Abstract

Enhancement of the activation of GABA_A receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABA_A receptor complex is a molecular target for these drugs in the mammalian central nervous system. We set out to elucidate the role of the two predominant (α₁ and β₂) subunits of GABA_A receptor in sedative drug action by studying mice lacking these two subunits. Both α₁ (−/−) and β₂ (−/−) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABA_A agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time induced by the β-selective drug etomidate was decreased only in β₂ (−/−) knockout mice. In contrast, α₁ (−/−) mice were more resistant to the α₁-selective drug zolpidem than β₂ (−/−) or wild-type animals. Knockout mice of both strains were similar to wild-type mice in their responses to pentobarbital. The duration of loss of the righting reflex produced by ethanol was decreased in male mice for both null alleles compared with wild-type mice, but there were no differences in ethanol-induced sleep time in mutant females. Deletion of either the α₁ or β₂ subunits reduced the muscimol-stimulated ³⁶Cl⁻ influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABA_A receptors. Our results show that removal of either α₁ or β₂subunits of GABA_A receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABA_A receptor in mechanisms mediating sedative/hypnotic effects.