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Government of India CENTRAL INSTITUTE OF PSYCHIATRY, RANCHI

Neurotransmitters and Psychiatry Chairperson: Dr. Nishant Goyal

Presenter: Dr. Sachchidanand Singh Discussant: Dr. Daljeet Singh Ranawat

Venue: B. H. Hall Date: 23.08.2012

INTRODUCTION

Neurons in the human brain communicate with one another by releasing chemical messengers called neurotransmitters.

All neurotransmitter molecules undergo a similar cycle of use involving: (1) synthesis and packaging into vesicles in the

presynaptic cell; (2) release from the presynaptic cell and binding to receptors on one or more postsynaptic cells; and (3)

rapid removal and/or degradation. The total number of neurotransmitters is not known, but is well over 100.

Abnormalities of neurotransmitter function contribute to a wide range of neurological and psychiatric disorders. As a

result, altering aspects of neurotransmitter release, binding, and reuptake or removal by pharmacological or other means is

central to many therapeutic strategies.

NEUROACTIVE SUBSTANCES

A variety of biologically active substances, as well as metabolic intermediates, are capable of inducing neurotransmitter or

neuromodulator effects. The molecular spectrum of neuroactive substances ranges from ordinary intermediates of amino

acid metabolism, like glutamate and GABA, to highly effective peptides, proteohormones and corticoids. Neuroactive

molecules target receptors with pharmacologically different profiles (Halbach and Dermietzel, 2006). Neuroactive

substances can be broadly classified into two main classes namely, neurotransmitters and neuromodulators although

functional overlap between neurotransmitters and neuromodulators is quite common.

Criteria for a Neurotransmitter

Neurotransmitters are the most common class of chemical messengers in the nervous system. A neuroactive substance has

to fulfill certain criteria before it can be classified as a neurotransmitter (Werman, 1966).

It must be of neuronal origin and accumulate in presynaptic terminals, from where it is released upon

depolarization.

The released neurotransmitter must induce postsynaptic effects upon its target cell, which are mediated by

neurotransmitter-specific receptors.

The substance must be metabolically inactivated or cleared from the synaptic cleft by reuptake mechanisms.

Experimental application of the substance to nervous tissue must produce effects comparable to those induced by

the naturally occurring neurotransmitter.

NEUROMODULATOR

A neuromodulator, as the name implies, modulates the response of a neuron to a neurotransmitter. A neuromodulating

substance may have an effect on a neuron over a long period of time, and that effect may be more involved with fine

tuning than with activating or directly inhibiting the generation of an action potential (Halbach and Dermietzel, 2006).

CLASSIFICATION OF NEUROTRANSMITTERS (Stahl, 2008)

Category Neurotransmitters

Amines Serotonin, Dopamine, Norepinephrine (Noradrenaline), Epinephrine (Noradrenaline), Acetylcholine,

Tyramine, Octopamine, Phenylethylamine, Tryptamine, Melatonin, Histamine, Agmatine.

Amino acids Gamma-aminobutyric acid (GABA), Glycine, Glutamic acid (glutamate), Aspartic acid (aspartate),

Gamma-hydroxy-butyrate, d-serine.

Circulating

hormones

Angiogensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor, Estrogens, Androgens,

Progestins, Thyroid hormones, Cortisol.

Hypothalamic

releasing

hormones

Corticotrophin-releasing hormone (CRH), Gonadotropin releasing hormone (GnRH), Luteinizing

hormone releasing hormone (LHRH), Somatostatin, Thyrotropin releasing hormone (TRH), Growth

hormone releasing hormone (GHRH).

Pituitary

peptides

Corticotrophin (ACTH), Growth hormone (GH), Lipotrophin, Alpha-melanocyte-stimulating hormone

(alpha-MSH), Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin.

Gut hormones Cholecystokinin (CCK), Gastrin, Motilin, Pacreatic polypeptide, Secretin, Vasoactive intestinal

peptide (VIP).

Opioid peptides Dynorphin, Beta-endorphin, Met-enkephalin, Leu-enkephalin, Kyotorphin, Nociceptin (orphanin FQ).

Miscellaneous

peptides

Bombesin, Bradykinin, Carnosine, Calcitonin G related peptide, CART (cocaine and amphetamine

related transcript), Neuropeptide Y, Neurotensin, Delta sleep factor, Galanin, Focretin, Melanocyte

concentration hormone.

Gases Nitric oxide (NO), Carbon monoxide (CO).

Lipid

neurotransmitter

Anandamide.

Neurokinins/

Tachykinins

Substance P, Neurokinin A, Neurokinin B.

Purines

ATP (adenosine triphosphate), ADP (adenosine diphosphate), AMP (adenosine monophosphate)

Adenosine.

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AMINE NEUROTRANSMITTERS SEROTONIN

Serotonin is also known as 5-hydroxytryptamine (5-HT). It is an intermediate product of tryptophan metabolism, and is

primarily located in the enterochromaffin cells of the intestine, the serotoninergic neurons of the brain, and platelets of the

blood. 5-HT is well established as a neurotransmitter in the central nervous system (CNS), but it also plays diverse roles

in the cardiovascular system, including platelet aggregation and regulation of vascular tone. The name serotonin is derived

from two words serum (because the substance can be found in blood serum) and vasotonic (because it provides vasotonic

properties) (Halbach and Dermietzel, 2006).

Synthesis and metabolism

Serotonin is synthesized from the amino acid tryptophan and the steps are shown in figure 1. After synthesis, 5-HT is

taken up into synaptic vesicles by a vesicular monoamine transporter (VMAT2) for storage (Stanford, 2001).

Tryptophan Hydroxylase Decarboxylase

TRYPTOPHAN 5-HYDROXYTRYPTOPHAN SEROTONIN

Rate limiting (5-HT)

MAO B Dehydrogenase

5-HYDROXYINDOLEACETICACID 5HYDROXY TRYPTOPHOL

(5-HIIA)

Figure 1: Synthesis and metabolism of serotonin. MAO- Monoamine oxidase (Adopted from Halbach and Dermietzel,

2006)

Levels of 5-HIAA are often measured as a correlate of serotonergic system activity, although the relationship of these

levels to serotonergic neuronal activity remains unclear (Berger et al., 2009). Other metabolic products of 5-HT are also

possible and one such metabolite, 5-hydroxytryptophol, which results from the reduction of its intermediate metabolite, 5-

hydroxyindolacetaldehyde, has been identified in the brain (Stanford, 2001).

Distribution

The CNS contains less than 2 percent of the serotonin in the body; peripheral serotonin is located in platelets, mast cells,

and enterochromaffin cells. Over 80 percent of all the serotonin in the body is found in the gastrointestinal system, where

it modulates motility and digestive functions. Terminals expressing serotonin can be found in nearly every brain area, but

their general density is low (Halbach and Dermietzel, 2006).

Figure 2: Major serotonin projections. Serotonin has both ascending and descending projections. PFC- prefrontal cortex;

BF- basal forebrain; Sr- striatum; NA- nucleus accumbens; T- thalamus; HY- hypothalamus; A- amygdala; H-

hippocampus; NT- brainstem neurotransmitter centers; SC- spinal cord; C- cerebellum. (Adopted from Stahl, 2008)

The clusters of 5-HT cell bodies were classified in nine separate nuclei which are regarded as forming two major groups:

Superior and Inferior group. Neurons in the superior group projects rostrally, innervate limbic and sensory areas of the

forebrain with considerable overlap between different nuclei. Here fibres originating from dorsal raphe nucleus (DRN) are

the major source of 5-HT terminals in the basal ganglia and cerebellum. Neurons in the median raphe nucleus (MRN)

provide the major input to the hippocampus and the septum. The inferior group projects mainly to the brainstem nuclei,

the head nuclei of some cranial nerves and the spinal cord (Stanford, 2001).

Receptors

At least 14 distinct serotonin receptor subtypes have been identified to date based on their structure, pharmacology, brain

distribution, and effector mechanisms. 5-HT1 receptors comprise the largest serotonin receptor subfamily, with human

subtypes designated 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F, 5-HT1P, 5-HT1S (Halbach and Dermietzel, 2006).

Behavioural and physiological responses affected by 5-HT receptors are shown in table 1.

5-HT1A is found on postsynaptic membranes of forebrain neurons primarily in the hippocampus, cortex, septum and on

serotonergic neurons, where it functions as an inhibitory somatodendritic autoreceptor. The downregulation of 5-HT1A

autoreceptors by the chronic administration of serotonin reuptake blockers has been implicated in their antidepressant

effects, and SSRIs may produce some behavioral effects via increase in hippocampal neurogenesis mediated by

postsynaptic 5-HT1A receptor activation (Berger et al., 2009).

5-HT1B and 5-HT1D receptors resemble each other in structure and brain localization, although the 5-HT1D receptor is

expressed at lower levels. 5-HT1B/D receptors are found on axon terminals of serotonergic and non-serotonergic neurons,

where they act to reduce neurotransmitter release. The 5-HT1B receptor has been implicated in the modulation of

locomotor activity levels, consistent with its high level of expression in basal ganglia. It has also been suggested as a

modulator of aggression (Berger et al., 2009).

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5-HT1E and 5-HT1F receptor subtypes are less well characterized. The highest levels of 5-HT1E receptor expression are

found in the striatum and entorhinal cortex, while 5-HT1F receptor expression is highest in the dorsal raphe nucleus,

hippocampus, cortex, and striatum. In addition, 5-HT1B and the 5-HT1D and 5-HT1F receptors are found in the cerebral

vasculature and the trigeminal ganglion respectively, and are stimulated by the antimigraine drug sumatriptan possibly by

mediating vasoconstriction and inhibition of nociceptive transmission (Berger et al., 2009).

5-HT1P sites display a pharmacology distinct from other 5-HT receptors and are mainly located in the gut but, because

they have not been identified in the CNS until now (Halbach and Dermietzel, 2006).

5-HT1S receptors are mainly expressed in the spinal cord. Although these receptors appear to be the predominant 5-HT1

receptor population in the spinal cord (Halbach and Dermietzel, 2006).

5HT2 receptor has been renamed 5-HT2A to indicate that it is a member of a 5-HT receptor subfamily. A second receptor

initially termed 5-HT1C has been renamed 5-HT2C to indicate its membership within this subfamily. The third known 5HT2

receptor, termed 5-HT2B, located in the stomach fundus, though it has limited distribution in the brain. High levels of 5-

HT2A receptors are found in the neocortex and in peripheral locations such as platelets and smooth muscle. 5-HT2A

receptor blockade correlates with the therapeutic effectiveness of atypical antipsychotics. The 5-HT2A receptor has also

been implicated in the cognitive process of working memory, a function believed to be impaired in schizophrenia (Berger

et al., 2009).

5-HT2C receptor is expressed in many CNS regions including the hippocampal formation, prefrontal cortex, amygdala,

striatum, hypothalamus, and choroid plexus and its stimulation has been proposed to produce anxiogenic effects as well as

anorectic effects, which may result from interactions with the hypothalamic melanocortin and leptin pathways. It may also

play a role in the weight gain and development of type II diabetes mellitus associated with atypical antipsychotic

treatment (Matsui-Sakata et al., 2005).

5-HT3 receptor is expressed within the hippocampus, neocortex, amygdala, hypothalamus, and brainstem, including the

area postrema. Peripherally, it is found in the pituitary gland and enteric nervous system. 5-HT3 receptor antagonists such

as ondansetron are used as antiemetic agents and are under evaluation as potential antianxiety and cognitive-enhancing

agents. The functional 5-HT3 receptor appears to be comprised of at two distinct subunits, termed 5-HT3A and 5-HT3B

(Berger et al., 2009).

5-HT4, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7 receptor subtypes functions are not known due to lack of selective agonists

and antagonists. The 5-HT4 receptors are expressed in the hippocampus, striatum, substantia nigra, and superior colliculus.

The 5-HT4 receptors have been shown to modulate the release of neurotransmitters including acetylcholine, 5-HT, and

dopamine and have been implicated in the serotonergic regulation of cognition and anxiety. The two 5-HT5 receptor

subtypes are highly homologous, although only one of these subtypes is expressed in the human brain, in the neocortex,

hippocampus, raphe nuclei, and cerebellum. 5-HT6 receptors may contribute to the actions of the several antidepressant,

antipsychotic, and hallucinogenic drugs that bind with high affinity (Berger et al., 2009). Highest levels of 5-HT7

receptors are found in hypothalamus and thalamus and have been proposed to contribute to the serotonergic modulation of

circadian rhythms, and drugs that block these receptors may have antidepressant effects (Halbach and Dermietzel, 2006).

Behavioural and physiological

changes

5-HT1A 5-HT1B 5-HT2 5-HT3 5-HT4 5-HT7

Anxiety/panic * * *(?)

Cognition *(?)

Food intake * * * *

Hallucinations *

Mood * *

Nausea/vomiting *

Obscessive behaviour *

Pain * * *

Psychosis *

Sexual function * *

Sleep/Circardian rhythm * * *

Thermoregulation * * *

Table 1: Behavioural and physiological responses affected by 5-HT receptors (Adopted from Stanford, 2001)

DOPAMINE

The first successful synthesis of dopamine (3, 4-dihydroxyphenethylamine, or 3-hydroxytryptamine) was achieved in

1910. Dopamine, like other neurotransmitters, is not capable of crossing the blood–brain barrier. However, the precursors

of dopamine, phenylalanine and tyrosine are taken up into the brain via an active transport mechanism and hence are able

to cross the blood–brain barrier (Halbach and Dermietzel, 2006).

Synthesis and metabolism

The biosynthesis of dopamine takes place within nerve terminals. Steps for synthesis and metabolism of dopamine are

shown in figure 3. Once formed, DA is then taken up into synaptic vesicles by a vesicular monoamine transporter

(VMAT2) (Stahl, 2008). The vesicles can be disrupted by reserpine and tetrabenazine (Webster, 2001). Dopamine is

released into the synaptic cleft. The dopaminergic signal is finally terminated by removal of dopamine from the synaptic

cleft by specific dopamine transporters (DAT) to the presynaptic terminal where it can be stored and reused.

PHENYLALANINE

Phenylalanine Hydroxylase

TYROSINE

Tyrosine Hydroxylase (Rate limiting enzyme)

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DIHYDROXYPHENYLALANINE

(DOPA)

MAO Decarboxylase COMT

DOPAC DOPAMINE 3-METHOXYTRYPTAMINE

Β- Hydroxylase

NORADRENALINE COMT NORMETANEPHRINE

N-Methyltransferase Extraneuronal

MAO

Intraneuronal ADRENALINE COMT METANEPHRINE

MAO

3,4 Dihydroxy Mandelic Acid 3, Methoxy 4, Hydroxy Mandelic Acid

COMT (VMA)

Figure 3: Synthesis and metabolism of dopamine, noradrenaline and adrenaline. COMT- catechol-O-methyl transferase,

DOPAC - dihydroxyphenylacetic acid, MAO - monoamine oxidase (Adopted from Halbach and Dermietzel, 2006)

Presynaptic membrane also contains some dopamine receptors. These receptors are so-called autoreceptors. Their

functional role is to monitor the extracellular dopamine concentration and to modulate the impulse-dependent release and

synthesis of dopamine. A blockade of these receptors facilitates the synthesis and presynaptic release of dopamine, while

their stimulation has the opposite effect. The blockade of monoamine catabolism by MAO inhibitors produces elevations

in brain monoamine levels. For example, peripheral MAO degrades dietary tyramine, an amine that can displace

norepinephrine from sympathetic postganglionic nerve endings, producing hypertension if tyramine is present in large

enough quantities. Thus, patients treated with MAO inhibitors are cautioned to avoid pickled and fermented foods that

typically have high levels of tyramine (cheese reaction). In humans, the predominant metabolites of dopamine is

homovanillic acid (HVA) (Berger et al., 2009).

Distribution of dopamine

Dopamine neurons are more widely distributed than other monamines, residing in the midbrain substantia nigra and

ventral tegmental area and in the periaqueductal gray, hypothalamus, olfactory bulb, and retina. In the periphery,

dopamine is found in the kidney where it functions to produce renal vasodilation, diuresis, and natriuresis (Berger et al.,

2009).

Figure 4: Major dopamine projections: Dopamine has widespread ascending projections that originate predominantly in

the brainstem (particularly the ventral tegmental area and substantia nigra) and extend via the hypothalamus to the

prefrontal cortex, basal forebrain, striatum, nucleus accumbens, and other regions. PFC- prefrontal cortex; BFr- basal

forebrain; St- striatum; NA- nucleus accumbens; T- thalamus; HY- hypothalamus; A- amygdala; H- hippocampus; NT-

brainstem neurotransmitter centers; SC- spinal cord and C- cerebellum (Adopted from Stahl, 2008)

There are five dopamine pathways in the brain and depicted in figure:

(a) Nigrostriatal dopamine pathway: It projects from the substantia nigra to the basal ganglia or striatum, is part of the

extrapyramidal nervous system and controls motor function and movement.

(b) Mesolimbic dopamine pathway: It projects from the midbrain ventral tegmental area to the nucleus accumbens in the

ventral striatum, a part of the limbic system of the brain thought to be involved in many behaviours such as pleasurable

sensations and motivation, the powerful euphoria of drugs of abuse, as well as delusions and hallucinations (positive

symptoms) of psychosis.

(c) Mesocortical dopamine pathway: It also projects from the midbrain ventral tegmental area and sends its axons to

areas of the prefrontal cortex, where they may have a role in mediating cognitive symptoms and executive function

(dorsolateral prefrontal cortex) and affective symptoms (ventromedial prefrontal cortex) of schizophrenia.

(d) Tuberoinfundibular dopamine pathway: It projects from the hypothalamus to the anterior pituitary gland and controls

prolactin secretion.

(e) The fifth dopamine pathway arises from multiple sites, including the periaqueductal gray, ventral mesencephalon,

hypothalamic nuclei, and lateral parabrachial nucleus, and it projects to the thalamus. Its function is not currently well

known.

Figure 5: Five dopamine pathways in the brain (Adopted from Stahl, 2008)

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Receptors (Berger et al., 2009)

There are five dopamine receptors, designated as D1, D2, D3, D4, and D5 and distinguished on the basis of differential

binding affinities of a series of agonists and antagonists, distinct effector mechanisms, and distinct distribution patterns

within the CNS. On the basis of their structure, pharmacology, and primary effector mechanisms, the D3 and D4 receptors

are considered to be ―D2-like,‖ and the D5 receptor ―D1-like.‖

D1 receptor: It is the most widespread dopamine receptor and is present in nigrostriatal and mesocorticolimbic pathways,

with high levels in the dorsal striatum, nucleus accumbens, and amygdala. In contrast, little number of D1 is found in

dopamine cell body regions such as the substantia nigra pars compacta and the ventral tegmental area. Locomotor

stimulation appears to involve activation of both D1 and D2 receptors. Electrophysiological studies have also indicated that

D1 receptor activation is required for striatal D2 receptor activation to produce its maximal effect. D1 receptors have also

been implicated in the cognitive functions of dopamine such as the control of working memory and attention.

D2 receptor: The relative abundance (in decreasing concentration) of these receptors are as follows: striatum,

mesencephalon, spinal cord, hypothalamus and hippocampus. It may have either a postsynaptic function or an

autoreceptor function. D2 receptors are also expressed in the anterior pituitary and mediate the dopaminergic inhibition of

prolactin and α-melanocyte-stimulating hormone release. D2 receptors have long been implicated in the pathophysiology

and treatment of schizophrenia. The extrapyramidal side effects of antipsychotic drugs have been attributed to the

blockade of striatal D2 receptors.

D3 receptor: It is widely distributed in the basal forebrain, olfactory tubercle, nucleus accumbens, striatum and substantia

nigra, but they are infrequent in limbic and extrapyramidal regions. Because of their preferential limbic expression, they

have been postulated to represent an important target for antipsychotic drugs. The D3 receptor may play a role in the

control of locomotion.

D4 receptor: These are expressed in the frontal cortex, midbrain, amygdala, hippocampus, and medulla. It has been found

to be associated with an increased risk of schizophrenia as elevated D4 receptor levels have been found in postmortem

schizophrenic brains. Moreover, the atypical antipsychotic drug clozapine has a high affinity for the D4 receptor.

D5 receptor: Structural similarity with D1 receptor is reflected in the similar affinities of a wide variety of dopaminergic

drugs for these two receptors but their binding affinity of dopamine is higher for the D5 receptor than that for the D1

receptor. The expression of D5 receptors is found in hippocampus, hypothalamus, prefrontal cortex, and striatum.

NOREPINEPHRINE AND EPINEPHRINE

Norepinephrine and epinephrine belongs to the family of catecholamines. In contrast to epinephrine, which is mainly

restricted to the peripheral nervous system, norepinephrine is also a major transmitter in the central nervous system

(Halbach and Dermietzel, 2006).

Synthesis and metabolism

Norepinephrine or noradrenaline (NA) utilizes noradrenergic neuron as its neurotransmitter. NA is synthesized from the

precursor amino acid tyrosine, which is transported into the nervous system from the blood by means of an active

transport pump. Steps for synthesis and metabolism of dopamine are shown in figure 3. The action of NE can be

terminated by a transport pump for norepinephrine (NE) that prevents it from acting in the synapse. The transport pump

that terminates synaptic action of NE is called the "NE transporter" or "NET" and sometimes the "NE reuptake pump."

This NE reuptake pump is located on the presynaptic noradrenergic nerve terminal (Stahl, 2008).

Distribution

Figure 6: Major norepinephrine projections. Norepinephrine has both ascending and descending projections. Ascending

noradrenergic projections originate mainly in the locus coeruleus of the brainstem; they extend to multiple brain regions,

as shown here, and regulate mood, arousal, cognition, and other functions. Descending noradrenergic projections extend

down the spinal cord and regulate pain pathways. PFC- prefrontal cortex; BF- basal forebrain; S- striatum; NA- nucleus

accumbens; T-thalamus; HY- hypothalamus; A- amygdala; H- hippocampus; NT- brainstem neurotransmitter centers; SC-

spinal cord; C- cerebellum (Adopted from Stahl, 2008)

Receptors (Halbach and Dermietzel, 2006)

The effects elicited by norepinephrine binding depend on the three types of receptors: α1, α2 and β. Each subfamily

consists of three distinct receptor subtypes.

α1 receptors (subtypes designated α1A, α1B, and α1D): These receptors are believed to play a significant role in regulating

smooth muscle contraction. All three subtypes are expressed in the brain, in areas including the cerebral cortex,

hippocampus, septum, amygdala, and thalamus. Their contributions to the central actions of norepinephrine remain to be

determined, although some studies point to a role in facilitation of locomotor responses and arousal.

α2 receptor subtypes (designated α2A, α2B, and α2C): They display both presynaptic autoreceptor and postsynaptic actions.

Within the brain the stimulation of α2 autoreceptors (likely the α2A subtype) which have been implicated in arousal states.

This mechanism has been proposed for sedative effects and blood pressure lowering effect of the α2 receptor agonist

clonidine. This action may relate to the utility of clonidine in lowering blood pressure and in suppressing the sympathetic

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hyperactivity associated with opiate withdrawal. Activation of α2 receptors inhibits the activity of serotonin neurons of the

dorsal raphe nucleus.

β adrenergic receptors (subtypes designated β1, β2, and β3): They are found both in the brain and in many peripheral

tissues. β1 receptors are present in heart while β2 receptors mediate bronchial muscle relaxation and vasodilation within

skeletal muscle. β3 receptors are found in adipose tissue, where they stimulate fat catabolism. β1 and β2 receptors are

widely distributed in the CNS. They have been suggested to play a role in the consolidation of memory through actions

within the amygdala. Propranolol is a widely used nonspecific antagonist of both β1 and β2 receptors. In addition to its

utility for the treatment of hypertension and arrhythmias, its effectiveness in blunting autonomic symptoms underlies its

utility in the management of social phobia and post-traumatic stress disorder.

ACETYLCHOLINE

Acetylcholine (ACh) was the first neurotransmitter discovered. ACh plays a significant role in synaptic transmission in

the central and peripheral nervous system.

Synthesis and metabolism

Acetylcholine is synthesized by the transfer of an acetyl group from acetyl coenzyme A to choline in a reaction mediated

by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then stored in synaptic vesicles through the action of a

vesicular acetylcholine transporter (VAchT).

ATP + Acetate + CoEn-A

Acetate activating reaction

Acetyl CoEn-A

CHOLINE

Choline acetyl transferase

ACETYLCHOLINE + CoEn-A

Acetylcholinesterase

CHOLINE

Figure 7: Synthesis and metabolism of acetylcholine CoEn-A – Coenzyme A (Adopted from Halbach and Dermietzel,

2006)

Distribution (Halbach and Dermietzel, 2006)

The cholinergic system of brain tissue can be divided into three different sub-systems:

1. Cholinergic motoneurons in the spinal cord: The collaterals of these neurons activate small interneurons in the

ventral horn of the spinal cord (Renshaw cells), which express nicotinic receptors.

2. Interneurons and local projection neurons: The most representative neurons of this type are interneurons in the

striatum. These interneurons interact with the dopaminergic terminals of neurons which project from the substantia

nigra into the striatum. In addition, sparsely distributed cholinergic interneurons are located in the cortex, the

hippocampus and in the olfactory bulb.

3. Projection neurons: Group Ch1 and Ch2 correspond with cholinergic neurons in the region of the medial septal

nucleus and with neurons in the diagonal band of Broca respectively. These neurons project to the hippocampus.

Group Ch3 is located in the horizontal band of Broca and innervate the olfactory bulb. Members of group Ch4 are

represented by neurons of the magnocellular region of the preoptic nucleus, the magnocellular region of the nucleus

basalis of Meynert and in the substantia innominata. These neurons project to the cerebral cortex and to the amygdala.

Members of groups Ch5 and Ch6 are located in tegmental areas of the brain. They possess ascending projections to

the thalamus and to the hypothalamus as well as descending projections. The descending projections approach the

pons, the nucleus vestibularis, the locus coeruleus and various raphe nuclei. The neurons of group Ch7 occur in the

habenula. They project to the interpeduncular nucleus. Finally, neurons of group Ch8 are located in the parabigeminal

nucleus and send projections into the superior colliculus.

Receptors (Berger et al., 2009)

The ACh receptors consist of two major groups: the G-protein-coupled muscarinic and the ligand-gated ion channels

nicotinic receptors. They can be distinguished by their selectivity to the alkaloids nicotine and muscarine.

The nicotinic receptors

(1) Skeletal muscle subunits (α1, β1, δ and ε): In the periphery, nicotinic acetylcholine receptors are found in skeletal

muscle, autonomic ganglia, and the adrenal medulla.

(2) Standard neuronal subunits (α2–α6 and β2–β4): In the brain, they are found in the neocortex, hippocampus, thalamus,

striatum, hypothalamus, cerebellum, substantia nigra, ventral tegmental area, and dorsal raphe nucleus. They mediate

presynaptic enhancement of acetylcholine, dopamine, norepinephrine, 5-HT, GABA and glutamate release. Nicotinic

receptors have been implicated in cognitive function, especially working memory, attention, and processing speed.

(3) Subunits capable of forming homomeric receptors (α7–α9): The α7 nicotinic acetylcholine receptor subtype has been

implicated as one of many possible susceptibility genes for schizophrenia, with lower levels of this receptor being

associated with impaired sensory gating.

The muscarinic receptors

In the periphery, muscarinic receptors mediate the effects of postganglionic parasympathetic nerve release of

acetylcholine. Five muscarinic receptor subtypes have been cloned, and these have been divided into two families on the

basis of intracellular signaling mechanism:

M1 receptor group: These are M1, M3, and M5 receptors. M1 receptors are the most abundantly expressed muscarinic

receptors in the forebrain, including the cortex, hippocampus, and striatum. Pharmacological evidence has suggested their

involvement in memory and synaptic plasticity.

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M2 and M4 receptors group: The M2 and M4 receptors may act as inhibitory autoreceptors and heteroreceptors to limit

presynaptic neurotransmitter release. M2 receptors appear to mediate tremor, hypothermia, and analgesia induced by

muscarinic agonists. M3 receptors are found in smooth muscles and salivary glands. M4 receptors are expressed in the

hippocampus, cortex, striatum, thalamus, and cerebellum. Striatal M4 receptors may oppose the effects of D1 dopamine

receptors and have been implicated as putative targets for anticholinergics used as antiparkinsonian agent.

HISTAMINE Histamine was first known to be a substance released by mast cells in response to allergen stimulation. It has a

physiological mediator within different tissues, including the CNS (Halbach and Dermietzel, 2006).

Synthesis and Metabolism Both postsynaptic and presynaptic histaminergic receptors and precursor of histamine metabolism have been found in the

brain. The enzyme L-histidine-decarboxylase (HDC or HD) is responsible for the biosynthesis of histamine in the CNS

(Berger et al., 2009).

Distribution

Figure 8: Major histamine projections. Histamine neurons arise from the tuberomammillary nucleus of the hypothalamus

and project widely throughout the brain and to the spinal cord. Histamine is predominantly involved in sleep and

wakefulness. PFC- prefrontal cortex; BF- basal forebrain; S- striatum; NA- nucleus accumbens; T- thalamus; HY-

hypothalamus; A- amygdala; H- hippocampus; NT- brainstem neurotransmitter centers; SC- spinal cord; C- cerebellum.

(Adopted from Stahl, 2008)

Receptors (Berger et al., 2009)

Four different receptor subtypes, namely, H1, H2, H3 and H4, binds histamine specifically. These can be distinguished by

their different binding patterns and different biological effects.

H1 receptors: Apart from periphery these receptors are distributed in the thalamus, cortex, and cerebellum. H1 receptor is

the mediator of allergy, sedation and weight gain produced by a number of antipsychotic and antidepressant drugs.

H2 receptors: Apart from periphery, H2 receptors are widely expressed in the neocortex, hippocampus, amygdala, and

striatum and produces excitatory effects in neurons of the hippocampal formation and thalamus. Several studies indicates

that the stimulation of these receptors produces antinociceptive effects.

H3 receptors: These are located presynaptically on axon terminals. Those located on histaminergic terminals act as

autoreceptors. In addition, H3 receptors are located on nonhistaminergic nerve terminals, where they act as

heteroreceptors to inhibit the release of a variety of neurotransmitters—including norepinephrine, dopamine,

acetylcholine, and serotonin. Particularly high levels of H3 receptor binding are found in the frontal cortex, striatum,

amygdaloid complex, and substantia nigra. Antagonists of H3 receptors have been proposed to have appetite suppressant,

arousing, and cognitive-enhancing properties.

H4 receptors: It has identified recently and is detected predominantly in the periphery, in regions such as the spleen, bone

marrow, and leukocytes.

MELATONIN

In the human brain, secretion of melatonin by the pineal gland is regulated by the suprachiasmatic nucleus (SCN) of the

anterior hypothalamus. Melatonin secretion is stimulated by darkness and inhibited by light, thus regulating sleep, core

body temperature, hormone production, heart rate, and blood pressure via circadian rhythm. During wake time, the SCN

promotes wakefulness by transmitting stimulatory signals through the entire CNS. Plasma melatonin levels are lowest

during the day, abruptly increase close to habitual bedtime, peak during the night, and decrease as wake time approaches

(Turek and Gillette, 2004).

Melatonin has a very short half-life of 0.5 to 6 minutes. Exogenous melatonin interacts with the MT1, MT2, and MT3

receptors in the SCN. Activation of the MT1 receptor suppresses neuronal firing in the SCN, thereby promoting sleep.

MT2 receptor appears to be primarily associated with circadian rhythm phase shifts, while the implication of binding to

MT3 receptors is much less understood (Doghramji, 2007).

TRACE AMINES

Trace amines are an endogenous group of amines structurally and metabolically related to classical monoamine

neurotransmitters. Tyramine is a naturally occurring monoamine compound and is derived from the amino acid tyrosine.

Tyramine occurs widely in plants and animals, and is metabolized by the enzyme monoamine oxidase. In the CNS,

tyramine is present in two forms: p-tyramine and m-tyramine. In the periphery, p-tyramine is easily hydroxylated to

octopamine, which has some direct effect on α1 adrenoceptors, while tyramine functions by releasing norepinephrine

(Halbach and Dermietzel, 2006).

The most feared adverse effect of irreversible MAOIs is the tyramine induced hypertensive crisis characterised by severe

hypertension, headaches, tachycardia, diaphoresis, and vomiting. All patients who are treated with an irreversible MAOI

should be instructed to avoid foods with substantial tyramine content like, certain fermented foodstuffs, including red

wine, tap beer, cheese, yeast extracts, and pickled fish. It causes a vasopressor response that is dramatically accentuated in

patients taking an MAOI due to patient's inability to deaminate tyramine (which is normally broken down by MAOA in

the gut), resulting in displacement of intracellular stores of norepinephrine from sympathetic innervating blood vessels

(Shulman and Walker, 1999).

8

Octopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic

and dopaminergic systems. It is also found naturally in numerous plants (Tang et al., 2006). It has been much studied in

invertebrates but, due to lack of research, much is not known about octopamine or its role in humans.

Phenylethylamine (PEA) is another trace amine and is well known for psychoactive drug and stimulant effects. It is

biosynthesized from the amino acid phenylalanine by enzymatic decarboxylation. One study suggests that a large

percentage of endogenous depressions may be due to a deficit of PEA in the brain (Halbach and Dermietzel, 2006).

AMINO ACID NEUROTRANSMITTERS

γ-AMINOBUTYRIC ACID (GABA)

GABA, is the major inhibitory neurotransmitter on the postsynaptic membrane due to a consequence of the

hyperpolarization of the neuron in the brain where it is broadly distributed. Faulty GABAergic neurotransmission has

been implicated in a broad range of neuropsychiatric disorders including anxiety disorders, schizophrenia, alcohol

dependence, and seizure disorders (Halbach and Dermietzel, 2006).

Endogenous GABA binds to GABA-a receptors in the basolateral amygdala and inhibits anxiety responses. Alterations in

GABAergic transmission can result in severe disturbances in brain activity and a deficit in GABAergic transmission can

lead to epileptogenesis. Some metabolic alterations in GABA levels in the brain occur coincidentally with some

degenerative brain diseases, which include Huntington’s chorea (associated with a degeneration of GABAergic nigro-

striatal neurons) and Parkinsonism (Halbach and Dermietzel, 2006).

Synthesis and metabolism:

GABA is synthesized almost exclusively from glutamate. Steps for synthesis and metabolism GABA are shown in figure

8. Vitamin B6 derivative pyridoxal phosphate is a cofactor in the synthesis of GABA, which is why seizures occur in

Vitamin B6 deficiency (Halbach and Dermietzel, 2006).

Kreb’s cycle Transaminase

GLUCOSE KETOGLUTARATE GLUTAMATE

Amine Decarboxylase

Deaminase Transaminase (Rate limiting)

SUCCINIC ACID GABA

Figure 9: Synthesis and metabolism GABA (Adopted from Halbach and Dermietzel, 2006)

Once inside the neuron, GABA can be broken down by GABA transaminase (GABA-T); residual GABA is sequestered

and stored into secretory vesicles by vesicle GABA transporters. Tiagabine is a potent GABA transport inhibitor that is

used to treat epilepsy. One of the mechanisms of action of valproic acid is the competitive inhibition of GABA-T. γ-

Vinyl-GABA is a suicide substrate inhibitor of GABA-T that is used as an anticonvulsant (vigabatrin) in Europe (Stahl,

2008).

Distribution GABAergic cells are found in striatum where they constitute 95% of total neurons. They are found in globus pallidus,

substantia nigra cerebellum, thalamus, hippocampus and in the cerebral cortex. In the striatum, GABAergic neurons

project directly to the substantia nigra (pars reticulate). In addition, there are striatal GABAergic neurons that project to

the globus pallidus to synapse on pallidal-subthalamic GABAergic neurons that regulate the excitatory output from the

subthalamic nucleus. In the cerebellum, GABAergic Purkinje cells are its main efferent system (Halbach and Dermietzel,

2006).

GABA Receptors (Joseph and Coyle, 2009)

Three types of GABA receptors can be classified; and these are designated as GABA-a, GABA-b and GABA-c receptors

and they differ in their pharmacological properties and physiological behaviour.

GABA-a receptor: It is localized throughout CNS and found in both neurons and glial cells. It is also found in

unmyelinated cells and autonomic ganglia. GABA- a receptor consists of a pentameric structure, which forms an ion pore.

The pentameric structure is composed of two α-subunits, one β-subunit and one γ-subunit. The fifth unit in the pentamer is

variable and can be provided either by one of the α- or γ-subunits or a delta-subunit. The GABA-a receptor possesses

three different binding sites, one for GABA (binding site is at the interface of α and β subunits), second for

benzodiazepines (binding site is at the interface between the γ and α subunits) and a third binding site specific for

barbiturates. The GABA-a receptor complex is noteworthy for multiple allosteric modulatory interactions. These include

benzodiazepines, barbiturates, general anesthetics, ethanol, and neurosteroids.

GABA-b receptors: They are particularly prominent in the cerebral cortex, thalamus, superior colliculus, cerebellum and

dorsal horn of the spinal cord. GABA-b receptors are heterodimers of two subunits, GABA-b1 and GABAB-b2.

Presynaptically located GABA-b receptors modulate neurotransmitter release by depressing Ca2+ influx through voltage-

activated Ca2+ channels of the N type. Both autoreceptors and heteroreceptors types of presynaptic GABA-b receptors are

expressed I the CNS.

GABA-c receptors: They have been identified in the pituitary and in horizontal and bipolar neurons of the retina but their

exact role in psychiatry have not been established till date.

GLYCINE

Glycine along with GABA is the main inhibitory neurotransmitter of CNS. N-Methyl-D-aspartate (NMDA) and glutamate

are selective agonists for one of the principal receptor types (NMDA receptors) involved in excitatory synaptic

transmission. Glycine may serve as a co-factor for NMDA-receptors because glycine is needed for the opening of the ion

channel of the NMDA receptor. Both NMDA- and glycine-binding sites are present on this receptor; and glycine mediates

its effects through the strychnine-insensitive binding site. It is synthesized in the brain from L-serine by enzyme serine

hydroxymethyltransferase. Termination of the synaptic action of glycine is through reuptake into the presynaptic terminal

by the glycine transporter II (GlyT2), which is quite distinct from GlyT1 that is expressed in astrocytes and modulates

NMDA receptor function. The GlyT1 transporter is found in the spinal cord, pons, medulla, diencephalon and retina and,

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to a lower concentration, in the olfactory bulb and brain hemispheres. GlyT2 is more restricted to spinal cord, brain stem

and the cerebellum (Joseph and Coyle, 2009).

GLUTAMATE AND ASPARTATE

The amino acids L-glutamate and L-aspartate are the most abundant excitatory neurotransmitter in the CNS.

Synthesis and metabolism

Glutamate in the brain is synthesized de novo from glucose through Kreb’s cycle, which generates α-ketoglutarate. The α-

ketoglutarate receives an amino group via a transaminase reaction, converting it to glutamic acid. A second metabolic

pathway which is particularly important for replenishing synaptic glutamate is termed as glutamine cycle, wherein

astrocytes which are present around the glutaminergic synapse, express glutamate transporters (EAAT1 and 2) that

remove glutamate from the synapse, thereby terminating its action (Joseph and Coyle, 2009).

The postsynaptic effects of glutamate are mediated by two families of receptors. The first is glutamate-gated cation

channels that are responsible for fast neurotransmission called as ionotropic glutamate receptors. Three types of ionotropic

glutamate receptors have been identified, these include α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA),

kainic acid (KA), and N-methyl-D-aspartic acid (NMDA) receptors. The second type of glutamate receptor is the

metabotropic glutamate receptors (mGluR) which have been subgrouped into three classes. Group I mGluRs activate

phospholipase C, whereas Group II and III mGluRs inhibit adenylyl cyclase (Joseph and Coyle, 2009).

NMDA receptors (Halbach and Dermietzel, 2006)

The NMDA receptors are selectively activated by the drug NMDA and they are less selectively activated by glutamate

and aspartate. NMDA receptor consists of a complex of five transmembrane proteins with different specific binding sites

associated with an ion-channel. Under resting potential conditions, the NMDA receptors are inactivated. On

depolarization, the Mg++ block is released and the channel opens, thereby allowing the exchange of ions through the

channel pore. The opening of the NMDA receptor ion channel increases the permeability for Na+, K+ and Ca2+. One

essential consequence of the entry of extracellular Ca 2+ through the channel is the activation of a variety of processes

which alter the properties of the neuron. The NMDA receptors are heteromeric complexes, which consist of two different

subunits: NR1 subunits and NR2 subunits.

AMPA receptors

AMPA receptors are ionotropic receptors and they belong to the group of non-NMDA-receptors. The AMPA receptors

can be activated by the agonists α -amino-3-hydroxy-5-methyl-4-isoxazolleproprionat (AMPA), quisqualate and

glutamate.

Kainate receptors

Kainate receptors can be activated by kainate and glutamate. The precise function of the kainate receptors has not been

clarified in detail.

Metabotropic glutamate receptors

The metabotropic glutamate receptors (Qp) are coupled to G proteins and the signal transduction involves different

second-messenger systems. They generate slow postsynaptic responses after an adequate stimulus. The functional

significance of these receptors has been subject to investigation. They are considered to contribute to delayed neuronal

responses and to synaptic plasticity. Since application of agonists of metabotropic glutamate receptors can potentiate long-

term potentiation (LTP), it is believed that these receptors are involved in processes coupled to learning and memory

storage.

All primary sensory afferent systems appear to use glutamate as their neurotransmitter including retinal ganglion cells,

cochlear cells, trigeminal nerve, spinal afferents and the cerebral cortex. They project to a variety of subcortical structures,

these include hippocampus, basolateral complex of the amygdala, substantia nigra, nucleus accumbens, superior

colliculus, caudate nucleus, red nucleus and pons. Other important glutamatergic pathways include thalamocortical

projections, pyramidal neurons of the corticolimbic regions, temporal lobe circuit that responsible for the development of

new memories.

CIRCULATING HORMONES

ANGIOTENSIN

Central angiotensins are involved in sexual behaviour, stress, learning and memory. Large numbers of neurons expressing

angiotensin II have been identified in the circumventricular organs, hypothalamus, thalamus and amygdala. In the brain,

the presence of the three receptor types (AT I, AT II and AT IV) has been described. Angiotensin II enhances the release

of norepinephrine and dose-dependent 5-HT release. Activation of AT1 receptors can inhibit long-term potentiation, a

standard model of synaptic plasticity suggested as being involved in learning and memory storage (Halbach and

Dermietzel, 2006).

HYPOTHALAMO-PITUITARY-THYROID AXIS (HPT axis) Thyrotropin releasing hormone (TRH) is the tripeptide released mainly by the dorsomedial, ventromedial, and arcuate

nuclei of the hypothalamus. It stimulates release of the pituitary thyroid-stimulating hormone (TSH) and prolactin. This

in turn enhances the production of tri- and tetraiodthyronin (thyroxin) in the thyroid gland. TRH-immunoreactive cell

bodies are distributed predominantly in the olfactory bulbs, cortex, hippocampus, amygdala and in the paraventricular

nucleus of the hypothalamus (Stahl, 2008).

TRH has been reported to reduce stress and deprivation-induced eating, hypothetically by induction of satiation. It seems

likely that TRH is one of several functional elements in the integrative neuropeptide control of alcohol consumption via

short-term satiation (Kulkowsky et al., 2000). A decrease in TRH level and TRH receptor density has been found in

amyotrophic lateral sclerosis.

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPA axis)

The interactions among hypothalamus, pituitary and adrenal gland constitute the HPA axis, a major part of the

neuroendocrine system that controls reactions to stress, digestion, immune system, mood and emotions, sexuality, and

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energy storage and expenditure. Hypothalamus contains neuroendocrine neurons that synthesize and secrete vasopressin

and corticotropin-releasing hormone (CRH). These two peptides regulate anterior lobe of the pituitary gland. CRH and

vasopressin particularly stimulate the secretion of adrenocorticotropic hormone (ACTH) which acts on the adrenal

cortices and produces glucocorticoid hormones (mainly cortisol). Glucocorticoids in turn act back on the hypothalamus

and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle (Halbach and Dermietzel, 2006).

Cortisol is a major stress hormone and has effects on many tissues in the body, including on the brain. In the brain,

cortisol acts at two types of receptor - mineralocorticoid receptors and glucocorticoid receptors, and these are expressed

by many different types of neurons (Halbach and Dermietzel, 2006).

Function

Release of CRH from the hypothalamus is influenced by stress, physical activity, illness, by blood levels of cortisol and

by the sleep/wake cycle (circadian rhythm). In healthy individuals, cortisol rises rapidly after wakening, reaching a peak

within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late

evening, reaching a trough during the middle of the night. An abnormally flattened circadian cortisol cycle has been

linked with chronic fatigue syndrome, insomnia and burnout.

Dexamethasone suppression test (DST)

Dexamethasone suppression test (DST) is an important screening tool for assessment of Cushing’s syndrome. Various

variants of the test such as high dose, low dose and overnight 1 mg are used. High dose DST is helpful in differentiating

pituitary and adrenal etiologies of Cushing's syndrome, the suppression in cortisol level after Dexamethasone

administration being present in patients with pituitary origin Cushing’s syndrome. Overnight 1mg DST is used for

screening of Cushing’s syndrome. Herein, 1 mg of the synthetic steroid dexamethasone is administered at 11 p.m. and a

plasma cortisol level is assessed at 8 a.m. the following morning. Plasma cortisol levels of greater than 200 nmol/L

indicate a high likelihood of Cushing's syndrome. This test produces greater specificity and sensitivity than other

screening procedures, such as measurements of urinary free cortisol. In the early 1980s, the DST was believed to be a

useful marker of melancholic depression. However, the DST is now used infrequently, as its clinical use is limited by low

specificity and sensitivity. Additionally, medical illnesses, weight loss, stress, and concomitant medications confound the

DST results.

OXYTOCIN (OT) and VASOPRESSIN (AVP)

Oxytocin and vasopressin are synthesized in the Paraventricular and the Supraoptic nucleus of the hypothalamus, which

send axonal projections to the neurohypophysis. The actions of OT are mediated via a single receptor subtype (OTR),

which is distributed in the periphery and within the limbic CNS. In contrast to the OTR there are three AVP receptor

subtypes, V1a, V1b, and V2 receptors. The V2 receptor is localized in the kidney and is not found in the brain. The V1a

receptor is distributed widely in the CNS and is thought to mediate most of the behavioural effects of AVP. The V1b

receptor is concentrated in the anterior pituitary.

In addition to the hypophyseal OT and AVP systems, parvocellular hypothalamic and extrahypothalamic neurons produce

OT and AVP and send projections to the forebrain and brainstem. However, in the forebrain, these peptides are now

known to regulate a number of processes, ranging from anxiety, learning and memory to complex social behaviours

(Landgraf, 2006). It has been hypothesised that OT is involved in the regulation of the social brain, suggesting that

dysregulation of this peptide could potentially explain social deficits in certain psychiatric disorders such as autism

(Hammock and Young, 2006).

GUT HORMONES

Cholecystokinin (CCK) shows a heterogeneous distribution in both the peripheral and central nervous systems, with

specific binding sites and clearly defined projections. This neuropeptide has been detected in cortical areas and in limbic

structures such as hippocampus, amygdala, olfactory tubercle, substantia nigra, ventromedial thalamus, septum, nucleus

accumbens, ventral tegmental area, interpeduncular nucleus, hypothalamus, posterior lobe of the pituitary and spinal cord.

It is often colocalized with neurotransmitters or with other neuromodulators like GABA, norepinephrine, serotonin and

vasopressin (Dourish and Hill, 1987).

Within CNS, CCK is involved in different biological processes, including: Satiety, nociception, regulation of body

temperature, learning and memory. A strong reduction of cholecystokinin-containing neurons in the striatum has been

observed in Huntington’s chorea (Dourish and Hill, 1987). It has also been suggested that CCK-containing dopaminergic

neurons, in particular in the mesolimbic pathway, are implicated in disorders such as schizophrenia (Wang et al., 2002)

and Parkinson’s disease (Fujii et al., 1999).

Gastrin is a peptide hormone that occupies the same receptor as CCK and stimulates the secretion of gastric acid by the

stomach. It is a CCK agonist and produces anxiety and panic in patients with anxiety disorders and to a lesser extent in

those without anxiety disorders. Gastrin related peptide (GRP) has been shown to induce anxiety, whereas GRP-receptor

antagonists are anxiolytic (Wang et al., 2005).

OPIOID PEPTIDES

At least three different receptor systems for these ligands have been identified (µ, δ, and κ), and each these are activated

by the endogenous ligands beta-endorphins, enkephalins, and dynorphin respectively. Beta-endorphin is the principal

opioid peptide prototype. Methionine enkephalin (met-enkephalin) and leucine enkephalin (leu-enkephalin) are two small

pentapeptides that also possess direct opioid activity. The function of the endogenous opiates is analgesia and alteration of

pain perception, but effects on stress, appetite regulation, learning and memory, motor activity, and immune function also

appear to be importance (Halbach and Dermietzel, 2006).

Dynorphins modulate motor functions, feeding behaviour, stress, complex partial seizures and are involved in regulating

the secretion of pituitary hormones. Agonists of kappa receptors possess anti-nociceptive properties due to presence of

dynorphin receptors in the spinal pathways (Solbrig and Koob, 2004).

Nociceptin has been shown to have diverse effects on nociception, locomotion, feeding, anxiety, spatial attention,

reproductive behaviours and opiate tolerance (Halbach and Dermietzel, 2006).

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ENDOCANNABINOIDS

Mechoulam and colleagues (1994) discovered anandamide (a derivate of arachidonic acid), a lipid produced endogenous

substance in the brain that could activate cannabinoid receptors and function as a neurotransmitter. The name of this

substance was derived from the Sanskrit word, ananda, which translates as bliss. Several additional endocannabinoids

were soon discovered, 2-arachidonylglycerol (2-AG) (CB1=CB2), N-arachidonyldopamine (NADA) (CB1>CB2), 2-

arachidonoylglycerol ether (noladin ether) (CB1>CB2), and virodhamine (CB2>CB1). Anandamide (CB1>>CB2) is

about 10-fold less potent and has a shorter duration of action than tetrahydrocannabinols (THC) (Halbach and Dermietzel,

2006).

Anandamide formed from its precursor N-arachidonyl-phosphatidyl-ethanolamine (NAPE) and is catalyzed by the

enzyme phospholipase D. Because of rapid deactivation process, the endocannabinoids may primarily act near their sites

of synthesis by binding to and activating cannabinoid receptors on the surface of neighboring cells. The endocannabinoids

are hydrolyzed by an intracellular membrane-bound enzyme, termed anandamide amidohydrolase (AAH) (Sedlak and

Kaplin, 2009).

There are two types of cannabinoids receptor. CB1 receptor occurs at highest density in the basal ganglia, cerebellum,

hippocampus, hypothalamus, anterior cingulate cortex, and cerebral cortex, particularly the frontal cortex. CB1 receptors

tend to be localized to the presynaptic rather than postsynaptic side of the neuronal cleft, suggesting a role in regulation of

neurotransmission and act as retrograde messenger that diffuses from a postsynaptic neuron to act upon a presynaptic

neuron to further inhibit neurotransmitter like GABA, norepinephrine and acetylcholine release. CB2 is the second

cannabinoid receptor which is predominantly expressed on the surface of white blood cells of the immune system, but

small amounts appear to be present in the brainstem (Sedlak and Kaplin, 2009).

Cannabinoids also appear to increase the release of brain endorphin neurotransmitters and increase dopamine release in

the nucleus accumbens, a ―reward center‖ relevant to addiction and learning. The endocannabinoids have been implicated

in a variety of synaptic plasticity, including long term potentiation (LTP) and long-term depression (LTD).

COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT (CART)

Cocaine and amphetamine regulated transcript (CART) is a peptide found in brain regions mediating drug reward. CART-

containing neurons in the nucleus accumbens project to the VTA which diminishes locomotor responses to cocaine in

rodents. Cocaine or amphetamine upregulates CART production which in turn dampens downstream effects of dopamine

(Hubert et al., 2008).

NEUROPEPTIDE Y (NPY)

NPY is widely distributed throughout the CNS and has an important role in the regulation of basic physiological function,

including learning and memory. It is a 36 amino acid peptide found in the hypothalamus, brainstem, spinal cord, and

several limbic structures and is involved in the regulation of appetite, reward, anxiety, and energy balance. NPY is

localized along with serotonergic and noradrenergic neurons and is thought to facilitate the containment of negative

effects following exposure to stress (Adrian et al., 1983).

NEUROTENSIN (NT)

Neurotensin (NT) is a tridecapeptide that play a role in neuroendocrine regulation and coordination as a signaling

molecule. Gonadal and adrenal steroids and thyroid hormones alter neurotensin levels in the hypothalamus, preoptic area,

and arcuate nucleus. Neurotensin has a close neuroanatomical relation with serotonin and dopaminergic pathways and is

involved in the control of anterior pituitary activity, stimulating the release of prolactin and TSH. It also has a role in the

regulation of a subpopulation of serotonergic neurons in the dorsal raphe and frontal cortex and GABAergic and

glutamatergic neurons. Stimulation of serotonin neurons may be responsible for its analgesic effects and reduction of

stress response, whereas the effects on dopamine suggest a possible antipsychotic role. Most antipsychotic drugs increase

neurotensin concentrations in the nucleus accumbens and caudate nucleus. Because of neurotensin's association with the

nigrostriatal dopamine and the serotonin systems, it is suspected of playing a role in movement disorders caused by

antipsychotic drugs (Binder et al., 2001).

NITRIC OXIDE (NO)

In the early 1990s, nitric oxide was the first gas to be ascribed a neurotransmitter function and proved to be an atypical

neurotransmitter. NO is synthesized endogenously within the cells with the help of nitric oxide synthase enzyme (NOS).

Three different types of this enzyme are known to exist. Neuronal nitric oxide synthase (nNOS) is the predominant form

in brain. Endothelial NOS (eNOS) is predominantly found in blood vessels. Inducible NOS (iNOS) exists in many tissues

in minute amounts. Major mechanism of action of NO is cGMP production via intracellular guanyl cyclase enzyme

activation (Halbach and Dermietzel, 2006).

NO regulates cerebrovascular perfusion, modulation of wakefulness, mediation of nociception, olfaction, food intake and

drinking. It also contributes to mechanisms attributed to learning and memory, neurogenesis, and neurodegenerative

disease. Evidence has suggested a role for NO in the regulation of sleep–wake cycles. A role for nitric oxide has been

suggested in antidepressant response as SSRI can directly inhibit NOS activity (Sedlak and Kaplin, 2009).

CARBON MONOXIDE (CO)

CO plays an important role in regulation of olfactory neurotransmission, blood vessel relaxation, smooth muscle cell

proliferation, and platelet aggregation. CO is produced by the action of heme oxygenase (HO) on heme, during the later’s

metabolism. Three forms of HO exist. HO1 induced by a great variety of stimuli, ranging from oxidative stress,

inflammation, dopamine, steroids, and growth factors. It is found in pituitary cells, hilus of the dentate gyrus,

hypothalamus, cerebellum and brainstem. HO2 is expressed in cortical and hippocampal pyramidal cells, dentate gyrus

granule cells, olfactory bulb, thalamus, hypothalamus, brainstem, and cerebellum. HO3 is an isoform whose significance

is poorly understood (Wu and Wang, 2005).

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NEUROKININS/TACHYKININS

Tachykinins were defined as peptides sharing the common carboxy-terminal amino acid sequence. These peptides were

named neurokinin A (NKA, neuromedin L or substance K), neuropeptide K (NPK), neurokinin B (NKB or neuromedin

K). Several classes of tachykinin receptors, NK1 for Substance P, NK2 for NKA and NK3 for NKB have been discovered.

Within CNS Substance P has been found in spinal cord, septum, striatum, amygdala, periaqueductal gray, pons and brain

stem (Regoli et al., 1994). Tachykinins show prominent physiological effects in the peripheral autonomic functions,

immune response and sensory transmission of pain in the spinal cord (Adell, 2004).

PURINES

The purine nucleoside adenosine is a component of nucleic acids and of the nucleotides adenosine triphosphate (ATP),

adenosine diphosphate (ADP) and cyclic AMP, all of which play important roles in cellular metabolism. Besides their

general function in cell metabolism, ATP and adenosine can themselves act as neuroactive substances. The effects of

adenosine and the nucleotides are mediated by activation of distinct P1 (adenosine) and P2 (ATP) cell-surface receptors

present on neurons, astrocytes, and microglia, as well as other cells that are present in the CNS. These receptors are

generically known as purinergic receptors (Ralevic and Burnstock, 1998).

ADENOSINE TRIPHOSPHATE (ATP)

For many years ATP has been clearly established as an important intracellular mediator of neuronal function. It provides

energy to the cell. The concept that it may act as a neurotransmitter stems from the finding of Burnstock and his

colleagues that it was a mediator of the nonadrenergic, noncholinergic (NANC) innervation of intestinal and bladder

smooth muscle where ATP is released during stimulation of NANC nerves; mimicing of the responses to nerve

stimulation (Burnstock, 1970). It is now clear that ATP is a cotransmitter in many neuron types in both peripheral and

central nervous systems. More recently, ATP has been shown to be a cotransmitter with NA, 5-HT, glutamate, dopamine

and GABA in the CNS. ATP and NA act synergistically to release vasopressin and oxytocin, which is consistent with

ATP cotransmission in the hypothalamus. ATP, in addition to glutamate, is involved in long-term potentiation in some

hippocampal neurons that are associated with learning and memory (Burnstock et al., 2008).

ADENOSINE

Adenosine is an endogenous neuromodulator in the peripheral and central nervous system. Adenosine comes from the

hydrolysis of ATP. Four receptor subtypes have been identified, including A1, A2A, A2B, and A3 receptors. Of these, the

A2A receptor has been a primary target and has been functionally linked and coexpressed with dopamine D2 receptors in

the striatopallidal enkephalinergic neurons, which modulate motor movements that are altered in neurodegenerative

disorders such as Parkinson's disease and exogenously administered adenosine receptor agonists have been shown to exert

a neuroprotective effect. High numbers of A2A receptors are in the striatum and nucleus accumbens, with lower numbers

in the olfactory tubercle, hippocampus, and cerebral cortex (Illes and Norenberg, 1993).

Adenosine is a potent inhibitor of dopamine, GABA, glutamate, acetylcholine, serotonin, and norepinephrine release via

presynaptic A1 receptors. Furthermore, adenosine has been demonstrated to be involved in pain, cognition, movement and

sleep. It has also been proposed that endogenous adenosine formation is involved in opioid antinociception (Sollevi,

1997). It accumulates in the basal forebrain and cerebral cortex during prolonged wakefulness and decreases during sleep,

suggesting that it may serve to transmit the homeostatic signal for sleep and adenosine infusion promotes NREM (Inoue et

al., 1996).

CONCLUSION

Until recently, studies on neurotransmission have focused on a small number of neurotransmitters and a narrow group of

proteins involved in neurotransmitter function. Today, powerful molecular and genetic approaches are being used to

identify and understand new proteins and mechanism involved in neurotransmitter function and control. So far, just a tens

of perhaps thousands of neurotransmitter-related proteins, have been successfully targeted by pharmacological agents that

have translated into important treatments of psychiatric disorder but there is promise of many more such treatments to

come. Moreover, this huge diversity of neurotransmitter related proteins is now emerging as a large resource for studies of

genetic risk factors of psychiatric disorder and investigations of biological markers of illness diagnosis and progression,

and treatment outcome.

DISCUSSION

INTRODUCTION

Neurotransmitters by their action on various receptors have been seen to exert a gamut of actions and thus their

abnormalities have been implicated in neuropsychiatric illnesses. On occasions, there is imbalance in a single

neurotransmitter and on others; there is disturbed interplay of various transmitters being implicated in causation of

neuropsychiatric illnesses. This makes the need of developing treatment modalities which try to correct these underlying

abnormalities in these illnesses. Here we shall discuss the abnormalities in these transmitters in neuropsychiatric illnesses

and potential targets of psychotropic medications for correction of various neurotransmitter imbalances.

NEUROTRANSMITTERS AND PSYCHIATRIC DISORDERS

Neurotransmitters & Dementia

The most common dementia is Alzheimer's disease and the leading theory for its etiology is the amyloid cascade

hypothesis. The classic and pathognomonic microscopic findings are senile plaques, neurofibrillary tangles, neuronal loss

(particularly in the cortex and the hippocampus), synaptic loss (perhaps as much as 50 percent in the cortex), and

granulovascular degeneration of the neurons.

The neurotransmitters that are most often implicated in the pathophysiological condition of Alzheimer's disease are

acetylcholine and norepinephrine, both of which are hypothesized to be hypoactive in Alzheimer's disease. Apart from

13

decreased acetylcholine and choline acetyltransferase concentrations in brain, degeneration of cholinergic neurons is

present in the nucleus basalis of Meynert. Decreased norepinephrine activity in Alzheimer's disease is suggested by the

decrease in norepinephrine-containing neurons in the locus coeruleus. Two other neurotransmitters found decreased are

somatostatin and corticotrophin (Salloway et al., 2004).

The neuroprotective function of heme oxygenase (HO) may be impaired in Alzheimer's disease as HO is found in amyloid

plaques. The amyloid precursor protein (APP), a source for toxic amyloid-β fragments, can bind to and inhibit HO

neuroprotective function, and APP mutants associated with early-onset Alzheimer's disease are the most potent at

blocking HO function (Cutajar and Edwards, 2007). Carbon monoxide has been implicated in the development of

hippocampal LTP, although lines of evidence are contradictory. HO inhibitors that block carbon monoxide production

lead to impaired induction of LTP and reduced calcium-dependent release of glutamate neurotransmitter (Kim, 2006).

Neurotransmitters & Addiction

Neuroimaging studies have been crucial in understanding changes in the various neurotransmitter systems implicated in

addiction in the living human brain. Predominantly reduced striatal dopamine transmission appears to play an important

role in psychostimulant, alcohol and heroin addiction, while addiction to cannabis may be mediated primarily by the

endocannabinoid system.

Drugs of abuse mimic or enhance the actions of neurotransmitters and endogenous chemical messengers in the nervous

system act at receptors for these neurotransmitters. Opioids are presumed to be habit-forming because of actions at opiate

receptors, and nicotine because of action at nicotinic acetylcholine receptors. Acute administration of most drugs of abuse

increases dopamine transmission in the basal ganglia and that dopamine transmission in this brain region plays a crucial

role in mediating the reinforcing effects of these drugs (Koob et al., 2001). The mesolimbic dopamine pathway is made up

of dopaminergic cells in the ventral tegmental area (VTA) projecting into the nucleus accumbens (NAc), located in the

ventral striatum, and is considered crucial for drug reward (Wise et al., 1987). The mesostriatal and mesocortical

pathways are also recognized in contributing to predicting drug reward (anticipation) and addiction (Wise et al., 2009).

The reinforcing properties of tobacco use are proposed to involve the stimulation of nicotinic acetylcholine receptors

located in mesolimbic dopaminergic reward pathways (Dani, 2001).

Neurotransmitters and Schizophrenia

Schizophrenia is a clinical syndrome of variable, but profoundly disruptive, psychopathology that involves cognition,

emotion, perception, and other aspects of behaviour. In its etiology, dopamine hypothesis has major role. Schizophrenia

results from excessive dopaminergic activity. Hyperactivity of mesolimbic dopamine neurons gives rise to positive

symptoms of psychosis, such as delusions and hallucinations and also important for motivation, pleasure, and reward. It

may also play a role in aggressive and hostile symptoms in schizophrenia and related illnesses, especially if serotonergic

control of dopamine is aberrant in patients who lack impulse control. All known antipsychotic drugs capable of treating

positive psychotic symptoms are blockers of the D2 dopamine receptor.

Deficiencies in nigrostriatal dopamine pathway cause movement disorders, including Parkinson's disease, characterized

by rigidity, akinesia/bradykinesia (i.e., lack of movement or slowing of movement), and tremor. Dopamine deficiency in

the basal ganglia can also produce akathisia and dystonia. In schizophrenia, the nigrostriatal pathway in untreated patients

may be relatively preserved. Similarly functioning of tuberoinfundibular dopamine neurons may remain relatively

preserved if not disrupted by lesions or drugs (D2 blockers) and its disruption may cause prolactin levels to rise. Elevated

prolactin levels are associated with galactorrhea, amenorrhea and sexual dysfunction (Stahl, 2008).

The glutamate hypothesis of schizophrenia is centered on the clinical observation that N-methyl-D-aspartate (NMDA)

receptor antagonists, such as phencyclidine (PCP) and ketamine, produce a syndrome that is indistinguishable from

schizophrenia (Tsai et al., 2002). Among the various glutamate pathways hypofunction of cortico-brainstem pathway

produces positive symptoms due to increased activity of mesolimbic pathway and cognitive, negative, and affective

symptoms due to decreased activity of mesocortical pathway.

GABA has a regulatory effect on dopamine activity, and the loss of inhibitory GABAergic neurons could lead to the

hyperactivity of dopaminergic neurons. Acetylcholine receptors play a role in the regulation of neurotransmitter systems

involved in cognition, which is impaired in schizophrenia. Decreased levels of nicotinic and muscarinic receptors are

reported in the hippocampus frontal cortex, thalamus, and striatum in schizophrenia (Hyde and Crook, 2001).

Neurotransmitters and Mood disorders

Mood disorders are a group of clinical conditions characterized by a loss of that sense of control and a subjective

experience of great distress. While the main neurotransmitters which are involved in etiology of mood disorders are

serotonin and norepinephrine, role of others are also described e.g. GABA, glutamate, prolactin.

The medial forebrain bundle (MFB) is the key ascending NE pathway to anterior cortical structures. Stimulation of the

MFB elicits increased levels of goal-directed and reward-seeking behaviour. Sustained stress eventually results in

decreased MFB neurotransmission, which may account for anergia, anhedonia, and diminished libido in depression

(Leonard, 1997). Apart from NE, serotonin and dopamine also have role in goal-directed behaviour (Stockmeier, 2003). 5-

HT is also an important regulator of sleep, appetite, body temperature, metabolism, and libido. Serotoninergic neurons

projecting to the suprachiasmatic nucleus (SCN) of the hypothalamus help regulate circadian rhythms (e.g., sleep–wake

cycles, body temperature, and HPA axis function). Decreased mesocortical and mesolimbic DA activity has obvious

implications in the cognitive, motor, and hedonic disturbances associated with depression (Opmeer et al., 2010).

Role of GABA in depression has been found by presence of its low concentration in plasma, CSF, and brain. GABA

receptors are upregulated by antidepressants, and some GABAergic medications have weak antidepressant effects (Hasler

et al., 2007). Glutamate work in conjunction with hypercortisolemia to mediate the deleterious neurocognitive effects of

severe recurrent depression (Pittenger et al., 2007). Evidence of increased HPA activity is apparent in 20 to 40 percent of

depressed outpatients and 40 to 60 percent of depressed inpatients. Elevated HPA activity in depression has been

documented via excretion of urinary free cortisol (UFC), 24-hour (or shorter time segments) intravenous (IV) collections

of plasma cortisol levels, salivary cortisol levels, and tests of the integrity of feedback inhibition (Heim et al., 2008).

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Approximately 5 to 10 percent of people evaluated for depression have previously undetected hypothyroidism, as

reflected by low levels of circulating thyroid hormone (Belmaker et al., 2008).

For growth hormone role in depression the most consistent finding is a blunted response to clonidine, an α2-receptor

agonist and desipramine. Decreased CSF somatostatin levels have been reported in depression, and increased levels have

been observed in mania (Thase, 2009).

Neurotransmitters and Suicide

Postmortem brain studies of suicide victims showed serotonin-system dysfunction leading to reduced level of serotonin

and its major metabolite, 5-HIAA. These studies employ radiolabelled ligands specific for a particular receptor or

transporter in order to measure its density (Bmax) and affinity (KD). Of 18 studies reported, 12 found significant reductions

in the presynaptic serotonin-transporter binding sites (SERT) in suicide victims, either in the frontal cortex or in other

brain regions (Mann et al, 1998).

There are few noradrenergic neurones arrayed at a lower density in the locus coeruleus of suicide victims, but no

morphological anomalies (Arango et al, 1996). Neurobiological studies of suicide attempters had shown levels of HVA

and 5-HIAA in cerebrospinal fluid of suicide attempters represent a more varied type of behaviour than completed

suicides, yet neurobiological studies of suicide attempters have shown a remarkable consistency in pointing to a

serotonergic dysfunction (Lester et al., 1995). Suicide victims with a diagnosis of major depression are reported to have a

pronounced reduction in NPY levels in the frontal cortex and caudate nucleus. Chronic administration of antidepressant

drugs increases NPY in the neocortex and hippocampus in rats. Additionally, low NPY response to stress has been

associated with increased vulnerability to depression and PTSD (Heilig, 2004). Treatments for depression, such as some

antidepressants, lithium, and ECT, increase NPY concentrations in a number of brain areas in rats, while significantly low

levels of NPY have been found in the temporal cortices of patients with schizophrenia (Karl and Herzog, 2007).

Neurotransmitters & Anxiety disorders

Patients with various form of anxiety disorders like PTSD, panic disorders and phobias have shown increased central NE

release and show exhibit greater anxiety, heightened acoustic startle, and higher heart rate and blood pressure (Stein et al.,

2007). In study by Shalev et al. (2008) exposure to traumatic reminders in the form of combat films resulted in increased

epinephrine and NE release. Galanin is also coexpressed with norepinephrine neurons in the locus coeruleus, and thus it

projects to structures involved in the fear pathway, including the amygdala, hippocampus, and prefrontal cortex. It also

acts as an autoreceptor to reduce firing of the LC (Rajarao et al., 2007).

Drugs that act by decreasing the firing of NE neurons, including substances such as alcohol, opioids, and benzodiazepines,

are commonly used, and abused, by patients with anxiety disorders as a form of self-medication (Preter et al., 2008).

Similarly driven by stress, hypothalamic levels of CRH are increased, and the HPA axis becomes active or perhaps even

hyperactive, resulting in increased levels of cortisol and dehydroepiandrosterone (DHEA). Cortisol level is also found

increased through a complex negative feedback system mediated via moderate- to low-affinity glucocorticoid receptors

(GRs) and high-affinity mineralocorticoid receptors (MRs).

Dopamine innervation of the mPFC appears to be particularly vulnerable to stress. Thus, low-intensity stress (such as that

associated with conditioned fear) or brief exposure to stress increases dopamine release and metabolism in this region

even without any notable changes in other mesotelencephalic dopamine regions.

Serotonin has also been shown to have a dual role in anxiety. The serotonin hypothesis of anxiety states that 5-HT may be

anxiogenic through its action on the prefrontal cortex and amygdala, causing a heightened awareness to threats, and may

be anxiolytic by its action on the dorsal periaqueductal grey (dlPAG), thereby inhibiting fight-or-flight behaviours

(Garakani et al., 2009). The role of GABA-A receptors in anxiety disorders are mainly based on anxiolytic effects of

barbiturates, benzodiazepines, alcohol, anesthetics, neuroactive steroids, and several anticonvulsant medications.

Hypersecretion of opioids in the CNS of patients with PTSD has been postulated to be an adaptive response to traumatic

experienced. Naltrexone, an opioid receptor antagonist, decreases symptoms in autistic children and can improve

functioning, with decreases in social withdrawal, stereotypy, and abnormal speech being directly related to decrease in

beta-endorphin level. Naltrexone is helpful as an adjunct in the treatment of alcohol as well as opioid dependence,

reducing drinking and craving. In addition to the µ agonist methadone, buprenorphine, a partial µ agonist, has been

helpful for opioid dependence because of its alleviation of withdrawal and because of its blockade of opioid-induced

euphoria (Caceda et al., 2006).

Neurotransmitters and OCD

(A) Serotonin

Controlled pharmacotherapy studies demonstrated unequivocal superior efficacy of clomipramine, a serotonergic tricyclic,

over desipramine, a noradrenergic tricyclic, indicating definite role of serotonin in OCD (Zohar et al., 1987). This gave

rise to the 'serotonin hypothesis' of OCD, which was consistently proved by SSRI directly and lack of efficacy of non-

serotonergic drugs in this condition indirectly.

Evidences of serotonergic dysfunction in OCD

To demonstrate serotonergic dysfunction, the following assessments are done in various studies (Delgado et al., 1991).

(i) Platelet serotonin: Equivocal in OCD

(ii) CSF 5-HIAA & 5HT: Equivocal in OCD ; decreased CSF 5-HIAA with SSRI treatment

(iii) Imipramine binding: Normal in OCD

(iv) L-Tryptophan challenge: Equivocal.

Jacobson and Fornal (1995) proposed that serotonergic system facilitates gross motor output and inhibits sensory

information processing. Thus, destruction of 5HT system leads to stereotypic behaviour.

(B) Dopamine

Dopamine dysfunction in OCD subtypes are evidenced by Stein et al. (2000), de novo production of tics and exacerbation

of Trichotillomania (TTM) with dopamine and reduction with antagonists. Both of these conditions belong to OCD

spectrum and form a subtype as evidenced by genetic studies. Antipsychotics augment antiobsessional response in this

subtype. Less response to SSRI alone in tic related OCD.

(C) Glutamate

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Rosenberg et al. (2000) demonstrated reduction of high caudate glutamatergic concentration with paroxetine treatment in

pediatric OCD. This gives rise to the glutamate hypothesis of OCD. Glutamatergic neurotransmission is fast acting

system having inhibiting role on serotonin release in caudate nucleus. Increased glutamatergic flow from cortex and

thalamus to striatum may set a hyperactive circuit generating OC symptom.

(D) Noradrenaline Less evidence exists in favour of it. Improvement of OCD with oral clonidine still favours this

hypothesis in a small subgroup of patients.

Neurotransmitters and disorders of self

A series of studies using ketamine, an NMDA antagonist that increases glutamate release, has suggested that

dysregulation of the NMDA glutamate receptor may play a central role in dissociative symptoms. Administration of

ketamine to healthy volunteers produces dose-dependent increases in dissociation scores. High doses of ketamine produce

slowed perception of time, tunnel vision, derealization, and depersonalization, similar to that described by trauma victims.

Pretreatment with a benzodiazepine or with lamotrigine, an anticonvulsant that decreases glutamate release by about half

the dissociative effects of ketamine (Simeon et al., 2000).

Beyond glutamate, studies have implicated cannabinoid, opioid, serotonergic, and noradrenergic systems in dissociation

symptoms.

Neurotransmitters and Paraphilias

Dopamine, norepinephrine, and serotonin serve a modulatory role in human and mammalian sexual motivation, appetite,

and consummatory behaviour and the sexual effects of pharmacological agents that affect monoamine neurotransmitter

can have both significant facilitative and inhibitory effects on sexual behaviour (Kafka et al., 1994).

Neurotransmitters and Eating disorders

Contemporary theories have pointed to putative serotonin mechanisms, largely based on observations that individuals with

anorexia nervosa have abnormal CSF serotonin levels when ill, levels that may not completely reverse on partial weight

gain. To date, no firm data are available showing that serotonin abnormalities exist in vulnerable populations before the

onset of an eating disorder. Genetically interesting loci and polymorphisms have been associated with genes for the 5-HT1B, 5-HT1D, 5-HT2A, and 5-

HT2C receptors, norepinephrine transporter, dopamine receptor, Mao-A, deltoid opioid receptor, cannabinoid receptor

(CNR1), brain derived neurotropic factor (BDNF), preproghrelin, CLOCK (endogenous oscillator) system, uncoupling

proteins 2 (UCP2) and 3 (UCP3), beta-type estrogen receptor, hSKCa3 potassium channel, and human agouti protein

(Yager and Anderson., 2009).

Neurotransmitters and Impulse Control Disorders

In humans lower levels of the serotonin metabolite 5-HIAA are associated with violent suicide attempts and impulsive

aggression, further evidence supporting a role for reduced serotonin function leading to aggression in humans. Several

studies using this method of reducing serotonin have shown that there is an increase in aggression in human subjects after

tryptophan depletion. Likewise, studies have found a reduction in impulsive aggressive behaviour after treatment with

serotonin reuptake inhibitors (SRIs) (Grant et al., 2005).

Neurotransmitters and Adjustment Disorders

It has been proposed that the susceptibility of a given individual to suffer from adjustment disorder in wake of stressful

life events depends on interplay of various neurochemical, neuropeptide, and hormonal systems. The individuals with

higher measures of the HPA axis, CRH, locus coeruleus-norepinephrine, dopamine, and estrogen activity and the lower

values of dehydroepiandrosterone (DHEA), neuropeptide Y, galanin, testosterone, and 5-HT1A receptor and

benzodiazepine receptor function will have the highest risk to develop adjustment disorders after exposure to stress

(Katzman and Geppert., 2009).

Neurotransmitters and Pervasive Developmental Disorders

Initially role of serotonin has been suspected in autism but later it could not be proved. Further role of dopamine has been

proposed. A hyperdopaminergic functioning of the brain might explain the overactivity and stereotyped movements seen

in autism. This would be consistent with the general observation that administration of stimulants, which increase levels

of dopamine, sometimes worsens behavioural functioning in autism. It is clear that agents that block dopamine receptors

are effective in reducing the stereotyped and hyperactive behaviours of many autistic children (Volkmar et al., 2009).

Neurotransmitters and Attention-Deficit/Hyperactivity Disorder

ADHD symptomatology emerges from an imbalance among various neurotransmitters, including norepinephrine,

epinephrine, and dopamine. Molecular genetic studies have targeted genes that code for dopamine receptors, the DRD4

genes, and the gene that controls extracellular dopamine concentrations, the dopamine transporter (DAT) gene (Shaw et

al., 2007).

NEUROTRANSMITTERS –POTENTIAL TARGETS OF PSYCHOTROPIC DRUGS

Antipsychotics

Nearly every patient with schizophrenia will benefit from pharmacological treatment. Antipsychotic medication which

may be typical or atypical is the mainstay of pharmacological treatment and are effective for reducing the impact of

psychotic symptoms.

Typical Antipsychotics

The therapeutic actions of typical antipsychotic drugs are due to blockade of D2 receptors, specifically in the mesolimbic

dopamine pathway. This has the effect of reducing the hyperactivity in this pathway and so are the positive symptoms.

However typical antipsychotics block other D2 receptors of brain and produce unwanted side effects (Kapur, 2003).

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Secondary negative symptoms of schizophrenia appears due blockade of D2 receptors in the mesolimbic system, this may

not only reduce positive symptoms but also block reward mechanisms, leaving patients apathetic, anhedonic, lacking

motivation, and with reduced interest and joy from social interactions producing secondary negative symptoms.

Antipsychotics also block D2 receptors in the mesocortical DA pathway where DA may already be deficient in

schizophrenia. This can cause or worsen negative and cognitive symptoms (Keefe et al., 2007).

Blocked of D2 receptors in the nigrostriatal DA pathway produces drug-induced Parkinsonism or extrapyramidal

symptoms and chronic blockade of these receptors gives rise to tardive dyskinesia (Artaloytia et al., 2006). Prolactin

elevation can be seen by D2 receptors blockade in the tuberoinfundibular DA pathway. Apart from blocking D2 receptors

typical antipsychotics also block muscarinic cholinergic receptors and so give rise to anticholinergic side effects which is

in reverse proportion to their EPS causing potential producing (Stahl, 2008).

Atypical Antipsychotics

To prevent the aforementioned side effects atypical antipsychotics have been developed. What makes an antipsychotic

―atypical‖ is one or more of the following property…

1. Ability to block 5-HT2A receptors along with D2 receptors i.e. serotonin dopamine antagonist

2. Rapid dissociation from D2 receptors

3. Partial agonist action on D2 receptors

4. 5-HT1A partial agonist action

Atypical antipsychotics are associated with significant cardiometabolic risk e.g. weight gain, obesity, dyslipidemia,

diabetes, and cardiovascular disease due to blockade of H1 histamine receptors, M3 muscarinic cholinergic receptor and

5-HT2C serotonin receptor (Reist et al., 2007). While sedation is due to D2, M1, Hl and alpha-1 adrenergic receptors

blocking properties (Kern et al., 2006).

Antidepressants

Treatment of depression involves various antidepressants. Many classes of antidepressants has been discovered and each

class has different action on various neurotransmitters (Stahl., 2008).

The pharmacological action at monoamine transporters is entirely consistent with the monoamine hypothesis of

depression and anxiety. Adaptive changes in neurotransmitter receptor sensitivity takes some weeks that is why

antidepressants take time to show clinical effects despite rapid elevation of monoamines in the brain areas.

Monoamine oxidase inhibitors

These are all irreversible enzyme inhibitors and thus bind to MAO covalently and irreversibly and destroy its function

forever. Enzyme activity returns only after new enzyme is synthesized.

MAO exists in two subtypes, A and B. Both forms are inhibited by the original MAO inhibitors, which are therefore

nonselective. The A form preferentially metabolizes the monoamines most closely linked to depression (i.e., serotonin and

norepinephrine), whereas the B form preferentially metabolizes trace amines such as phenethylamine (Millan., 2004).

Several MAO inhibitors are available like phenelzine, tranylcypromine, and isocarboxazid.

Tricyclic antidepressants

The tricyclic antidepressants were so named because their chemical structure contains three rings. They block the reuptake

pumps for norepinephrine or for both norepinephrine and serotonin (Nelson., 2009). Some tricyclics have much more

potency for inhibition of the serotonin reuptake pump (e.g., clomipramine) others are more selective for norepinephrine

over serotonin (e.g., desipramine, maprotiline, nortriptyline, protriptyline). They have role in OCD and panic disorder

along depression.

All of these agents block muscarinic cholinergic receptors, histamine 1 receptors, alpha 1 adrenergic receptors, and

voltage-sensitive sodium channels producing various side effects.

1. Blockade of histamine 1 receptors causes sedation and weight gain.

2. Blockade of Ml muscarinic cholinergic receptors dry mouth, blurred vision, urinary retention, and constipation.

3. Blockade of M3 cholinergic receptors interfere with insulin action.

4. Blockade of alpha 1 adrenergic receptors causes orthostatic hypotension and dizziness.

5. Blockade of voltage-sensitive sodium channels in the heart and brain (in overdose) may cause cardiac arrhythmias,

seizure and coma.

Serotonin selective reuptake inhibitors (SSRIs) All SSRIs act by inhibition of serotonin reuptake. Since serotonin does not influence all brain areas equally, it does not

necessarily influence all the symptoms of depression equally.

The undesirable side effects of SSRIs not only to involve specific serotonin receptor subtypes but also the action of

serotonin at these receptors in specific areas of the body, including brain, spinal cord, and gut. These are as follows-

1. Acute stimulation of 5-HT2A and 5-HT2C receptors from raphe to amygdala and limbic cortex, such as

ventromedial prefrontal cortex, may cause acute mental agitation, anxiety, or panic attacks.

2. Acute stimulation of 5-HT2A receptors in the basal ganglia may lead to acute changes in motor movements

(akathisia, psychomotor retardation, dystonia) due to serotonin's inhibition of dopamine neurotransmission.

3. Stimulation of 5-HT-2A receptors in the brainstem sleep centres may cause rapid muscle movements, called

myoclonus, disrupt slow-wave sleep and cause nocturnal awakenings.

4. Stimulation of 5-HT-2A and 5-HT-2C receptors in the spinal cord may inhibit the spinal reflexes of orgasm and

ejaculation and cause sexual dysfunction.

5. Stimulation of 5-HT-3 receptors in the hypothalamus or brainstem may cause nausea or vomiting.

6. Stimulation of 5-HT-3 and/or 5-HT-4 receptors in the GI tract may cause increased bowel motility, GI cramps,

and diarrhoea.

Tolerance develops nausea, vomiting and GI side effects over period of time but persistence of other symptoms will likely

require adding or switching to a different pharmacological mechanism that boosts DA, NE, and/or GABA (Sussman.,

2009).

Serotonin norepinephrine reuptake inhibitors (SNRIs)

Norepinephrine transporter (NET) inhibition increases DA in prefrontal cortex. Although SNRIs are commonly called

"dual action" serotonin-norepinephrine agents, they actually have a third action on dopamine in the prefrontal cortex.

SNRIs may produce the following side effects:

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1. Acute stimulation of beta 1 and/or beta 2 receptors in the cerebellum or peripheral sympathetic nervous system may

cause motor activation or tremor.

2. Acute stimulation of noradrenergic receptors in the amygdala or limbic cortex, such as ventromedial prefrontal cortex,

may cause agitation.

3. Acute stimulation of noradrenergic receptors in the brainstem cardiovascular centres and descending into the spinal

cord may alter blood pressure.

4. Increased norepinephrine activity at alpha 1 receptors may produce symptoms reminiscent of "anticholinergic" side

effects. This is not due to direct blockade of muscarinic cholinergic receptors but to indirect reduction of net

parasympathetic tone due to increased sympathetic tone. Thus, a "pseudoanticholinergic" side effect is produced.

Norepinephrine and dopamine reuptake inhibitors (NDRIs)

Bupropion is the prototypical agent of this group. Bupropion has only weak reuptake blocking properties for dopamine

(DAT inhibition) and for norepinephrine (NET inhibition). Bupropion is especially targeted at the symptoms of the

"dopaminc-deficiency syndrome." (Thase et al., 2006).

Alpha 2 antagonists as serotonin norepinephrine disinhibitors (SNDIs)

Blocking alpha 2 receptors raise both serotonin and norepinephrine. Norepinephrine turns off its own release by

interacting with presynaptic alpha 2 autoreceptors on noradrenergic neurons. Norepinephrine also turns off serotonin

release by interacting with presynaptic alpha 2 heteroreceptors on serotonergic neurons. If an alpha 2 antagonist is

administered, norepinephrine can no longer turn off its own release and so the serotonin release e.g. Mirtazepine.

Mood stabilizers

Lithium

Lithium is proven effective in manic episodes and in the prevention of recurrence, especially for manic episodes and

perhaps to a lesser extent for depressive episodes (Jefferson and Greist., 2009). Mode of action of lithium includes second

messengers, such as

1. The phosphatidyl inositol system, where lithium inhibits the enzyme inositol monophosphatase

2. Modulation of G proteins

3. Regulation of gene expression for growth factors and neuronal plasticity by interaction with downstream signal

transduction cascades, including inhibition of glycogen synthetase kinase 3 (GSK3) and protein kinase C.

Anticonvulsants as mood stabilizers

Based on the theory that mania may "kindle" further episodes of mania, similar to seizures trials of some anticonvulsants

in bipolar disorder have been found effective (Weisler et al., 2006).

Valproic acid

Three possible mode of action of valproic acid has been suggested

1. Inhibition of voltage-sensitive sodium channels

2. Boosting the actions of the neurotransmitter GABA

3. Regulating downstream signal transduction cascades- e.g. inhibition of GSK3 and blockade of phosphokinase

C (PKC) and myristoylated alanine rich C kinase substrate (MARCKS), increase effects of ERK kinase, cytoprotective

protein B-cell lymphoma/leukemia-2 gene (BCL2), GAP43.

Valproate is proven effective for the acute manic phase of bipolar disorder. It is also commonly used long term to prevent

the recurrence of mania, although its prophylactic effects have not been as well established including its antidepressant

actions. It is drug of choice for all types of seizures except partial seizures (Weisler et al., 2006).

Carbamazepine and Oxcarbazepine

Thus carbamazepine is hypothesized to act by blocking voltage-sensitive sodium channels (VSSCs), perhaps at a site

within the channel itself, also known as the alpha subunit of VSSCs. The action of carbamazepine on the alpha subunit of

VSSCs is different from the hypothesized actions of valproate. It is proven effective in bipolar mania and is often utilized

as maintenance treatment for preventing manic recurrences. Carbamazepine is drug of choice for partial seizures (Weisler

et al., 2006).

Lamotrigine

Lamotrigine is approved as a mood stabilizer to prevent the recurrence of both mania and depression. Lamotrigine is not

approved for bipolar mania. Mode of action includes-

1. Binding to the open channel conformation of VSSCs

2. Reduce the release of the excitatory neurotransmitter glutamate.

Levetiracetam

It is an anticonvulsant with a very novel mechanism of action that is it binds to the SV2A protein on synaptic vesicles.

Levetiracetam selectively and potently binds to this site on synaptic vesicles, presumably changing neurotransmission by

altering neurotransmitter release, thereby providing anticonvulsant actions (Ketter and Wang., 2009).

Topiramate

It is approved as an anticonvulsant and it has also been considered as an adjunctive treatment for bipolar disorder. Exact

binding site for topiramate is not known, but it seems to enhance GABA function and reduce glutamate function by

interfering with both sodium and calcium channels. Topiramate is also a weak inhibitor of carbonic anhydrase (Ketter and

Wang., 2009).

Zonisamide

Zonisamide is another anticonvulsant that is not approved for bipolar disorder but is sometimes used to treat this

condition. Its mechanism of action is to enhance GABA function and reduce glutamate function by interfering with both

sodium and calcium channels (Ketter and Wang., 2009).

Gabapentin and Pregabalin

These are used in treatments for various pain conditions, from neuropathic pain to fibromyalgia, and for various anxiety

disorders. Gabapentin and pregabalin are "alpha 2 delta ligands" of voltage-sensitive calcium channels (VSCCs).

Blockade of VSCCs prevents the release of neurotransmitters such as glutamate in pain and anxiety pathways and also

prevents seizures.

Riluzole

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Riluzole has anticonvulsant actions in preclinical models. It binds to VSSCs and prevents glutamate release in an action

similar to that postulated for lamotrigine (Ketter and Wang., 2009).

Antianxiety agents

Benzodiazepines

The mechanism of action of benzodiazepines is on GABA-A receptors. Intramuscular or oral administration of

benzodiazepines can have a calming action immediately and provide valuable time for mood stabilizers with a longer

onset of action to begin working. Clonazepam and lorazepam are used mostly.

Benzodiazepines, perhaps the best-known and most widely used anxiolytics, act by enhancing GABA-A actions at the

level of the amygdala and the prefrontal cortex within CSTC loops to relieve anxiety. Benzodiazepines allosterically

increase the frequency of channel opening in response to GABA. Therefore, benzodiazepines do not directly activate the

receptor, but they enhance the phasic responses to synaptically released GABA. Notably, antagonists and inverse agonists

for the benzodiazepine receptor have been developed that demonstrate anxiogenic effects (Joseph and Coyle, 2009).

Antiobsessive agents

The unequivocal efficacy of SSRIs in OCD is a ―pharmacological bridge‖ implicating dysfunctional serotonergic system.

The mechanism of antidepressant response of SSRIs in the form of desensitization of terminal 5-HT autoreceptors after 2-

3 weeks of administration in hippocampus (Blier et al., 1998) is difficult to extrapolate in OCD because of two reasons-

Anti-OCD effect of SSRIs takes a longer time delay than antidepressant effect and cortico-striatal circuit is implicated in

OCD unlike hippocampus implicated in depression.

After 8 weeks of treatment with the paroxetine, there was clear evidence of enhanced 5-HT release and terminal

autoreceptor desensitization in frontal cortex, suggesting enhanced 5-HT release in orbitofrontal cortex (OFC) after

prolonged SSRI treatment is consistent with delayed anti-OCD effect. A further study documented post synaptic 5-HT2

receptor mediating effect of released 5-HT in the synapse (El Mansari et al., 1997).

Miscellaneous

Stimulants

Stimulant drugs are the first class of compounds reported as effective in treating behavioural disturbances evident in

children who have attention deficit hyper activity disorder (ADHD). Stimulants are sympathomimetic drugs structurally

similar to endogenous catecholamines. These drugs have been shown to enhance dopaminergic and noradrenergic

transmission (Bymaster et al., 2002; Volkow et al., 2001).The most commonly used compounds in this class include

methylphenidate, d-methyl-phenidate, d-amphetamine, and a mixed-amphetamine product (Biederman and Spencer,

2008). Psychotogenic drugs (e.g., methamphetamine) inhibit the release of striatal neurotensin via an inhibitory effect of

the dopamine D1 receptor (Binder et al., 2001).

Non-Stimulants

Randomized clinical trials have suggested that tricyclic antidepressants (TCAs) and atomoxetine are potent

norepinephrine reuptake inhibitors (NRIs), perhaps restoring a more normal ratio of epinephrine and norepinephrine.

Serotonin is thought to play a secondary role in the pathology of ADHD.

Drugs for Dementia

Leading treatments for Alzheimer's disease today include the cholinesterase inhibitors, based upon the cholinergic

hypothesis of amnesia (Salloway et al., 2004), and memantine, an NMDA antagonist (Doraiswamy et al., 2003), based

upon the glutamate hypothesis of cognitive decline. Amyloid plaques destroy cholinergic neurons in the basal forebrain

(i.e., nucleus basalis of Meynert) relatively early in this disorder, causing memory disturbance and providing the basis for

symptomatic treatment with drugs that boost the enzyme acetylcholine. Memantine blocks this tonic glutamate release

from having downstream effects, thus returning the glutamate neuron to a new resting state despite the continuous release

of glutamate. Hypothetically, this stops the excessive glutamate from interfering with the resting glutamate neurons

physiological activity, therefore improving memory; it also hypothetically stops the excessive glutamate from causing

neurotoxicity, therefore slowing the rate of neuronal death and also the associated cognitive decline that this causes in

Alzheimer's disease (Reisberg et al., 2003).

Dopamine can be degraded by the activity of MAO and aldehyde dehydrogenase to dihydroxyphenylacetic acid

(DOPAC). MAO B is the dominant enzyme in the human brain and inhibitors of it such as selegiline, have some value in

the treatment of Parkinson’s disease by prolonging the action of the remaining endogenous DA as well as that formed

from administered levodopa. It can also be metabolized by the activity of COMT to form 3-methoxytryptamine (3-MT).

DOPAC and 3-MT are then further degraded to form HVA. COMT inhibitors like, entacapone and tolcapone are used to

protect o-methylation, in the treatment of Parkinson’s disease (Webster, 2001).

Ramelteon, a melatonin receptor antagonist, primarily interacts with the MT1 and MT2 receptors in the SCN and induces

sleep (Roth, 2006).

Neurotransmitters and Electroconvulsive Therapy (ECT)

ECT has several neurotransmitter effects on the brain (Prudic., 2009).

1. Downregulation of Beta-1 receptors, Upregulation and sensitization of 5-HT receptors- Similar to effect of

antidepressant drugs.

2. Decreased DA autoreceptors mediated inhibition, with no effect on post synaptic D2 receptor.

3. Increased GABA – Elevated seizure threshold.

4. Increased CSF concentrations of acetylcholine and down regulation of cortical muscarinic receptors- May be

responsible for memory impairment.

Neurotransmitters and Transcranial magnetic stimulation

Rapidly alternating magnetic fields are applied to the scalp to induce small, focused electrical currents in superficial

cortex. Remote sites may be activated transsynaptically. Electrical current depolarizes the affected cortical neurons,

thereby causing nerve impulses to flow out of the underlying brain areas. That activates a brain circuit beginning in

19

dorsolateral prefrontal cortex and connecting to other brain areas, such as ventromedial prefrontal cortex and amygdala,

with connections to the brainstem centers of the monoaminergic neurotransmitter system (5-HT, dopamine and

norepinephrine) the net result could be monoaminergic modulation (Avery et al., 2006).

Neurotransmitters and Vagus nerve stimulation

The vagus nerve has direct and indirect anatomical connections with the monoaminergic neurotransmitter system in the

brainstem, especially the noradrenergic locus coeruleus and the serotonergic midbrain raphe. It is possible that trans-

synaptic excitation of neurotransmitter centers from input received via the vagus nerve is capable of boosting the output of

neurotransmitters from these monoamine neurotransmitter centers and thereby boosting the therapeutic action of drugs in

depressed patients with insufficient response to antidepressants. The onset of antidepressant action by VNS is generally

delayed by several weeks, and the major side effect may be hoarseness from the spread of electrical stimulation in the

neck to the vocal cords (Nemeroff et al., 2006).

Neurotransmitters and Psychotherapy

Several published studies in recent years are consistent in demonstrating changes following psychotherapy in brain

activity and neurotransmitter levels in patients with psychiatric disorders when compared with healthy comparison

subjects. Some of the changes accompanying successful psychotherapy resembled those seen with pharmacotherapy, with

the suggestion that at least in some cases, psychotherapy and medications may act on a common set of brain targets (Etkin

et al., 2005). Though most of these studies in this regard have focused on brain anatomical and metabolic profiles, a few

have assessed the level of neurotransmitters in patients treated with psychotherapy. In their study, Viinamäki et al. (1998)

compared 5-HT metabolism in brain areas (PFC and thalamus) in patients suffering from borderline personality disorder

plus depression using SPECT. The individual who received 1 year of psychodynamic psychotherapy showed remarkable

improvement in 5HT reuptake as compared to the individual who received no treatment. Sharpley (2010) had tried to

review the evidences regarding the neurobiological effects of psychotherapy for depression. He had suggested a

hypothetical pathway linking the nurturing effects of the therapist patient bonding and restoration of neuroendocrinal

balance. This pathway might provide a neurobiological causal link between psychotherapy and alleviation of depression.

INDIAN STUDIES

Very few studies have been undertaken in this context. Pandey et al. (1987) in their study had found that patients with

schizophrenia have lower central serotonin turnover than control group whereas there was no significant difference in

central dopamine turnover in these two groups. Chatterjee (1988) assessed the levels of anterior pituitary hormones in

patients of schizophrenia using radioimmuno-assay and found significantly low level of prolactin and leutinizing hormone

in the patient group as compared to controls. More recently, in their study done on patients with schizophrenia, Anand et

al. (2002) assessed the level of CSF amines and their metabolites in drug naïve patients with psychosis and found

significant positive correlation between CSF 5-HIAA levels and negative and disorganization dimensions. Also they

found significant negative correlation between CSF HVA and psychosis dimension. Thus they found implication of

serotonin in negative and disorganized dimension, whereas serotonin-dopamine interaction could be implicated in

schizophrenia dimension. Rao et al. (2010) in their review article have suggested that biomarkers in neuropsychiatry can

be of great help to clinician for early diagnosis of these disorders, but at the same time, they have pointed towards lack of

Indian literature in this regard. They have strongly advocated the need for further research in molecular understanding of

neuropsychiatric disorders.

Studies at CIP

Kumar and Khess (2006-08) Prolactin and leptin serum levels and alcohol craving and found that no significant

correlation was found between prolactin and craving measured with OCDS.

Alam and Sinha (2008-10) change in thyroid status in lithium treated adult patients with mood disorder and found

that patients on long term lithium therapy was found to have increased thyroid volume and trend towards

hyperthyroidism as compared to patients receiving other mood stabilizers.

Chopra and Ram (1998) Basal thyroid indices in affective illness: A controlled study and found that the no

significant difference was found in the value of total T3, total T4 and total TSH with respect to age of the

subjects, marital status, religion, domicile and socio-economic status in the sample.

Arora and Ram (2002-04) Urinary monoamine metabolites in schizophrenia: Effect of treatment fount that there

was significant difference in the amount of homovanilic acid (metabolite of dopamine) between the patients and

controls at baseline

CONCLUSION

Neurotransmitters have a significant role to play in almost all neuropsychiatric illnesses. It assumes more importance

when it comes to either understanding the etiology of the disease in question or treating the illness with pharmacological,

physical or even psychological treatment modalities. It would not be an understatement if we say that neurotransmitter

imbalance is the basic underlying pathology in all of the above discussed illness. The pharmacological agents of almost all

the groups, be it antipsychotics, antidepressants, mood stabilizers or any other group, all act primarily by correcting the

underlying neurochemical imbalance in nervous system. With passing time, role of more and more neurotransmitters are

being investigated and research is finding different level of response in case of different neurotransmitters. Indian

literature in this regard is meager but with advancing technological more and more options are opening up for further

research in this field.

20

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