GABA receptors
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, derivativesof 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 GABAA 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 anddirectly 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 . 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 byflumazenil. 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. 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 .
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 thedeveloping 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.
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, derivativesof 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 GABAA 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 anddirectly 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 . 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 byflumazenil. 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. 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 .
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 thedeveloping 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.
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