It is currently believed that the interaction of benzodiazepines with a specific neuronal membrane receptor initiates 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 studied, including purification of the receptor, characterization of multiple binding sites on the receptor complex which recognizes agonist, antagonists or inverse agonists. Recent work has focused on using 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 barbiturate and GABA receptor-mediated chloride flux and has resulted in the first reliable method for studying the function of the GABA receptor in vitro. Using this method we have studied the interaction of the popular anxiolytic/intoxicant ethyl alcohol with the GABA receptor complex and have found that ethanol and all short-chain alcohols tested are capable of stimulating this receptor and at low pharmacologically-relevant concentrations. In related studies we have identified a novel imidazobenzodiazepine, Ro15,45l3, which blocks both the in vitro effects of ethanol on GABA receptor-mediated 36Cl-uptake as well as many of the behavioral effects of ethanol. 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, ethanol, and """"""""stress"""""""" on benzodiazepine receptors in vivo.
