RECEPTORS IN THE CENTRAL NERVOUS SYSTEM--BIOCHEMISTRY TO BEHAVIOR

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Benzodiazepines interact with a specific neuronal membrane receptor to initiate a series of neuronal events resulting in an enhancement of GABA-mediated chloride permeability. The latter results behaviorally in the major pharmacological actions of benzodiazepines, namely their anxiolytic, anticonvulsant, hypnotic and muscle relaxant actions. In addition to benzodiazepines, a variety of sedative/hypnotic agents of the minor tranquilizer class (e.g. the barbiturates) appear to interact with one or more components of the benzodiazepine/GABA receptor complex, and thus the latter has been proposed as a common site of minor tranquilizer action. Several aspects of the benzodiazepine/GABA receptor complex are currently being studies. Recent work has employed an in vitro system for measuring GABA receptor- effector coupling in a subcellular preparation from rat brain (the synaptoneurosome). This technique has greatly facilitated studies on the regulation of the GABA receptor-coupled chloride ion channel. Using this method, we have studied the interaction of ethanol with the GABA receptor complex and have found that ethanol, related short-chain alcohols and several anesthetic agents are capable of stimulating this receptor and at pharmacologically-relevant concentrations. In related studies we have identified a novel imidazobenzodiazepine, Ro15-4513, which blocks both the in vitro effects of ethanol on GABA receptor- mediated 36C1- uptake as well as many of the behavioral effects of ethanol. Chronic administration of ethanol to rats results in a decrease in GABA receptor-mediated 36Cl-uptake in synaptoneurosomes, an effect that is reversible since it is not observed after the ethanol withdrawal syndrome. In other studies we have examined the use of the radiolabelled benzodiazepine receptor antagonist Ro15-1788 for measuring benzodiazepine receptors in vivo. Our results have validated the suitability of this technique and have demonstrated significant effects of barbiturates, naturally-occurring steroid hormones, ethanol and "stress" on benzodiazepine receptors in vivo.