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 Angiogensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor, Estrogens, Androgens, hormones Progestins, Thyroid hormones, Cortisol. Hypothalamic Corticotrophin-releasing hormone (CRH), Gonadotropin releasing hormone (GnRH), Luteinizing releasing hormone releasing hormone (LHRH), Somatostatin, Thyrotropin releasing hormone (TRH), Growth hormones hormone releasing hormone (GHRH). Pituitary Corticotrophin (ACTH), Growth hormone (GH), Lipotrophin, Alpha-melanocyte-stimulating hormone peptides (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 Bombesin, Bradykinin, Carnosine, Calcitonin G related peptide, CART (cocaine and amphetamine peptides related transcript), Neuropeptide Y, Neurotensin, Delta sleep factor, Galanin, Focretin, Melanocyte concentration hormone. Gases Nitric oxide (NO), Carbon monoxide (CO). Lipid Anandamide. neurotransmitter Neurokinins/ Substance P, Neurokinin A, Neurokinin B. Tachykinins 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 TRYPTOPHAN Rate limiting MAO B 5-HYDROXYTRYPTOPHAN Decarboxylase SEROTONIN (5-HT) 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, 5hydroxyindolacetaldehyde, 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; Hhippocampus; 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 5HT2A 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 5-HT1A 5-HT1B 5-HT2 5-HT3 5-HT4 5-HT7 changes * * *(?) 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 bloodbrain 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 bloodbrain 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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MAO DOPAC

DIHYDROXYPHENYLALANINE (DOPA) Decarboxylase COMT DOPAMINE - Hydroxylase NORADRENALINE COMT N-Methyltransferase

3-METHOXYTRYPTAMINE

NORMETANEPHRINE Extraneuronal METANEPHRINE

MAO Intraneuronal MAO ADRENALINE COMT

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).

3,4 Dihydroxy Mandelic Acid

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; NTbrainstem 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 D 1 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 -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; SCspinal 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: 1, 2 and . Each subfamily consists of three distinct receptor subtypes. 1 receptors (subtypes designated 1A, 1B, and 1D): 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. 2 receptor subtypes (designated 2A, 2B, and 2C): They display both presynaptic autoreceptor and postsynaptic actions. Within the brain the stimulation of 2 autoreceptors (likely the 2A subtype) which have been implicated in arousal states. This mechanism has been proposed for sedative effects and blood pressure lowering effect of the 2 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 2 receptors inhibits the activity of serotonin neurons of the dorsal raphe nucleus. adrenergic receptors (subtypes designated 1, 2, and 3): They are found both in the brain and in many peripheral tissues. 1 receptors are present in heart while 2 receptors mediate bronchial muscle relaxation and vasodilation within skeletal muscle. 3 receptors are found in adipose tissue, where they stimulate fat catabolism. 1 and 2 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 1 and 2 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 (1, 1, and ): In the periphery, nicotinic acetylcholine receptors are found in skeletal muscle, autonomic ganglia, and the adrenal medulla. (2) Standard neuronal subunits (26 and 24): 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 (79): The 7 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; HYhypothalamus; 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 neurotransmittersincluding 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 1 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 MAO A in the gut), resulting in displacement of intracellular stores of norepinephrine from sympathetic innervating blood vessels (Shulman and Walker, 1999).
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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 -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 Huntingtons chorea (associated with a degeneration of GABAergic nigrostriatal 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). Krebs 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. 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 -subunits, one -subunit and one -subunit. The fifth unit in the pentamer is variable and can be provided either by one of the - or -subunits or a delta-subunit. The GABA-a receptor possesses three different binding sites, one for GABA (binding site is at the interface of and subunits), second for benzodiazepines (binding site is at the interface between the and 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 voltageactivated 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 Krebs cycle, which generates -ketoglutarate. The 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 -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 -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 longterm 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 3045 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 Cushings 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 Cushings syndrome. Overnight 1mg DST is used for screening of Cushings 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 Huntingtons 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 Parkinsons 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 (, , and ), 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), 2arachidonoylglycerol 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. CARTcontaining 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 sleepwake 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 laters 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
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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- 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). 5HT 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., sleepwake 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 2-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 agonist methadone, buprenorphine, a partial 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 nonserotonergic 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 5HT2C 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 follows1. 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 includes1. 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 23 weeks of administration in hippocampus (Blier et al., 1998) is difficult to extrapolate in OCD because of two reasonsAnti-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 rst class of compounds reported as eective in treating behavioural disturbances evident in children who have attention decit 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 Parkinsons 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 Parkinsons 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
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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 transsynaptic 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, Viinamki 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 nave 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.

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