LHRH and
DA demonstrated in vitro on incubation with progesterone or preg
nenolone. Thus, it seems likely that sex steroids can regulate
membrane excitabil ity, possibly via a special membrane site,
since the action of estrogen on the mem brane appears to be
antagonized by antiestrogens (see Moss and Dudley 1985). An effect
of membrane fluidity should, however, also be considered. These
mem brane changes could also affect the interactions among
intramembrane macro molecular complexes, such as ion pumps, ion
channels, etc. In particular, it seems likely that the membrane
actions of gonodal steroids could also modulate the re
ceptor-receptor interactions (see the paragraph below on
glucocorticoid recep tors). This steroid action could thus have a
role on information handling by neural networks. In fact, as
discussed above, intramembrane receptor-receptor interactions
represent an important integrative mechanism in synaptic trans
mission allowing for a divergence and convergence of information
flow in the synapses (see Fig. 7). They also increase the number of
information signals which can be produced.
It should also be mentioned that gonadal steroids such as estrogen
influence the transduction mechanisms; this is illustrated by a
reduction ofhistamine-stim ulated adenylate cyclase following 7
days of treatment with estrogen and reduc tion in
isoproterenol-stimulated adenylate cyclase upon chronic estrogen
treat ment (see McEwen et al. 1981).
It must be emphasized, however, that not only can VT influence WT,
but WT can also influence VT, as illustrated in Fig. 8. Thus,
indications exist that cate cholamine and serotonin (5-HT)
receptors also can regulate steroid receptor syn-
Hormones and Synaptic Transmission 15
thesis (see Ginsburg et ai. 1977; Kitayama et aI., unpublished
observations). Thus, the networks of the brain regulate their own
sensitivity to hormonal signals by controlling the amount of
steroid receptors present in the nerve cells. Of special interest
in this regard is the fact that unsaturated fatty acids can affect
sex steroid hormone receptors in the brain (see Kato 1985). Thus,
transmitter receptors such as catecholamine receptors may, via
regulation of phospholipase C, control the formation of unsaturated
fatty acids, such as arachidonic acid, which when reach ing
cytoplasmatic steroidal receptors inhibit the binding capability of
these recep tors (see Kato 1985).
4 Actions of Glucocorticoids on Wiring Transmission
4.1 General Aspects
The existence of specific receptors for glucocorticoid steroids in
the central ner vous system was first provided in biochemical
studies by McEwen et ai. (1969, 1970). The nuclear concentration of
3H-corticosterone, as seen using autoradiog raphy , indicated that
the receptors for glucocorticoid hormones are mainly nu clear in
location. They were found principally within hippocampal formation,
the septal area and the amygdaloid cortex. Corticosterone target
neurons were also observed in the thalamus, but not within the
hypothalamus, and in the preoptic area (see Stumpf and Sar, 1975a,
1981; see McEwen 1982; see Ganten and Pfaff 1982). However, by
means of monoclonal antibodies against the rat liver glu
cocorticoid receptor (GR) in combination with the indirect
immunoperoxidase technique, we have been able to demonstrate GR IR
nerve and glial cells all over the brain and spinal cord of the
male rat (Fig. 9) (Fuxe et ai. 1985 b-d, 1987; Ag nati et al.
1985). The GR immunoreactivity in the nerve cells was found mainly
in the nucleus, but also in the cytoplasm (Figs. 10 and 11).
Following 2-4 day ad renalectomy the nuclear GR immunoreactivity
of the nerve cells was found to dis appear but the weak
cytoplasmatic GR immunoreactivity remained. Following 4 h of
treatment with corticosterone the GR immunoreactivity reappeared in
the cell nuclei (Fig. 11). GR IR glial cells were mainly found in
the white matter (Fig.9), where they formed bands of cubic-like
structures between the fiber bundles, probably mainly representing
glial cells of the oligodendroglia type.
"
• • • • • • • •
• •
•
• • • , • • • • • •
• • .. • Fig. 10. Cellular localization of glucocorticoid receptor
(OR) immunoreactivity (OR IR) in nerve cells of the frontoparietal
cortex of the male rat. In the pyramidal nerve cells the OR
immunoreactivity is seen not only in the nucleus but also in the
pericaryon and in the apical dendrite. Bar, 200 Ilm
Fig.n. Localization of glucocorticoid receptor (GR)
immunoreactivity in pyramidal nerve cell nuclei and sur rounding
cytoplasm in the hippocam pal subregion CAl and its modulation by
adrenalectomy with or without sub sequent corticosterone treatment
(4 h, 10 mg/kg, i.p.). Transverse sections. After adrenalectomy
(ADX), the OR immunoreactivity is observed exclu sively in the
pericarya of the pyramidal nerve cells. After corticosterone (cort)
treatment OR immunoreactivity even stronger than that present in
the con trol animals is found in the nerve cell nuclei.
Konig-Klippel level A4100 Ilm
GR control CAl
GR ADX CAl
GR ADX.cort. CA1
18 K. Fuxe et al.
Fig. 12. Distribution of glucocorticoid receptor (OR)
immunoreactivity in the anterior and dorsal periventricular part of
the of the hypothalamus of the male rat. Densely packed strongly OR
immunoreactive (IR) nerve cell nuclei are found in the anterior
parvocellular nucleus of the paraventricular hypothalamic nucleus
(ap) and in the periventricular hypo thalamic nucleus (pv). Weakly
to moderately OR IR nerve cell nuclei are found in the an terior
hypothalamic nucleus (AHy), the medial preoptic nucleus (MPO) and
the bed nu cleus of the stria terminalis, preoptic part (BSTPO).
3, third ventricle
In agreement with our observations showing a widespread
distribution of OR IR neurons in the central nervous system, an in
vitro quantitative auto radio graphic analysis of adrenal steroid
binding sites showed a widespread distribution of glucocorticoid
binding sites in the rat central nervous system. The highest con
centrations were found in the dentate gyrus, the lateral septum,
the nucleus trac tus solitarius, the nucleus paraventricularis and
the amygdaloid complex (see de Kloet 1985; Rostene et al.
1985).
Fig. 14. Distribution of glucocorticoid receptor (OR)
immunoreactivity in the frontoparie tal cortex. The highest
densities of OR immunoreactive nuclei are observed in layers 2, 3
and 6 of the cortex and in the nucleus caudatus putamen. DAB-nickel
combination was used. Level: 1.3 mm behind Bregma. FrPaM,
frontoparietal cortex, motor area; FrPaSS, frontoparietal cortex,
somatosensory area; CC, corpus callosum; ec, external capsule; cg,
cingulum; LV, lateral ventricle; fl, fimbria of hippocampus; CPu,
caudate putamen; AD, anterodorsal thalamic nucleus; DG, dentate
gyrus; PCg, posterior cingulate cortex; CA3, field CA3 of
hippocampus. Bar, 250 ~m
~- . - ~
'- -- "'
-: :-
:- .:;
~~ ~
_ ... - ~ .
, . .
> .... ~
..
.. •
, ....
... .. . ... ;-
. .' . . . Fig. 16. Distribution of glucocorticoid receptor
immmunoreactive (OR IR) nerve cell nuclei in the anterior cingulate
cortex. High densities of strongly OR IR nerve cells are found
especially in layers 2 and 3. Bar, 250 Jlm
ox
Fig. 17. Distribution of glucocorticoid (OR) immunoreactivity in
the hypothalamus, dorsal striatum and piriform cortex. Note the low
number of weak OR immunoreactive (IR) pro files in the globus
pallidus, ventral pallidum and substantia innominata. High
densities of strongly OR IR profiles are localized in the
claustrum, in the endopiriform nucleus and in the olfactory and
piriform cortex. Approximate level: 1.3 mm below bregma. DAB-nickel
combination was used. ie, internal capsule; ox, optic chiasm; LH,
lateral hypothalamic area; SO, supraoptic hypothalamic nucleus; GP,
global pallidus; CPu, caudate putamen; FStr, fundus striati; VP,
ventral pallidum; Sf, substantia innominata; AA, anterior
amygdaloid area; CxA, cortex-amygdala transition zone; ct,
claustrum; En, endopiriform nucleus; LOT, nucleus of the lateral
olfactory tract; PO, primary olfactory cortex; Ce cen tral
amygdaloid nucleus; Bar, 250 Jlm
22 K. Fuxe et al.
BST
ic
Fig. IS. Distribution of glucocorticoid receptor immunoreactivity
in nerve cells of various anterior thalamic nuclei. DAB-nickel
combination was used. Approximate level: 1.3 mm behind bregma. 3,
third ventricle; sm, striae medullaris thalamus; PVA,
paraventricular thalamic nucleus, anterior part; PT, paratenial
thalamic nucleus; AD, anterodorsal tha lamic nucleus; A V,
anteroventral thalamic nucleus; BST, bed nucleus striae terminalis;
AM, anteromedial thalamic nucleus; Rt, reticular thalamic nucleus;
Re, reuniens thalamic nucleus; ie, internal capsule; f, fornix; Pe,
periventricular hypothalamic nucleus. Bar, 250 !lm
Hormones and Synaptic Transmission 23
Table 3. Sites of coexistence of GR JR, monoaminergic and
peptidergic neurons
Neurons
Noradrenaline A1-A7
Growth hormone - releasing factor IR Arcuate nucleus
Somatostatin IR Periventricular hypothalamic nucleus
Neuropeptide Y IR C1-C3 area A1 area Arcuate nucleus
(I.-Melanocyte - stimulating hormone IR Arcuate nucleus
Perifornical nucleus Central amygdaloid nucleus
Cholecystokinin IR Paraventricular hypothalamic nucleus Hippocampus
Periventricular hypothalamic nucleus
p-Endorphin IR Arcuate nucleus
50 o
75
100
Nomenclature of monoaminergic neurons according to Dahlstrom and
Fuxe (1964) GR, glucocorticoid receptor; JR, immunoreactive
Fig.19. High densities of glucocorticoid receptor immunoreactive
nerve cell nuclei are found in the nucleus caudatus putamen
DAB-nickel combination was used. Star, fibrae capsulae internae;
ec, external capsule. Bar, 200 11m
24 K. Fuxe et al.
OR Immunor .. cllye
igh
(den,'I1 .. )
1mm
Fig. 20. Camera lucida drawing ofthe distribution of glucocorticoid
receptor (OR) and cor ticotropin-releasing factor (CRF)
immunoreactivities in the septal and preoptic area of the male rat,
based on two-colour immunocytochemistry (see Harfstrand et al.
1986). Double labelled nerve cells are represented by triangles.
Stars indicate CRF immunoreactive cells without any demonstratable
OR immunoreactivity. ac, anterior commisure; ox, optic chiasm; LV,
lateral ventricle; LSD, laterodorsal part of the septal area; SFi,
nucleus fim brialis septalis; SHy, nucleus septohypothalamicus;
MnPo, nucleus preopticus medianus; BSTM, BSTL, medial and lateral
components of the bed nucleus of striae terminalis; LPO, lateral
preoptic nucleus; MPO, medial preoptic nucleus
By means of two-color immunocytochemistry we have demonstrated that
the vast majority of the NA, A and 5-HT neurons of the lower brain
stem contain strong OR immunoreactivity (see Fuxe et al. 1985 b;
Harfstrand et al. 1986). These results indicate that
glucocorticoids can in part control brain function via modulation
of the synthesis and release ofNA, A and 5-HT and their respective
peptide comodulators. In view of the known function of NA, A and
5-HT path ways it is now possible to better understand how
glucocorticoids can regulate cardiovascular and neuroendocrine
function, the sleep-wakefulness cycle, attention and mood in
man.
The various DA cell groups of the brain showed variability with
regard to the number of DA nerve cell bodies positive for
glucocorticoid receptors. Approxi mately 50% of the DA cells of
groups A8, A9 and AlOin the ventral midbrain contain a weak to
moderate degree of OR immunoreactivity. As seen in Table 3, the
arcuate DA cell bodies all contain OR immunoreactivity, while the
All DA
Hormones and Synaptic Transmission 25
Fig. 21. Demonstration of nuclear glucocorticoid receptor
immunoreactivity by means of FITC fluorophor in all neuropeptide Y
(NPY) immunoreactive nerve cells of the medial parvocellular part
ofthe arcuate nucleus (mARC) . NPY immunoreactivity is located in
the cytoplasm and demonstrated by rhodamine fluorophor. Two-colour
immunofluorescence methodology. Arrows point to some of the
double-labelled cells. Arrows with bars indicate glucocorticoid
receptor immunoreactive cells lacking NPY immunoreactivity. ME,
median eminence; 3, third ventricle. Bar, 100 !lm
cell group of the posterior hypothalamus showed no GR
immunoreactivity in any of its cell bodies (see Hiirfstrand et al.
1986).
As seen in Table 3, all the CRF IR cells of the paraventricular
hypothalamic nucleus projecting into the median eminence, as well
as all the arcuate growth hormone-releasing factor (GRF) IR neurons
projecting into the median emi nence, contain GR immunoreactivity
(Cintra et al. 1987). Many of the CRF IR cells of the preoptic
nuclei and of the bed nucleus of the nucleus striae terminalis are
also GR immunoreactive (Fig. 20). Thus, glucocorticoids can
directly control the CRF and GRF neurons by an action at the
nuclear level, probably represent ing the mechanisms underlying
the central feedback action of glucocorticoids on GRF and CRF
synthesis leading to an inhibition ofGRF and CRF secretion (the
delayed feedback). Also the neuropeptide Y (NPY) neurons of the
parvocellular part of the arcuate nucleus all contain GR
immunoreactivity (Fig. 21). This GR
26 K. Fuxe et al.
IR is as strong as the one demonstrated in the CRF IR neurons.
About 50% of the a-melanocyte-stimulating hormone (a-MSH) IR
neurons of the arcuate nu cleus and of the perifornical area
exhibited GR immunoreactivity. Furthermore, all the p-endorphin IR
neurons of the arcuate nucleus were GR immunoreactive (Table 3).
Moreover it was discovered that a-MSH immunoreactivity exists in
cortical pyramidal cells, which are also GR immunoreactive.
4.2 Morphometric and Microdensitometric Analysis of GR
Immunoreactivity in the Central Nervous System
These analyses have been carried out using a computerized system
for image anal ysis (IBAS II, Zeiss Kontron Munich, FRG). For
details on the methodology, see Agnati et al. (1984 b, 1985). A
semiquantitative method to assess the relative amount of antigen
has been developed: discrimination is performed at a level ca
pable of excluding the background and the field area, (F AC)o is
measured. The same procedure is repeated at different levels of
discrimination allowing the selec tion of higher and higher grey
tone values. After each discrimination procedure the corresponding
field area, (F AC)i, is measured. Thus, the percent rations Yi = (F
AC)if(F AC)o can be calculated. By considering the plot of the Yi
values as a function of the respective levels of discrimination, a
curve can be obtained (Fig. 22) which expresses the relative
content of antigen per area in the sampled field. The ED25, ED50
and ED75 of the curve represent indices oflow, medium and high
content of antigen, respectively (see Zoli et al. 1986).
It is also possible to convert the exponential decay of the curve
into a straight line. This linear transformation is useful, since
the slope of the straight line can be used as a relative
quantitative index of antigen content, which is more sensitive than
the ED values (see below).
One result from the morphometric analysis is demonstrated in Fig.
23, which shows a density map of the GR IR neurons within the area
of the paraventricular hypothalamic nucleus. The number of GR IR
nerve cells is given per unit of square, in relation to the various
subnuclei of this region. It is seen that the largest amounts of GR
IR neurons are observed within the parvocellular part (FP). High
densities are also found within the periventricular hypothalamic
nucleus. Scat tered GR IR cells are found within the magnocellular
part, and none are found at this rostrocaudallevel within the
dorsal parvocellular subnuclei. A density map illustrating the
coexistence and distribution of the tyrosine hydroxylase (TH) and
GR immunoreactivity in the arcuate nucleus is shown in Fig.
24.
A microdensitometric analysis has been performed in a number of
regions of the telencephalon and diencephalon, namely the caudate
putamen, nucleus amygdaloideus medialis, somatosensory
frontoparietal cortex, periventricular hypothalamic nucleus and the
parvocellular part of the paraventricular hypotha lamic nucleus.
As seen in Fig. 22, the ED50 index shows similar amounts of GR
immunoreactivity in the striatum, the amygdaloid cortex and the
neocortex. All the indices are higher for the parvocellular part of
the paraventricular hypotha lamic nucleus, giving evidence for
higher amounts of immunoreactivity in this re gion than in the
other regions analysed. It should be noticed, however, that
the
Hormones and Synaptic Transmission 27
Striatum (CPu) Amygdala (Me)
ED25 = 32.5 ED25 = 32.5
\ ED75 = 26.5
\ ED75 = 26.8
75
50 . . <:> \ \ :;:! 25 . x ., '. ' . "0 .......... ::::::.
'-. u 0 I ,r I ,. -< 35 30 25 20 15 35 30 25 20 15 ~ ,
Fronto-parietal cortex (FtPa) N. paraventricularis (Pa)
~ 100 N. periventricularis (Pe)
• ED25 = 32.0 • Pa Pe
75 ED50 = 27.1 32.0 EED75 = 21.8 30.5
50 \ 25 \
35 30 25 20 15 35 30 25 20 15
Striatum (CPu) Amygdal<l (Me)
2
.~ <:> . :;:!
~ . .
'" "0 0 I I I I· I I I j.
.( 35 30 25 20 15 35 30 25 20 15 ~ Fronto-parietal cortex (FtPa) N.
paraventricularis (Pa) ,
N. periventricularis (Pe) u -<
.", .. ~ . ~ ' . "'-
0 I I i I I i i I II
35 30 25 20 15 35 30 25 20 15
levels of discrimination
Fig. 22. Schematic representation of the procedure introduced in
immunocytological stud ies to obtain a relative quantitative
estimation of the antigen content. In the figure· the ef fects of
subsequent discriminations are illustrated. Mter each
discrimination the field area of positive immunoreactivity, (FAC)i,
is measured. The percent ratios Yi=«FAC)i/ (FAC)o) x 100 are
calculated and by means of these values the estimation of the
antigen content is performed. The Yi values are plotted as a
function of the different levels of dis crimination. A
characterization of the curve is obtained by means of the ED values
(upper panels). A more precise characterization of the curve is
obtained after linear transformation by considering the slope
values (lower panels), which are given with the respective 95% con
fidence interval
Fi g.
2 3.
D en
si ty
d is
tr ib
ut io
n pl
ot o
Hormones and Synaptic Transmission 29
Coexistence of TH and GR immunoreactivity In nerve cells in
medlobasal hypothalamus
microns 1000~--r---'---~---r--~--~r---r---~--'---~
v+
Fig.24. Density map illustrating the coexistence of tyrosine
hydroxylase (TH) and glu cocorticoid receptor (GR) immunoreactive
(IR) nerve cell bodies of the arcuate nucleus. The number of
positive cells is shown in each square. In the black triangle is
indicated the number of OR IR nerve cell bodies and in the white
triangle the number of TH IR nerve cell bodies. The circles around
the numbers in the white triangles indicate that the TH IR nerve
cells have a nuclear OR immunoreactivity (coexistence). The
orientation is indicated in the upper right part of the picture.
The outline of the ventral surface and of the third ventricle is
also given in the density map. ME, median eminence; M, medial; V,
ventral; D, dorsal; L, lateral
curve within the periventricular hypothalamic nucleus is highly
skeweq, and therefore a certain amount of high grey tones may have
escaped in this type of evaluation. By considering the slope values
of the respective straight lines (see Fig.22) an improved
estimation of GR immunoreactivity may be obtained. Again, the
parvocellular part of the paraventricular hypothalamic nucleus has
the highest index as inferred from the low slope value. Using this
type of semiquan titative method it is possible to study changes
in the GR immunoreactivity in highly discrete neuronal populations
of the central nervous system.
30 K. Fuxe et al.
4.3 Studies on Presynaptic Features of Monoamine Neurons
The effects of corticosterone on regional DA and NA levels and
utilization in the hypothalamus depend upon the endocrine state of
the animal. However, a consis tent finding has been the ability of
corticosterone to increase NA utilization in the median eminence,
even in hypophysectomized and adrenalectomized rats (see Andersson
et al. 1981). In addition, corticosterone was able to increase NA
levels selectively in the subependymallayer of the median eminence,
indicating an ac tivation also of NA synthesis. These results may
reflect the existence of an inhibi tory noradrenergic mechanism in
the median eminence, controlling CRF release via an axoaxonic
modulation. It is suggested that the primary action is on a GR IR
local circuit neuron in the hypothalamus which can interact via an
axoaxonic influence with the noradrenergic network in the median
eminence (Andersson et al. 1981). Indications were also obtained
that glucocorticoids can reduce NA uti lization in the
magnocellular part of the paraventricular hypothalamic nucleus. NA
utilization in this region was also turned off by sustained
hypersecretion of adrenocorticotropic hormone (ACTH). These results
may indicate the existence of a facilitatory noradrenergic
mechanism involved in vasopressin regulation. It is again suggested
that the GR IR local circuit neurons are involved in producing this
highly selective influence on NA turnover in this part of the
paraventricular hypothalamic nucleus involving axoaxonic
interactions in that nucleus. We have
e " .. >
• ~ .. e t ~ '0 ~
'" i Adll • • SoIY.nl
Adll . ·Cortlcoelerone 10mg/ kg e.C 4h :: Adll. -RU 28g88 10mg/ kg
LC 4h
Adll.·Aldoeterone 100ug/ kg e.c 4h
Figs.25-27. Effects of corticosterone, RU 26988 and aldosterone on
regional noradrena line (NA) levels in discrete nuclei of the
preoptic area (Fig.25) and of the hypothalamus (Fig. 26) and on
cathecolamine (CA) levels of the median eminence (Fig. 27) of
adrenalec tomized male rats (4 days after adrenalectomy).
Means+SEM (n=6) . Significances refer to rats treated with solvent
alone: *p<0.05; **p<O.Ol (Dunn test). PVO, area anterior to
the anterior periventricular hypothalamic nucleus; PV II, posterior
periventricular hypo thalamic region; POP, pose, POM,
periventricular, suprachiasmatic and medial parts of the preoptic
area. NIST, ventral part of the bed nucleus of striae terminalis. P
AFM, P AFP, magno- and parvocellular parts of the paraventricular
hypothalamic nucleus; DM, dor somedial hypothalamic nucleus; SEL,
subependymallayer of the median eminence; MPZ, medial palisade zone
of the median eminence; LPZ, lateral palisade zone of the median
eminence; BZ, border zone, an area located at the border of the
medial and lateral hypo thalamus between the fornix and the
ventral surface of the brain; PV I, anterior periven tricular
hypothalamic region
Fig. 26
• :J iii ~
~ 1 U • a. • ~ "0 ~
MPZ
.~ Ad" •• RU 28988 10mg/ kg e.c 4h
; Ad".· Aldoeterone 100ug/ kg e.C 4h
LPZ
administered the selective GR agonist RU26988 (Moguilevski and
Raynaud 1980; Veldhuis et al. 1982) in a dose of 10 mg/kg s. c. to
adrenalectomized male rats. Marked depletion ofNA stores is
observed after 4 h in large numbers of preoptic and hypothalamic NA
nerve terminal systems but not in the median eminence CA nerve
terminals (Figs. 25-27). These changes are associated with a
lowering ofNA utilization in several regions outside the median
eminence using the TH inhibition method. It seems possible that
these marked and widespread actions of the selec tive GR agonist
on NA neurons are mediated via activation ofGR in the NA cell
bodies in the medulla oblongata, giving rise to the hypothalamic
and preoptic NA innervation. Thus, via genomic actions GR may
control the activity of NA-syn thesizing enzymes and the
production of receptor proteins controlling the excit ability and
the firing rate of the NA neurons. Recent findings also indicate
that glucocorticoids control coexistence in both monoamine and
peptide neurons.
32 K. Fuxe et al.
Thus, upon adrenalectomy there is an increase in the number of NPY
IR nerve terminals in the hypothalamus, partly caused by an
increased amount ofNPY IR in the
phenylethanolamine-N-methyltransferase (PNMT) IR terminals (Fuxe et
al. 1985a). Also, a number of papers (see Swanson et al. 1986) have
shown that upon adrenalectomy CRF IR neurons of the paraventricular
hypothalamic nu cleus begin to exhibit vasopressin and angiotensin
immunoreactivity. These ef fects are also reversed by treatment
with glucocorticoids. These results indicate that glucocorticoids
normally act to suppress the gene expression of peptide co
modulators, at least in some monoamine and peptide neurons. When
discussing the effects of glucocorticoids on the CRF neurons it is
of special interest to note that the acetylcholine-induced
secretion of CRF from CRF IR neurons in vitro is reduced upon in
vitro treatment with glucocorticoids. These results again underline
that glucocorticoids, by regulating the gene expression of various
types of receptor-linked proteins belonging to the cholinergic
receptor mechanism, may appropriately regulate the sensitivity of
the CRF IR neurons (see Vale et al. 1985). In line with this
interpretation it has also been noted by Schonbrunn (1985) that
glucocorticoids decrease the number of somatostatin receptors in
GH4 C1 cells.
Other presynaptic transmitter mechanisms which are influenced by
glucocor ticoid receptors are 5-HT utilization in the hippocampal
formation (de Kloet 1985). Furthermore, vasoactive intestinal
peptide (VIP) immunoreactivity is increased in the hippocampus of
adrenalectomized animals (see McEwen 1982). Adrenalectomy also
increases GABA uptake into synaptosomes of the hippo campal
formation. All these effects are probably mediated via actions by
glucocorticoids on hippocampal and/or raphe glucocorticoid
receptors.
4.4 Studies on Monoamine Receptor Mechanisms
Evidence has been obtained for a glucocorticoid receptor
involvement in the reg ulation of fJ-adrenergic receptors in the
hippocampal formation and in the neo cortex (Roberts et al. 1981;
Ogren et al. 1981). It was found that the 6-hydroxy
dopamine-induced increase in the density values of 3H
-dihydroalprenolol binding sites in the hippocampal formation was
significantly greater upon adrenalectomy (Roberts et el. 1981).
Adrenalectomy alone did not influence the binding charac teristics
of the fJ-adrenergic receptors. In view of the learning impairments
noted upon lesion of the ascending NA bundle to the cerebral cortex
in combination with adrenalectomy (see Ogren et al. 1981), the
further increase of the biochemical supersensitivity in the
fJ-adrenergic receptors observed may reflect a potentiation of a
compensatory biochemical phenomenon in the hippocampal formation to
re store NA receptor activity and hippocampal function. The
results amplify the ex istence of interactions between central
noradrenergic mechanisms and central glucocorticoid receptors in
avoidance learning, an interaction which may take place
predominantly within the hippocampal formation and the cerebral
cortex. It must also be considered that the NA cells in the locus
coeruleus all contain a strong GR immunoreactivity predominantly
located in their nuclei (Harfstrand et al. 1986), which must
contribute to the interactions between NA and glucocor ticoids in
the intact rat.
Hormones and Synaptic Transmission 33
Glucocorticoid receptors have also been shown to affect
transduction mech anisms within the hippocampal formation. Thus,
glucocorticoids facilitated his tamine-stimulated cyclic AMP
formation but suppressed NA-stimulated cyclic AMP formation as well
as VIP-dependent cyclic AMP stimulation (see McEwen 1982; McEwen et
al. 1985a).
It has also been shown that the receptor-receptor interactions (see
Fuxe and Agnati 1985) are modulated by glucocorticoids. Thus,
glucocorticoids increase the ability of VIP to increase the density
values of 5-HT 1 receptors within the dor sal subiculum (see
McEwen et al. 1985a). Not only the transduction mechanisms but also
the substrates for the protein kinases are affected by the
glucocorticoid receptors within the hippocampal formation. Thus,
the phosphoprotein synap sin I is found in increased
concentrations upon treatment with glucocorticoid hormones (see
Nestler et al. 1981). Synapsin I is regulated via activation of
cyclic AMP-dependent and calcium-dependent protein kinases.
In Fig. 28 it is illustrated that steroid hormones via nuclear
actions may con trol the synthesis of receptors for peptides and
catecholamines. As examples, the
Principle for steroidal regulation of CA transmission
GR
Homoregulation via GR on / CA receptor sensitivity
'" Heteroregulatlon by GR via NPY receptors on CA synthesis and CA
receptor sensitivity
GR - Effects on the gain of the receptor amplifier mechanism
Fig. 28. Illustration of some principles for the steroid regulation
of the pre- and postsyn aptic features of catecholamine (CA)
transmission and of corticotropin-releasing factor (CRE) neurons.
Noradrenaline and adrenaline neurons both innervate the CRF immu
noreactive neurons in the paraventricular hypothalamic neurons, and
glucocorticoid recep tor (G R) immunoreactivity has been
demonstrated in both the nerve cell nuclei and the peri carya of
the catecholamine as well as of the CRF neurons. Thus, the
glucocorticoid recep tors may regulate both the pre- and
postsynaptic features of the classical transmission and the
cotransmission lines in the catecholamine synapses. The direct
regulation of the catecholamine transmission is termed
"homoregulation" and the indirect regulation of the catecholamine
synthesis and catecholamine receptor sensitivity, for example via
modula tion of neuropeptide Y (NPy) receptor mechanisms and NPY
stores is called "heteroregu lation". The available evidence
indicates a profound effect of glucocorticoids on the regu lation
also of the synthesis of the cotransmitter, in this case NPY (see
Fuxe et al. 1985 a). It is also indicated that the glucocorticoid
receptor, via the nuclear actions, can also reg ulate the receptor
transducer mechanism (amplifier mechanism)
34 K. Fuxe et al.
NPY receptors and the Q(radrenergic receptors are shown. Thus,
glucocorticoids may regulate the synthesis of the proteins
containing the transmitter recognition sites leading to changes in
the receptor density values and lor may regulate the coupling
proteins such as the GTP-binding proteins which control the gain of
the receptor-amplifying mechanism and/or may regulate the protein
kinases involved in the phosphorylation of proteins, e.g. those in
the membranes controlling trans duction of signals. Another
important aspect of Fig. 28 is the fact that glucocor ticoids can
regulate CRF synthesis and release not only via a direct action on
the CRF IR neurons, but also via an influence on the afferent
input. In this case the effects on the adrenergic input is
illustrated. Thus, the glucocorticoids can influ ence the CRF
neurons via both direct and indirect actions. The final outcome is
the result of the integration of all these signals influencing the
CRF neurons. Again, it should be emphasized that the
glucocorticoids can modulate coexistence in neurons. In this case
the effect on coexistence of NPY and A is exemplified.
It must be considered that glucocorticoids not only influence
information handling, but also exert effects on the metabolic state
of the neurons. These ac tions are probably of importance for the
survival of the neurons. It has thus been seen that glucocorticoids
can reduce the lesion-induced axon sprouting in the gyrus dentatus
(see Scheff et al. 1980). Furthermore, McEwen and colleagues
(1985a) have demonstrated that treatment with glucocorticoids
produces not only a downregulation of the glucocorticoid receptors
in the hippocampal forma tion, but also a nerve cell loss. Thus,
glucocorticoids may, for example, inhibit the synthesis of a
trophic factor in the pyramidal nerve cells. In this way the
inhibitory effect of the hippocampal formation on the CRF neurons
is lost (see Angelucci 1985), and the corticosterone serum levels
become markedly increased, especially after stress.
Our observations that there are glucocorticoid receptors in glial
cells, espe cially in the oligodendroglia cells, explain the
ability of glucocorticoids to induce glycerol phosphate
dehydrogenase in oligodendroglia cells (see McEwen 1982). WT in
brain may be influenced by these effects of glucocorticoids on
oligodendro glia cell, since these effects may lead to alteration
in the myelination and nerve conduction velocities (Scheff et al.
1980; Friedrich and Bohn 1980; Henkin 1970). In addition,
morphological changes have been noticed, such as hypertrophy of as
troglia under the influence of glucocorticoids (see Scheff et al.
1980).
5 Actions of Thyroid Hormones on Wiring Transmission
5.1 General Aspects
In 1958 Ford and Gross provided evidence for the existence of a
hypothalamic site of action of thyroid hormones by demonstrating
the accumulation of radio active T 4 and T 3 in the
paraventricular region of the hypothalamus. Thyroid-con centrating
neurons have also been demonstrated within other areas of the hypo
thalamus (Stumpf and Sar 1978). The thyroid hormone receptors have
been char acterized as nuclear receptors (Oppenheimer et al. 1974;
Eberhart et al. 1976).
Hormones and Synaptic Transmission 35
Light-microscopic autoradiograms of brain after intravenous
administration of 125I_T 3 gives evidence for the localization of
125I_T 3 in discrete neuronal systems (Dratman et al. 1982).
Furthermore, the circulating form of the hormone T4 has been shown
to be differentially taken up in various brain areas by a
high-affinity transport mechanism. These results indicate that the
central nervous system must be an important site of action for
thyroid hormones. It has also been speculated that the amino acid
hormones T 4 and T 3 may be substrates in metabolic pathways in the
brain leading to the formation of adrenergically active
neurotransmitters (see Dratman et al. 1984). It should be noticed,
however, that T 4 does not produce any change in energy metabolism
in the adult brain.
5.2 Studies on Presynaptic Features of Monoamine Neurons
Andersson and Eneroth have demonstrated that the long-term feedback
action of thyroid hormones involves an action on hypothalamic
catecholamine nerve terminal networks involved in the regulation of
thyroid-stimulating hormone (TSH) secretion (Andersson et al. 1985;
Andersson and Eneroth 1987). It was found that thyroidectomy leads
to an activation of NA nerve terminal systems in the
paraventricular hypothalamic nucleus and to an inactivation of the
DA nerve terminal systems of the external layer of the median
eminence. These effects were reversed by restitution therapy with T
3 or T 4' Chronic but not acute admin istration of T 3 and T 4 to
the hypophysectomized rat was capable of increasing DA utilization
within the external layer of the median eminence, as well as pro
ducing a reduction ofNA utilization within the paraventricular
hypothalamic nu cleus. Thus, a long-term feedback action of
thyroid hormones on TSH secretion involves inter alia the
activation of DA nerve terminals in the median eminence, inhibiting
the release of TSH-releasing hormone (TRH). It was suggested that
these actions of thyroid hormones involve an activation of nuclear
receptors in the medial basal hypothalamus, possibly located in
some of the tuberoinfundibu lar DA nerve cell bodies. Furthermore,
the feedback action of thyroid hormones on TSH secretion also
involves the inactivation of a facilitory noradrenergic mechanism
in the paraventricular hypothalamic nucleus. It seems possible that
the thyroid hormone receptors in this case are located in the cell
bodies of the TRH IR neurons, which via recurrent collaterals
interact with the paraventricular NA nerve terminal systems,
explaining the highly localized change in the paraven tricular
hypothalamic nucleus.
It is of substantial interest that the modulation of the pituitary
thyroid activity could also produce highly discrete changes within
the DA nerve terminal net works of the forebrain. Thus,
thyroidectomy reduces DA utilization in the ante rior part of the
nucleus accumbens, while increasing DA utilization in the poste
rior part of the nucleus accumbens, where the costoring
cholecystokinin (CCK)/ DA nerve terminals exist. In agreement,
chronic but not acute treatment with T 3
or T 4 of the hypophysectomized rat produces an increase in DA
utilization within the anterior part of the nucleus accumbens.
These results are of substantial inter est, since DA nerve
terminal systems within the nucleus accumbens participate in the
control of locomotion and in the reward mechanisms (Fuxe et al.
1977 b,
36 K. Fuxe et al.
1986a; Ljungberg and Ungerstedt 1978). It may therefore be
speculated that the hyperactivity found in patients with
hyperthyroidism may be related at least partly to an activation of
the dopaminergic mechanism within the anterior part of the nucleus
accumbens. The results also imply the existence of nuclear recep
tors for thyroid hormones within the nucleus accumbens
itself.
5.3 Studies on Monoamine Receptor Mechanisms
Many investigations have demonstrated that the number and
functional activity of p-adrenergic receptors in peripheral tissues
increase within increasing concen trations of thyroid hormones in
the circulation (Williams and Lefk:ovits 1977).
3H_ Spiperone (striatum)
Sham operation 4 weeks
o 01 0.2 03 0.4 0.5 0.6 B pmol/mg prot.
o 4~~------------------_, ~ ~. Bmi• = 0.433 pmollmg prot.
~ 3 .~KO=0.104nM
o
o
Thyroidectomy 4 weeks
Fig. 29. Effects of thyroidectomy and restitution therapy with T 3
on the binding character istics of 3H-spiperone-Iabelled D2
receptors in striatal membranes. The Scatchard plots are shown. A
reduction of the Bmax levels is shown following thyroidectomy, as
well as preven tion of such a fall by replacement therapy with T 3
(10 /lg/kg, twice daily) (see Fuxe et al. 1984a)
Hormones and Synaptic Transmission 37
Within the striatum of the rat brain we have made the observation
that changes in the pituitary thyroid activity can produce
substantial changes in the density of D2 receptors without changing
DA utilization in various parts of the striatum (see Fuxe et al.
1984 a). These results open up the possibility that thyroid
hormones may accomplish a heterostatic regulation of the striatal
DA synapses, i.e. they may change the sensitivity of the
postsynaptic DA receptor mechanism by in creasing the number of D2
receptors without any associated changes in the pre synaptic
features of the DA transmission line (Fig. 29). This regulation has
been defined as a heterostatic regulation of the synaptic
transmission. As seen in Fig. 30, it allows a change of the set
point of the synapse. Thus, hormones such as thyroid hormones may
control synaptic heterostasis, which probably repre sents an
important part of functional synaptic plasticity (see also Fuxe et
al. 1984a, 1986a, b; Agnati et aI1986a). Again it is visualized
that the thyroid hor mones control the DA receptor mechanisms via
actions on nuclear thyroid hor mone receptors present in the
striatal neurons, leading to changes in the ex pression of the
gene for the proteins carrying the dopamine recognition
sites.
HOMEOSTATIC CONTROL V K CO.I High "delil, 10, lhe .ig.... Ironoml
.. ion (low o.c illollo ns
o,ound lhe •• 1 poinl)
. .. ; PAc:m!N PHO~VLAnON
HETEROSTATIC CONTROL V (I( , 61() CO.l Funclional o1""Plic
pl"licil, (di.placem.nl of Iho HI poonl)
~. R-;!f_v t , I (S.R.CII/OO» 1( , 61( S R-I O
.,~y& FROM THE LOCAL ENDOCRINE
CIRCUIT ~ACRINE SIGNALS
TRANSMISSION LINE
FB LOOP
S S,nlhHio R R ...... I • T,onomiU., binding o T,.noduc:t ion V
Inpul 10 lhe irrt, .... lu .. ,
olloClo, X Reo -Reo interaction
Fig. 30. Schematic representation of the mechanisms which may
contribute to two types of basic behaviours of synapses: the
constancy of the efficacy of the transmission line (synaptic
homeostasis) and the change of the level at which this constancy is
maintained (synaptic heterostasis)
38 K. Fuxe et al.
6 The Humoral Modulation of Volume Transmission
It should be considered that steroid hormones, thyroid hormones and
also pep tide hormones can affect some of the circumventricular
organs of the central ner vous system and in this way influence
the release of signals and the neuronal path ways from these
organs. Some chemical signals may affect the neuronal networks via
the ventricular system and the extracellular fluid. GR
immunoreactivity exists within the nerve cells of the subfomical
organ. The peptide hormones, such as angiotensin and atrial
natriuretic peptides, may be active here, since there is no
blood-brain barrier in the circumventricular organs and a high
density of angio tensin II (Saavedra et al. 1986; Healey et al.
1986) and atrial natriuretic factor re ceptors (Saavedra et al.
1986; Bianchi et al. 1986) exists in this region.
As stated above, it seems likely that the steroid and thyroid
hormones may influence the uptake of messengers and trophic factors
in glial cells and neurons, as well as their release from glial
cells and neurons. Thus, the release and the up take of paracrine
signals from neurons reaching a distant receptor population may be
highly influenced by steroid and thyroid hormones, which thus can
pro foundly influence VT in the nervous system.
It is also conceivable that the extracellular fluid pathways which
are of sub stantial importance in VT may be influenced by hormones
in view of the ability of glucocorticoids to control astroglia
functions.
7 Aspects on the Organization Principles of the eNS
It seems that the basic texture of some eNS structures is made up
of elementary units. Thus, it can be surmised that in the eNS there
are at least three types of basic organization: (a) Nuclei (which
may be represented by subnuclei of classical anatomical nuclei,
e.g. nucleus tractus solitarius), i.e. groups of neurons which
operate to perform in an integrative fashion a certain elaboration
of information, or to exert a certain trophic action. In
particular, it is possible to distinguish the diffuse type of
nuclear organization, such as the one of reticular formation, from
the compact nuclear organization of the thalamus and the
hypothalamus. (b) Elementary circuits, which show a highly
repetitive geometry, without clear cut morphological boundaries.
This organization is represented by the cerebellum and hippocampus.
(c) Modules, i.e. repetitive units made up by organized ele ments
of neuronal structures. We can recognize different types of modules
in the eNS. 1. "Structural" modules, i.e. repetitive clusters of
cell bodies and/or terminals,
characterized on the basis of transmitters and/or recognition sites
for trans ducer mechanisms and/or metabolic and trophic features,
as found by methods of chemical neuroanatomy. Modules may be
heterogenous regarding size and shape. This organization is present
in the striatum ("striosomes") (see GraybieI1986).
2. Local circuit modules, i.e. repetitive aggregates of nerve
terminals making synaptic contacts with one another controlling a
neuronal input and/or a
Hormones and Synaptic Transmission 39
MORPHOfUNCTIONAlORGA ZAllO Of THE DIAN EM! NCE
THE MEDIANOSOME CONCEPT
'ENTITY OF COEIlISTENCE· ... ATTERN OF PEPTIDE FRAG"'ENT'
• NUCLEAR STEROID RECEPTORS
SECRETION Of RElEASl'fG ANO _TORY FACTORS
TRANSPORT OF ~STANCES
Fig. 31. Schematic illustration of the medianosome concept and of
the sites of action of pep tide, steroid and thyroid
hormones
neuronal output. They can be recognized in the median eminence
("mediano somes") (Figs. 31 and 32) and in the olfactory
bulb.
3. Columns, i.e. repetitive sets of cells which form a vertical
structure throughout a brain region and are involved in the
integration of specific inputs. They are homogenous regarding size
and shape. This organization is present in the somatosensory,
visual, motor and frontal association cortex.
Other principles of organization such as somatotopy (i. e. the
segregation of a set of neurons or axons in the nuclei or pathways,
respectively, according to the body surface area, to which they are
connected) can be superimposed on the basic buildup of neuronal
circuits. Genetic and epigenetic influences can exert their ac
tions in the frame of these organizational principles. In the
following paragraphs we will develop the concept of the modular
organization of the CNS in the frame of the WT and VT.
40 K. Fuxe et al.
MODULAR ORGANISATION OF THE MEDIAN EMINENCE
(THE LHRH INNERVATION AND ITS FUNCTIONAL MODULES)
MEDIAN EMINENCE LEVEL
7.1 Modules of Wiring Transmission
Fig. 32. Illustration of the structural luteinizing hormone
releasing hormone (LHRH) medianosome and its subdivi sion into
functional or integra tive medianosomes, repre sented by the
various interac tion zones (LHRH/TH, LHRH/ENK etc.). The modu
lation caused by LH and sex hormones is indicated (for fur ther
aspects see Fig. 34)
The cortical columns were identifIed on the basis of functional
criteria, e.g. the neurons of a column respond to the same sensory
stimulus applied to a specific area of the skin. The columns have
been shown to be modality specifIC and site specific and were
subsequently demonstrated to have an anatomical correlate.
Recently, studies in chemical neuroanatomy have supplied
indications that the modular organization is not unique to the
cerebral cortex but also exists in other brain areas, such as the
striatum and the median eminence (Olson et al. 1972; Ten nyson et
al. 1972; Graybiel 1984; 1986; Fuxe et al. 1971, 1986c; Andersson
et al. 1984). Structural modules, defined on the basis of markers
of chemical trans mission, have been recognized in the striatum.
We have recently introduced the
Hormones and Synaptic Transmission 41
idea that there exist "integrative" modules in the brain, formed in
the interaction zones between various structural modules (Agnati et
al. 1986c; Fuxe et al. 1986 c). The overlap zones between two,
three or more structural modules corre spond to integrative
modules of higher and higher level (Fig. 32). Each integrative
module of any level may have different spatial and temporal
patterns of activity, resulting in a very ample spectrum of
functional states. Such an integrative mod ule may be considered
as the functional counterpart of the module, which is basi cally
defined by means of criteria borrowed from chemical
neuroanatomy.
7.2 Modules of Volume Transmission
Recently, by means of automatic image analysis, we have also been
able to estab lish the existence of islands of neurons which
contain glucocorticoid receptor im munoreactivity within the
striatum and the nucleus accumbens (Fig. 33). These results provide
the first evidence for the existence, at least in parts of the eNS,
of structural modules characterized on the basis of humoral inputs.
GR IR is lands have a rather uniform distribution and are
different from the striatal mod ules of the WT mentioned above
(see Zoli et al. 1988).
7.3 Functional Aspects on the Modular Organization
The best example of functional interactions between WT and VT
modules is pre sented by the local circuits formed by various
types of transmitter-identified nerve terminals at the median
eminence level (Fuxe et al. 1986c). In fact, at median emi nence
level (an interface area between brain and the endocrine system),
the vari ous types of transmitter-identified nerve terminal
networks form aggregates of nerve terminals, the medianosomes (see
Fig. 31), located in distinct parts of the median eminence forming
rostrocaudal strips. Such aggregates of nerve terminals regulate
the secretion of one hypothalamic hormone (e.g. a releasing
hormone) (see Fig. 34). The releasing factor secreted by the median
eminence controls the release of one adenohypophyseal hormone. The
differential activation of the vari ous elements forming a
medianosome results in a functional state which will pro vide the
appropriate output to control anterior pituitary hormone secretion.
Re ceptors for various hypothalamic and hypophyseal hormones, such
as thyreo tropic releasing hormone and corticotropin releasing
hormone, probably exist in various portions of the cell membranes
of the nerve terminals constituting the lo cal circuits of the
medianosomes (Taylor and Burt 1982; De Souza et al. 1985). Thus,
one important role of the hypothalamic and of the hypophyseal
hormones is to modulate the activity of the medianosomes, an action
which probably under lies the ultrashort and short-loop feedback
action of hypothalamic and of the hy pophyseal hormones,
respectively. From the above it becomes clear that one im portant
site of action of hormones in the brain is a local circuit module,
where the activated hormonal receptors of humoral modules interact
with activated transmitter receptors of wiring modules to adjust
the functional output.
42 K. Fuxe et al.
Fig. 33 A-D. Example of the elaboration of the sampled fields. A
Original image as it ap pears on the IBAS screen. B The
discrimination function has been performed on the orig inal image
to differentiate grey matter (black in the image) from white
matter. This pro cedure allows the determination of the field area
of the grey matter present in the sampled field. C The
discrimination function has been performed on the original image to
separate the specific staining (glucocorticoid receptor
immunoreactive profiles: white dots in the discriminated image)
from the background. This procedure allows the evaluation of the
number of the discriminated profiles. D The close function has been
performed on the discriminated image C. This procedure allows
determination of the field area covered by the islands and the
number and the size of the islands, defined as aggregates of three
or more original profiles
LHRH MEDIANOSOME
OF PROLACTIN BINDING SITES
PIF MEDIANOSOME
OF NERVE TERMINALS REGULATING LHRH
+ PlF SECRETION RESPECTIVELY (WIRING MODULES)
Fig. 34. Example of a possible interaction between volume
transmission modules (humoral modules of prolactin binding sites)
and of wiring transmission modules [wiring modules; structural
medianosomes for luteinizing hormone-releasing hormone (LHRH) and
prolac tin release-inhibiting factor (PIP) secretion]
8 Summary
There are two types of chemical transmission in brain, namely
wiring trans mission (WT) and volume transmission (VT). WT is the
classical type of trans mission which is neuronally linked and
operates with high speed, high safety and short term actions, their
divergency and plasticity being low. VT is a type of transmission
mainly operating via electronic and paracrine signals, diffusing in
the extracellular fluid to reach the appropriate targets. To
understand the actions of hormones and paracrine signals on WT, the
complexity of the individual synapse must be understood. It
consists of multiple transmission lines, which interact with one
another at the pre- and postsynaptic membrane via intra membrane
receptor-receptor interactions and via intracellular postreceptor
sig nals.
There exists a blood-brain barrier, leading to the exclusion of a
number ofpe ripheral hormonal signals. However, there also exist
chemical and physical "win dows" through which the brain receives
and delivers messages. Physical windows are represented by brain
areas devoid of a blood-brain barrier, such as the area
44 K. Fuxe et al.
postrema, the median eminence and the subfornical organ. The
chemical win dows are represented by facilitated transport, active
transports etc.
Steroid sex hormone-accumulating and estrogen IR nerve cells have
been demonstrated in the central nervous system and are
concentrated in the limbic forebrain, the medial preoptic area and
the hypothalamus. The nuclear location of the estrogen
immunoreactivity strongly supports the importance of the genomic
actions of estrogens. Estradiol-17fJ, progesterone and androgens
pro duce discrete changes in dopamine (DA), noradrenaline (NA) and
adrenaline (A) levels and utilization within the hypothalamus and
the preoptic area in male and female rats in various endocrine
states. The monoamines participate in both the central inhibitory
and facilitory feedback actions of estradiol-17 fJ on LHRH se
cretion. The various catecholamine (CA) nerve terminal networks are
probably influenced via local circuit interactions, in which the
steroid target cells partici pate. However, an accumulation of
steroid hormones has also been observed in DA and NA nerve cell
bodies. Estrogens also influence striatal DA mechanisms, indicating
that estrogens can also modulate motor functions and mental activi
ties, such as mood. These effects may be produced via indirect
actions involving the hypothalamus and/or the pituitary gland.
However, the vast majority of the effects of estrogens and other
gonadal steroids on the presynaptic pro