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Ol w of nipecotic acid, guvacine) which also have anticonvulsant activity at least in experimental animals. However, the major development in the pharmacology of the GABAergic system has been in drugs which facilitate the functioning of the GABA-A receptors. These will be discussed later.

There are three types of GABA receptor, A, B and C. Unlike the ionotropic GABA-A receptors, the GABA-B receptors are metabotropic and coupled via inhibitory G-proteins to adenylate cyclase. Not only do the GABA-B receptors inhibit the second messenger but they also modulate potassium and calcium channels in the neuronal membrane. Baclofen, the antispastic drug, owes its therapeutic efficacy to its agonistic action on these receptors while phaclofen, an experimental drug, acts as an antagonist. Unlike drugs that act on GABA-A receptors, GABA-B receptor agonists have antinociceptive properties which may account for the efficacy of drugs like baclofen in the treatment of trigeminal neuralgia. Experimental studies suggest that GABA-B antagonists may have antiepileptic activity. GABA-B receptors are widely distributed throughout the brain and in several peripheral organs. Their distribution differs from the GABA-A receptors. In the cortex and several other brain regions, GABA-B receptors occur on the terminals of both GABA and non-GABA neurons where they modulate neurotransmitter release.

GABA-C receptors have only recently been identified and their function is still uncertain. There is evidence that, besides GABA, the GABA receptor agonists muscimol and isogucacine have a high affinity for these receptors. A high density of GABA-C receptors has been detected in the retina where they appear to be involved in the development of retinal rod cells. In the brain, there is evidence that GABA-C receptors are concentrated in the superior colliculus where they have a disinhibitory role. There is also evidence that they play an important role in some aspects of neuroendocrine regulation both in the gastrointestinal tract and in the secretion of thyroid stimulating hormone.

The GABA-A receptors have been cloned and the structures of some of the 10 subtypes of this receptor have been described. As these subtypes appear to be heterogeneously distributed throughout the brain, it may ultimately be possible to develop drugs that will affect only one specific species of GABA-A receptor, thereby optimizing the therapeutic effect and reducing the possibility of non-specific side effects. It seems likely that this will be an important area for psychotropic drug development in the near future.

The GABA-A receptor is directly linked to chloride ion channels, activation of which results in an increase in the membrane permeability to chloride ions, and thereby the hyperpolarization of cell bodies. GABA-A receptors are also found extrasynaptically where, following activation, they can depolarize neurons. The convulsant drug bicuculline acts as a specific antagonist of GABA on its receptor site, while the convulsant drug picrotoxin binds to an adjacent site on the GABA-A receptor complex and

Folic Acid Psychotropic Drugs Decrease

Figure 2.12. Diagrammatic representation of the GABA-benzodiazepine supra-molecular complex. Compounds that increase inhibitory transmission may do so either by directly activating the GABA receptor site (e.g. muscimol) or by acting directly on the chloride ionophore (e.g. barbiturates). Benzodiazepines (e.g. diazepam) enhance the sensitivity of the GABA-A receptor to GABA. Compounds that decrease inhibitory transmission may do so by activating the picrotoxin site, which closes the chloride ionophore, or by blocking the GABA-A receptor.

Figure 2.12. Diagrammatic representation of the GABA-benzodiazepine supra-molecular complex. Compounds that increase inhibitory transmission may do so either by directly activating the GABA receptor site (e.g. muscimol) or by acting directly on the chloride ionophore (e.g. barbiturates). Benzodiazepines (e.g. diazepam) enhance the sensitivity of the GABA-A receptor to GABA. Compounds that decrease inhibitory transmission may do so by activating the picrotoxin site, which closes the chloride ionophore, or by blocking the GABA-A receptor.

directly decreases chloride ion flux; barbiturates have the opposite effect on the chloride channel and lock the channel open.

The inhibitory effect of GABA is mediated by the chloride ion channel (Figure 2.12). When the GABA-A receptor is activated by GABA or a specific agonist such as muscimol, the frequency of opening of the channel is increased and the cell is hyperpolarized. Barbiturates, such as phenobarbitone, and possibly alcohol, also facilitate the chloride ion influx, but these drugs increase the duration, rather than the frequency, of the channel opening. Recently, novel benzodiazepine receptor ligands have been produced which, like the typical benzodiazepines, increase the frequency of chloride channel opening. The cyclopyrrolone sedative/ hypnotic zopiclone is an example of such a ligand. Some glucocorticoids are also known to have sedative effects which may be ascribed to their ability to activate specific steroid receptor facilitatory sites on the GABA-A receptor.

In addition to the benzodiazepine receptor agonists which, depending on the dose administered, have anxiolytic, anticonvulsant, sedative and amnestic properties, benzodiazepines have also been developed which block the action of agonists on this receptor. Such antagonists may be exemplified by flumazenil. Other compounds have a mixture of agonist and antagonist properties and are termed partial agonists or antagonists. However, the complexity of the benzodiazepine receptor only became fully apparent recently when a series of compounds were discovered that had the opposite effects of the ''classic'' benzodiazepines when they activated the receptor. These inverse agonists were found to have anxiogenic, proconvulsant, stimulant, spasmogenic and promnestic properties in man and animals. Such compounds were found to decrease GABA transmission.

Naturally occurring inverse agonists called the b-carbolines have been isolated from human urine, but it now seems probable that these compounds are byproducts of the extraction procedure. Thus the benzodiazepine receptor is unique in that it has a bidirectional function. This may be of considerable importance in the design of benzodiazepine ligands which act as partial agonists (see Chapter 5). Such drugs may combine the efficacy of the conventional agents with a lack of unwanted side effects, such as sedation, amnesia and dependence. Partial inverse agonists have also been described. Such drugs appear to maintain the promnestic properties of the full inverse agonists without causing excessive stimulation and convulsions which can occur with full inverse agonists. The presence of a specific benzodiazepine site in the mammalian brain also raises the possibility that endogenous substances are present that modulate the activity of the site. While the precise identity of such natural ligands remains an enigma, there is evidence that substances like tribulin, nephentin and the diazepam-binding inhibitor could have a physiological and pathological function. There is also evidence that trace amounts of benzodiazepines (such as nordiazepine and lorazepam) occur in human brain, human breast milk and also in many plants, including the potato. Such benzodiazepines have been found in post-mortem brains from the 1940s and 1950s before the discovery of the benzodiazepine anxiolytics (see Chapter 19 for further details).

Modulation of GABA-A receptors

During brain development, the RNA expression of the sub-units which comprise the GABA-A receptor change so that each sub-unit exhibits a unique regional and temporal profile. Such changes may reflect the increase in the sensitivity of the foetal brain to GABA, and its decreased sensitivity to the benzodiazepines which indirectly enhance GABA-A receptor function. Thus during the later stages of development of the foetal brain, at a stage when the synapses are present, GABA acts as a neurotrophic factor that promotes neuronal growth and differentiation, synaptogenesis and the synthesis of GABA-A receptors. This may account for the increased sensitivity of these receptors to the actions of GABA as the concentration of the transmitter in the developing brain is relatively low. Thus as GABA has to diffuse to receptors which are relatively distant from the neurons from which it is released, the increased sensitivity of the GABA-A receptors ensures that they are activated even by a low concentration of the transmitter.

Changes have also been reported to occur in the sub-unit composition of the GABA-A receptor following chronic exposure to barbiturates, neurosteroids, ethanol and benzodiazepine agonists. These changes may underlie the development of tolerance, physical dependence and the problems which are associated with the abrupt withdrawal of such drugs.

Excitatory amino acid receptors: glutamate receptor

It has long been recognized that glutamic and aspartic acids occur in uniquely high concentrations in the mammalian brain and that they can cause excitation of nerve cells. However, these amino acids have only recently been identified as excitatory neurotransmitters because of the difficulty that arose in dissociating their transmitter from their metabolic role in the brain. For example, glutamate is an important component of brain proteins, peptides and a precursor of GABA. As a result of microdialysis and micro-iontophoretic techniques, in which the release and effect of local application could be demonstrated, and the synthesis and isolation of specific agonists for the different types of excitatory amino acid receptor (e.g. quisqualic, ibotenic and kainic acids), it is now generally accepted that glutamic and aspartic acids are excitatory transmitters in the mammalian brain.

Glutamate is uniformly distributed throughout the mammalian brain. Unlike the biogenic amine transmitters, glutamate has an important metabolic role as well as a neurotransmitter role in the brain being linked to the synthesis of GABA, where it acts as a precursor, and to the tricarboxylic acid cycle where it is metabolized to alpha-ketoglutaric acid. In nerve terminals, glutamate is stored in vesicles and released by calcium-dependent exocytosis. Specific glutamate transporters remove the amino acid from the synaptic cleft into both the nerve terminals and the surrounding glial cells.

Four main types of glutamate receptor have been identified and cloned. These are the ionotropic receptors (NMDA and alpha-amino-3-hydroxy-5-methylisoxazole, AMPA, and kainate types) and a group of metabotropic receptors of which eight types have been discovered. The AMPA and kainate receptors are involved in fast excitatory transmission whereas the NMDA receptors mediate slower excitatory responses and play a more complex role in mediating synaptic plasticity.

The ionotropic receptors have a pentameric structure. The most important of these, the NMDA receptors, are assembled from two sub-units, NRi and NR2, each of which can exist in different isoforms thereby giving rise to structurally different glutamate receptors in the brain. The functional significance of these different receptor types is presently unclear. The sub-units comprising the AMPA and kainate receptors, termed GluR1-7 and KA12 are closely related.

The NMDA receptors are unique among the ligand-gated cation channel receptors in that they are permeable to calcium but blocked by magnesium, the latter acting at a specific receptor site within the ion channel. The purpose of the voltage-dependent magnesium blockade of the ion channel is to permit the summation of excitatory postsynaptic potentials. Once these have reached a critical point, the magnesium blockade of the ion channel is terminated and calcium flows into the neuron to activate the calcium-dependent second messengers. Such a mechanism would appear to be particularly important for the induction of long-term potentiation, a process which underlies short-term memory formation in the hippocampus (Figure 2.13).

With regard to the action of psychotropic drugs on the NMDA receptors, there is evidence that one of the actions of the anticonvulsant lamotrigine is

Figure 2.13. Schematic model of the NMDA receptor. The flow of ions through the channel of the NMDA receptor can be regulated by a variety of factors. Glycine (Gly) and glutamate (Glu) must both bind to the NMDA receptor to cause opening of the ion channel. Polyamines bind to a distinct recognition site on the receptor to regulate the opening of the ion channel. Compounds such as MK-801 appear to bind in the open channel. At physiological concentrations of Mg++, the channel is blocked unless the membrane is depolarized. Zn++ also regulates the opening of the ion channel.

Figure 2.13. Schematic model of the NMDA receptor. The flow of ions through the channel of the NMDA receptor can be regulated by a variety of factors. Glycine (Gly) and glutamate (Glu) must both bind to the NMDA receptor to cause opening of the ion channel. Polyamines bind to a distinct recognition site on the receptor to regulate the opening of the ion channel. Compounds such as MK-801 appear to bind in the open channel. At physiological concentrations of Mg++, the channel is blocked unless the membrane is depolarized. Zn++ also regulates the opening of the ion channel.

to modulate glutamatergic function; the antidementia drug memantine also has similar action. Thus the therapeutic efficacy of some of the newer drugs used to treat epilepsy and Alzheimer's disease owe their efficacy to their ability to modulate a dysfunctional glutamatergic system.

Some of the hallucinogens related to the dissociation anaesthetic ketamine, such as phencyclidine, block the ion channel of the NMDA receptor. Whether the hallucinogenic actions of phencyclidine are primarily due to this action is uncertain as the putative anticonvulsant dizocilpine (MK 801) is also an NMDA ion channel inhibitor but is not a notable hallucinogen. Presumably the ability of phencyclidine to enhance dopamine release, possibly by activating NMDA heteroceptors on dopaminergic terminals, and also its action on sigma receptors which it shares with benzomorphan -like hallucinogens - contribute to its hallucinogenic activity.

In contrast to the ionotropic receptors, the metabotropic receptors are monomeric in structure and unique in that they show no structural similarity to the other G-protein-coupled neurotransmitter receptors. They are located both pre- and postsynaptically and there is experimental evidence that they are involved in synpatic modulation and excitotoxicity, functions which are also shared with the NMDA receptors. To date, no drugs have been developed for therapeutic use which are based on the modulation of these receptors.

The NMDA receptor complex has been extensively characterized and its anatomical distribution in the brain determined. The NMDA receptor is analogous to the GABA-A receptor in that it contains several binding sites, in addition to the glutamate site, whereby the movement of sodium and calcium ions into the nerve cell can be modulated.

These sites include a regulatory site that binds glycine, a site which is insensitive to the antagonistic effects of strychnine. This contrasts with the action of glycine on glycine receptors in the spinal cord where strychnine, on blocking the receptor, causes the characteristic tonic seizures.

In addition to the glutamate and glycine sites on the NMDA receptor, there also exist polyamine sites which are activated by the naturally occurring polyamines spermine and spermidine. Specific divalent cation sites are also associated with the NMDA receptor, namely the voltage-dependent magnesium site and the inhibitory zinc site. In addition to the excitatory amino acids, the natural metabolite of brain tryptophan, quinolinic acid, can also act as an agonist of the NMDA receptor and may contribute to nerve cell death at high concentrations.

Interest in the therapeutic potential of drugs acting on the NMDA receptor has risen with the discovery that epilepsy and related convulsive states may occur as a consequence of a sudden release of glutamate. Sustained seizures of the limbic system in animals result in brain damage that resembles the changes seen in glutamate toxicity. Similar changes are seen at autopsy in patients with intractable epilepsy. It has been shown that the non-competitive NMDA antagonists such as phencyclidine or ketamine can block glutamate-induced damage. The novel antiepileptic drug lamotrigine would also appear to act by this mechanism, in addition to its ability to block sodium channels, in common with many other types of antiepileptic drugs.

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer's disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future.

Nitric oxide - an important gaseous neurotransmitter

The discovery that mammalian cells generate nitric oxide (NO), a gas until recently considered to be an atmospheric pollutant, is providing new insights into a number of regulatory processes in the nervous system. There is evidence that NO is synthesized in the vascular epithelium where it is responsible for regulating the vascular tone of the blood vessels. When released from neurons in the brain, NO acts as a novel transmitter one of whose functions is in memory formation. In the periphery, the non-adrenergic non-cholinergic nerves synthesize and release NO which is responsible for neurogenic vasodilatation and the regulation of various gastrointestinal, respiratory and genitourinary tract functions. In addition, NO is also involved in platelet aggregation. These numerous actions of NO are attributed to its direct stimulatory action on soluble guanylate cyclase, thereby enabling it to act as a modulator of conventional neurotransmitters. In all tissues, NO is synthesized by the action of nitric oxide synthase on the amino acid arginine.

In the brain, nitric oxide synthase activity has been detected in all brain regions, the highest activity being located in the cerebellum. One of the main physiological roles of NO is in memory formation. There is evidence that in the hippocampus NO is released from postsynaptic sites to act on presynaptic neurons as a retrograde transmitter to release glutamate. This leads to a stable increase in synaptic transmission and forms the basis of long-term potentiation and the initiation of memory formation. Inhibition of nitric oxide synthase activity has been shown experimentally to impair memory formation. Other roles for NO include the development of the cortex and in vision where it assists in the transduction of light signals in the retinal photoreceptor cells. Other roles include feeding behaviour, nociception and olfaction. Recent evidence

Table 2.7. Nitric oxide and carbon monoxide as mediators

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