The British physiologist Langley, in 1905, was first to postulate that most drugs, hormones and transmitters produce their effects by interacting with specific sites on the cell membrane which we now call receptors. Langley's postulate was based on his observation that drugs can mimic both the specificity and potency of endogenous hormones and neurotransmitters, while others appear to be able to selectively antagonize the actions of such substances. Thus, substances which stimulate the receptor, or mimic the action of natural ligands for the receptor, are called agonists, while those substances blocking the receptor are called antagonists (this is expanded upon in Chapter 5). This revolutionary hypothesis was later extended by Hill, Gaddum and Clark, who quantified the ways in which agonists and antagonists interacted with receptors both in vitro and in vivo. More recently the precise structures of a large number of different types of transmitter receptors have been determined using cloning and other techniques, so that it is now possible to visualize precisely how an agonist or antagonist interacts with certain types of receptor.
To date, different types of cholinergic, ^-adrenergic and serotonergic receptors have been cloned, and their essential molecular features identified. In addition, a number of peptide receptors such as the insulin, gonadotrophin, angiotensin, glucagon, prolactin and thyroid stimulating hormone receptors have also been identified and their key structures determined. The location and possible functional importance of the different types of neurotransmitter receptors which are of relevance to the psychopharmacologist are summarized below. It must be emphasized that this list is by no means complete and that many of these receptor types are likely to be further subdivided as a result of the development of highly selective ligands.
Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins.
To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed M1 receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the M1 and M2 receptors occur in the brain. Recent studies have shown that M1 and M3 are located postsynaptically in the brain whereas the M2 and M4 receptors occur presynaptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the M1, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8).
The cholinergic system has the capacity to adapt to changes in the physiological environment of the brain. Thus the density of the cholinergic receptors is increased by antagonists and decreased by agonists. The reduction in the density of the receptors is a result of their rapid internalization into the neuronal membrane (receptor sequestration) followed by their subsequent destruction. This phenomenon may have a bearing on the long-term efficacy of cholinomimetic drugs and anti-cholinesterases which are currently used in the symptomatic treatment of
Figure 2.8. Location of muscarinic receptors and their link to second messenger systems.
Figure 2.8. Location of muscarinic receptors and their link to second messenger systems.
Alzheimer's disease. While it is widely believed that the relapse in the response to treatment is due to the continuing neurodegenerative changes in the brain which are unaffected by cholinomimetic drugs, it is also possible that such treatments could impair cholinergic function by causing an increased sequestration and destruction of muscarinic receptors. The possible detrimental effect of cholinergic agonists on memory is supported by the observation that the chronic administration of physostigmine or oxotremorine to rats decreases the number of muscarinic receptors and leads to an impairment of memory when the drugs are withdrawn. Conversely chronic treatment with a cholinergic antagonist such as atropine increases the number of cholinergic receptors and leads to a memory improvement when the drug is withdrawn. Whether these effects in experimental animals are relevant to the clinical situation in which cholinomimetic agents are administered for several months is unknown.
Although other transmitters such as noradrenaline, serotonin and glutamate are involved, there is now substantial evidence to suggest that muscarinic receptors play a key role in learning and memory. It is well established that muscarinic antagonists such as atropine and scopolamine impair memory and learning in man and that their effects can be reversed by anticholinesterases. Conversely, muscarinic agonists such as arecholine improve some aspects of learning and memory. However, cholinomimetic drugs such as carbachol which stimulate the inhibitory autoreceptors impair memory by blocking the release of acetylcholine in the hippocampus and cortex; the selective autoreceptor antagonist secoverine has the opposite effect.
Comment on the use of cholinomimetic drugs in the treatment of Alzheimer's disease
In addition to the accumulation of senile plaques (abnormal beta amyloid containing proteins) and neurofibrillary tangles (modified microtubular associated proteins) which characterize the disease, the most consistent neuropathological finding in patients with Alzheimer's disease is a degeneration of the projections from the main cholinergic cell body which comprise the nucleus basalis of Meynert. The degenerative changes involve the loss of M1 and M2 receptors and a reduction in the activity of choline acetyltransferase (CAT), the rate-limiting enzyme for the synthesis of acetylcholine. The reduction in CAT and the associated neuronal loss in the basal forebrain are the most consistent correlates of cognitive impairment seen in Alzheimer's disease. The treatment strategies are primarily aimed at increasing cholinergic transmission. These include the centrally acting reversible inhibitors of acetylcholinesterase such as tacrine, donepezil, rivastigmine, galanthamine and metrofinate. Physostigmine has also been used but its efficacy and peripheral side effects have limited its widespread clinical use. Such drugs have beneficial effects in about 40% of patients; the patients show an improved score in several tests of cognitive function. However, even in those patients who do show some improvement following the administration of these drugs at an early stage in the development of the disease, the benefit is limited to approximately 18 months. Furthermore gastrointestinal side effects are often problematic.
Following studies of the actions of specific agonists and antagonists on the nicotinic receptors from skeletal muscle and sympathetic ganglia, it was soon apparent that not all nicotinic receptors are the same. The heterogeneity of the nicotinic receptors was further revealed by the application of molecular cloning techniques. This has led to the classification of nicotinic receptors into N-m receptors and N-n receptors, the former being located in the neuromuscular junction, where activation causes end-plate depolarization and muscle contraction, while the latter are found in the autonomic ganglia (involved in ganglionic transmission), adrenal medulla (where activation causes catecholamine release) and in the brain, where their precise physiological importance is currently unclear. Of the specific antagonists that block these receptor subtypes, and which have clinical applications, tubocurarine and related neuromuscular blockers inhibit the N-m type receptor while the antihypertensive agent trimetha-phan blocks the N-n receptor.
In contrast to the more numerous muscarinic receptors, much less is known about the function of nicotinic receptors in the brain. In addition to nicotinic
Ma+ synaptic cleft b / ^^ • • N^4 pnit-synaptic membrane
their distribution in the neuromuscular junction, ganglia and adrenal medulla, nicotinic receptors occur in a high density in the neocortex.
Nicotinic receptors are of the ionotropic type which, on stimulation by acetylcholine, nicotine or related agonists, open to allow the passage of sodium ions into the neuron. There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain. In Alzheimer's disease it would appear that there is a selective reduction in the nicotinic receptors which contain the alpha 3 and 4 sub-units (Figure 2.9).
Unlike the muscarinic receptors, repeated exposure of the neuronal receptors to nicotine, both in vivo and in vitro, results in an increase in the number of receptors; similar changes are reported to occur after physostigmine is administered directly into the cerebral ventricles of rats. These changes in the density of the nicotinic receptors are accompanied by an increased release of acetylcholine. Following the chronic administration of physostigmine, however, a desensitization of the receptors occurs. Functionally nicotinic receptors appear to be involved in memory formation; in clinical studies it has been shown that nicotine can reverse the effects of scopolamine on short-term working memory and both nicotine and arecholine have been shown to have positive, though modest, effects on cognition in patients with Alzheimer's disease.
Ahlquist, in 1948, first proposed that noradrenaline could produce its diverse physiological effects by acting on different populations of adrenoceptors, which he termed a and b receptors. This classification was based upon the relative selectivity of adrenaline for the a receptors and isoprenaline for the b receptors; drugs such as phentolamine were found to be specific antagonists of the a, and propranolol for the b receptors.
It later became possible to separate these main groups of receptors further, into a1 and a2 based on the selectivity of the antagonists prazosin, the antihypertensive agent that blocks a1 receptors, and yohimbine, which is an antagonist of a2 receptors.
At one time it was thought that a1 receptors were postsynaptic and the a2 type were presynaptic and concerned with the inhibitory control of noradrenaline release. Indeed, novel antidepressants like mianserin, and more recently the highly selective a2 receptor antagonist idazoxan, or yohimbine, were thought to act by stimulating the relase of noradrenaline from central noradrenergic synapses. It is now established, however, that the a2 receptors also occur postsynaptically, and that their stimulation by such specific agonists as clonidine leads to a reduction in the activity of the vasomotor centre, thereby leading to a decrease in blood pressure. Conversely, the a2 antagonist yohimbine enhances noradrenaline release (see Figure 2.10).
The a1 receptors are excitatory in their action, while the a2 receptors are inhibitory, these activities being related to the different types of second messengers or ion channels to which they are linked. Thus, a2 receptors hyperpolarize presynaptic membranes by opening potassium ion channels, and thereby reduce noradrenaline release. Conversely, stimulation of a1 receptors increases intracellular calcium via the phosphatidyl inositol cycle which causes the release of calcium from its intracellular stores; protein kinase C activity is increased as a result of the free calcium, which then brings about further changes in the membrane activity.
Both types of receptor occur in the brain as well as in vascular and intestinal smooth muscle: a1 receptors are found in the heart whereas a2 receptors occur on the platelet membrane (stimulation induces aggregation) and nerve terminals (stimulation inhibits release of the transmitter). It is now recognized that there are several subtypes of a1 and a2 receptors, but their precise function is unclear.
So far three subtypes of b receptors have been identified and cloned. They differ in their distribution, the bi type being found in the heart, the b2 in lung, smooth muscle, skeletal muscle and liver, while the b3 type occurs in adipose tissue. There is evidence that b2 adrenoceptors occur on the lymphocyte membrane also but the precise function there is unknown.
The antihypertensive drug metoprolol is a clinically effective example of a b1 antagonist. All the b receptor subtypes are linked to adenylate cyclase as the second messenger system. It seems that both b1 and b2 receptor types occur in the brain and that their activation leads to excitatory effects. Of particular interest to the psychopharmacologist is the finding that chronic antidepressant treatment leads to a decrease in the functional responsiveness of the b receptors in the brain, and in the density of these receptors on lymphocytes, which coincides with the time necessary for the therapeutic effects of the drugs to be manifest. Such changes have been ascribed to the drugs affecting the activity of the G-proteins that couple the receptor to the cyclase sub-unit.
The adrenergic receptors have been purified and their genes cloned. They have seven membrane-spanning units, which are involved in binding the selective agonists and antagonists.
Two types of dopamine receptors have been characterized in the mammalian brain, termed D1 and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase.
Detailed studies of the binding of 3H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the D1 receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the D1 receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor; conversely, the D1 receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics.
There is still some controversy over the precise anatomical location of the dopamine receptor subtypes, but there is now evidence that the D2 receptors are located presynaptically on the corticostriatal neurons and postsynaptically in the striatum and substantia nigra. Conversely, the D1 receptors are found presynaptically on nigrostriatal neurons, and post-synaptically in the cortex. It is possible to differentiate these receptor types on the basis of their agonist and antagonist affinities.
In addition to these two subtypes, there is also evidence that the release of dopamine is partially regulated by feedback inhibition operating via the dopamine autoreceptor.
With the development of D1 and D2 agonists, however, emphasis has become centred on the pharmacological characteristics of the specific drug in order to determine whether an observed effect is mediated by D1 or D2 receptors. It is now apparent that dopamine receptors with the same pharmacological characteristics do not necessarily produce the same functional responses at the same receptor. For example, D2 receptors are present in both the striatum and the nucleus accumbens, but cause an inhibition of adenylate cyclase only in the striatum. Furthermore, recent studies indicate that dopamine receptors can influence cellular activities through mechanisms other than adenylate cyclase. These may include direct effects on potassium and calcium channels, as well as modulation of the phosphatidyl inositol cycle. To complicate the picture further, D1 and D2 receptors have opposite effects on some behaviours (e.g. chewing in rats) but are synergistic in causing other behaviours (e.g. locomotor activity and some types of stereotypy). The precise clinical importance of these interactions is unclear.
The densities and functional activities of dopamine receptors have been shown to change in response to chronic drug treatment and in disease. Thus an increase in the dopamine receptor density in the nigrostriatal pathway appears to be related to the behavioural supersensitivity observed following unilateral destruction of the dopaminergic system in the striatum. Dopamine receptor antagonists, such as the "classical" neuroleptics like chlorpromazine, are also known to increase the density of dopamine receptors in the striatal region. This contributes to the extrapyramidal side effects of such drugs, which frequently follows their prolonged use and reflects the drug-induced functional deficit of dopamine in the brain. Abrupt withdrawal of a neuroleptic following its prolonged administration is frequently associated with tardive dyskinesia, a disorder which may be partly due to the sudden activation of supersensitive dopamine receptors. Despite the appeal of this hypothesis, it should be emphasized that many other factors, such as brain damage and prior exposure to tricyclic antidepressants, may also predispose patients to this condition.
With regard to the change in dopamine receptor activity in disease, there is some evidence from post-mortem studies that the density of D2 receptors is increased in the mesocortical areas of the schizophrenic brain, and in the putamen and caudate nucleus in neuroleptic-free patients. Positron emission tomography of schizophrenic patients has, however, failed to confirm these findings. There is also evidence that the link between the D1 and D2 receptors is defective in some patients with diseases in which the dopaminergic system might be involved. Thus the well-known loss of dopaminergic function in patients with Parkinson's disease is associated with a compensatory rise in the density of postsynaptic D1 and D2 receptors. The long-term treatment of Parkinson's disease with L-dopa reduces the receptor density to normal (so-called receptor ''down-regulation''). Similarly, the densities of D1 and D2 receptors are reduced in the striata of patients with Huntington's chorea, as is the linkage between these receptors.
Dopamine has been implicated in a number of psychiatric conditions of which schizophrenia and the affective disorders are the most widely established. Five major subtypes of dopamine receptors have now been cloned. These are divided into two main groups, D1 and D2 respectively. The D1 receptors consist of D1 and D5 types and are positively linked to the adenylate cyclase second messenger system, while the D2 group consists of the D2, D3 and D4 receptors which are negatively linked to the adenylate cyclase system.
The D1 receptors have been subdivided into the D1A and D1B types and are coded by genes located on chromosomes 5 and 4 respectively. Several selective antagonists of the D1 receptors have been developed (for example, SCH 31966, SCH 23390 and SKF 83959), none of which have so far been developed for therapeutic use.
Apomorphine is an agonist at both the D1 and D2 receptors. From the pathological viewpoint, a malfunction of the D1 receptors has been implicated in the negative symptoms of schizophrenia but as there is a close interaction between these receptor types it is difficult to conclude whether the changes seen in schizophrenia are attributable to a primary decrease in D1 receptor function or an increase in D2 receptor function. The function of the D5 receptors is unclear; these receptors, though widely distributed in the brain, are only present in a relatively low density in comparison to the other dopamine receptor types.
The D2 receptor types, besides being subdivided into D3 and D4 types, are further divided into the D2 long and D2 short forms. D2 antagonists, in addition to virtually all therapeutically active neuroleptics, also include such novel drugs as raclopride, eticlopride and sniperone while quinpirole is an example of a specific D2 receptor agonist. The latter drugs are not available for therapeutic use. A malfunction of the D2 receptors has been associated with psychosis, extrapyramidal side effects and hyperprolactinaemia.
The human D3 gene has produced two variants, D3 and D3s. So far there do not appear to be any selective agonists or antagonists of the D3 receptor which enable the function of this receptor to be clearly distinguished from that of the D2 receptor. The D3 receptors are located in the ventral and limbic regions of the brain but absent from the dorsal striatum. This suggests that specific antagonists of the D3 receptors may be effective antipsychotics but without causing extrapyramidal side effects.
The D4 receptor has eight polymorphic variants in the human. However, even though several specific antagonists of this receptor type have been developed and shown to have antipsychotic activity in animal models of schizophrenia, the clinical findings have been disappointing. Because of the high density of the D4 receptors in the limbic cortex and hippocampus, but their absence from the motor regions of the brain, it was anticipated that such drugs have antipsychotic efficacy without the motor side effects. In support of this view, it has been shown that the atypical antipsychotic clozapine has a high affinity for the D4 receptors; other studies have also indicated that many of the atypical, and some of the typical, antipsychotics have similar affinities for these receptors.
In addition to the postsynaptic receptors, dopamine autoreceptors also exist on the nerve terminals, dendrites and cell bodies. Experimental studies have shown that stimulation of the autoreceptors in the somatodendritic region of the neuron slows the firing rate of the dopaminergic neuron while stimulation of the autoreceptors on the nerve terminal inhibits both the release and the synthesis of the neurotransmitter. Structurally, the autoreceptor appears to be of the D2 type. While several experimental compounds have been developed that show a high affinity for the autoreceptors, to date there is no convincing evidence for their therapeutic efficacy.
Gaddum and Picarelli, in 1957, were the first investigators to provide evidence for the existence of two different types of 5-HT receptor in peripheral smooth muscle. These receptors were termed D (for dibenzyline, an a1 adrenoceptor antagonist which also blocked 5-HT receptors) and M (for morphine, which blocked the contractile response mediated through the myenteric plexus in the intestinal wall). Studies undertaken in the 1980s revealed the existence of multiple binding sites for 5-HT receptors. The 5-HTd receptor was shown to have the characteristics of the 5-HT2 receptor, while the M receptor has been shown to be identical to the 5-HT3 receptor in the brain and gastrointestinal tract.
This biogenic amine transmitter contributes to the regulation of a variety of psychological functions which include mood, arousal, attention, impulsivity, aggression, appetite, pain perception and cognition. In addition, serotonin plays a crucial role in regulating the sleep-wake cycle and in the control of brain maturation. It is therefore understandable that a dysfunction of the serotonergic system has been implicated in a variety of psychiatric disorders such as schizophrenia, depression, alcoholism and in phobic states. Undoubtedly interest in the role of the serotonergic system in psychiatry has been stimulated by the therapeutic success of the selective serotonin reuptake inhibitors (SSRIs) which have proven to be effective in alleviating the symptoms of many of these disorders. The complexity of the serotonergic system lies in the number of different serotonin receptors within the brain. These are classified into seven distinct types that are heterogeneously distributed in the brain, each with its specific physiological function. The function of the serotonin receptors is a reflection of their structure. Thus the 5-HT3 receptors are ionotropic in nature whereas the remainder are metabotropic, coupled to specific G-proteins and share a common seven-membrane domain structure. These receptors have been cloned and their physiological activity shown to be associated with the activation of either phospholipase C (5-HT2 receptors) or adenylate cyclase (5-HT4-5-HT7). The 5-HT1A, 1B and 1D receptors are also coupled to adenylate cyclase but they inhibit the function of this second messenger system. Although the precise physiological activity of the different serotonin receptors is still the subject of ongoing studies, links between specific receptor subtypes and their possible involvement in specific neurological and psychiatric disorders have been identified. For example, the antimigraine drug sumatriptan decreases headache by activating the inhibitory 5-HT1B receptors located presynaptically on perivascular nerve fibres. This blocks the release of pain-causing neuropeptides and the conduction in the trigeminal vascular neurons. With regard to the 5-HT1A receptors, agonists such as buspirone and ipsapirone act as anxiolytics while the antidepressant effects of the SSRIs have been associated with an indirect reduction in the activity of the 5-HT1A receptors. Conversely the sexual side effects of the SSRIs are attributed to their indirect action on 5-HT2C receptors which follows the enhanced serotonergic function; these receptors may also be involved in the regulation of food intake which could help to explain the antibulimic action of the SSRIs.
Several different types of serotonin receptor (for example, 5-HT1A, 5-HT2A, 5-HT2c, 5-HT1B/1D) have been associated with the motor side effects of the SSRIs which may arise should these drugs be administered in conjunction with a monoamine oxidase inhibitor. The 5-HT3 receptor is an example of a non-selective cation channel receptor which is permeable to both sodium and potassium ions and, because both calcium and magnesium ions can modulate its activity, the 5-HT3 receptor resembles the glutamate-NMDA receptor. Antagonists of the 5-HT3 receptor, such as ondansetron, are effective antiemetics and are particularly useful when nausea is associated with the administration of cytotoxic drugs or some anaesthetic agents. However, they are ineffective against the nausea of motion sickness or that induced by apomorphine, suggesting that the 5-HT3 receptors function at the level of the vomiting centre in the brain. In addition, there is evidence from experimental studies that these receptors are involved in anxiety and in cognition. 5-HT3 antagonists have both anxiolytic and cognitive enhancing properties but it still remains to be proven that such properties are therapeutically relevant.
The precise function of the 5-HT4,5/6 and 7 receptors is less certain. All these receptors have been cloned and their distribution in the brain determined. There is some evidence that 5-HT4 receptors act as heteroceptors on cholinergic terminals and thereby modulate the release of acetylcholine. While the physiological role of the 5-HT5 6 and 7 receptors is unclear, it is of interest to note that several atypical neuroleptics, such as clozapine, and several antidepressants have a good affinity for these receptors. There is also evidence that selective agonists and antagonists, such as zacopride, ergotamine, methysergide and LSD, have a high affinity for the 5-HT4 and 5-HT5 receptors but how these effects relate to their pharmacological actions is presently unknown. Figure 2.11 summarizes the possible sites of action of different classes of psychotropic drugs on the serotonin receptors in the brain.
Clearly, much remains to be learned about the distribution and functional activity of these receptor subtypes before their possible roles in mental illness can be elucidated. A summary of the distribution of the different types of 5-HT receptors and their agonists is shown in Table 2.6.
There are two amino acid neurotransmitters, namely GABA and glutamate, which have been of major interest to the psychopharmacologist because of the potential therapeutic importance of their agonists and antagonists. The receptors upon which GABA and glutamate act to produce their effects differ from the ''classic'' transmitter receptors in that they seem to exist as receptor complexes that contain sites for agonists, in addition to the amino acid transmitters; these sites, when occupied, modulate the responsiveness of the receptor to the amino acid. For example, the benzodiazepines have long been known to facilitate inhibitory transmission, and their therapeutic properties as anxiolytics and anticonvulsants are attributable to such an action. It is now apparent that benzodiazepines occupy a receptor site on the GABA receptor complex which enhances the responsiveness of the GABA receptor to the inhibitory action of GABA. Similarly, it has recently been shown that the inhibitory transmitter glycine can act on a strychnine-insensitive site on the N-methyl-D-aspartate (NMDA) receptor, and thereby modify its responsiveness to glutamate.
Knowledge of the mechanisms whereby the amino acid transmitters produce their effects has been valuable in the development of psychotropic drugs that may improve memory, reduce anxiety, or even counteract the effects of post-stroke hypoxia on brain cell survival. Some of these aspects are considered later.
The major amino acid neurotransmitters in the brain are GABA, an inhibitory transmitter, and glutamic acid, an excitatory transmitter. GABA is widely distributed in the mammalian brain and has been calculated to contribute to over 40% of the synapses in the cortex alone. While it is evident that a reduction in GABAergic activity is associated with seizures, and most anticonvulsant drugs either directly or indirectly facilitate GABAergic transmission, GABA also has a fundamental role in the brain by shaping, integrating and refining information transfer generated by the excitatory transmitters. Indeed, because of its wide anatomical distribution, GABA may be involved in such diverse functions as vigilance, consciousness, arousal, thermoregulation, learning, food consumption, hormonal control, motor control and the control of pain.
At the cellular level, GABA is located in the interneurons. GABAergic neurons project both locally and, by long axons, to more distant regions of the brain. For example, GABAergic neurons project from the neostriatum to the substantia nigra. As with the biogenic amine neurotransmitters, the synthesis of GABA is highly regulated. GABA is synthesized by glutamate decarboxylase from glutamate. This enzyme acts as the rate-limiting step as its activity is dependent on the pyridoxal phosphate cofactor; it has been estimated that at least 50% of glutamate decarboxylase present in the brain is not bound to cofactor and is therefore inactive. Newly synthesized GABA is stored in vesicles in the nerve terminal and, following its release, its action is terminated by a reuptake mechanism into the glial cells which surround the neuron, and also into the nerve terminal. GABA is then metabolized by GABA transaminase to succinic semialdehyde, a component of the GABA-shunt pathway, and thence to the tricarboxylic acid cycle to generate metabolic energy. Thus GABA differs substantially from the conventional biogenic amine transmitters in that it is largely metabolized once it has been released during neurotransmission.
Of the many drugs that have been developed which modulate GABA function, the inhibitors of GABA transaminase have been shown to be effective anticonvulsants. These are derivatives of valproic acid that not only inhibit the metabolism of GABA but may also act as antagonists of the GABA autoreceptor and thereby enhance the release of the neurotransmitter. GABA-uptake inhibitors have also been developed (for example, derivatives
Table 2.6. Summary of the properties of 5-HT receptor subtypes in the mammalian brain
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