Deletion of the α1 or β2 subunit of GABAA receptors reduces actions of alcohol and other drugs

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 (alpha(1) and beta(2)) subunits of GABA(A) receptor in sedative drug action by studying mice lacking these two subunits. Both alpha(1) (-/-) and beta(2) (-/-) 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 beta-selective drug etomidate was decreased only in beta(2) (-/-) knockout mice. In contrast, alpha(1) (-/-) mice were more resistant to the alpha(1)-selective drug zolpidem than beta(2) (-/-) 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 alpha(1) or beta(2) subunits reduced the muscimol-stimulated Cl-36(-) 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 alpha(1) or beta(2) subunits 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.