Deletion of the α1 or β2 Subunit of GABA_AReceptors Reduces Actions of Alcohol and Other Drugs

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

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

“…While the finding of gender difference in this study is not clear, it should be noted here that this is not uncommon in animals (eg, Blednov et al 36 ) and human studies (eg, Bell et al 44 ). Nevertheless, this should be interpreted with caution as such difference may be caused by biased sampling or simply, a matter of chance.…”

“…An observation worth mentioning here is that, while there was no difference of pentobarbital action between wild types and the b2À/À and a1À/À mice, the duration of loss of righting reflex produced by ethanol was decreased in male mice for both null types; no differences were observed in ethanol-induced sleep in female mice. 36 These suggest that some genetic effects of the GABA subunit genes can be gender specific. Unfortunately, none of these animal studies examined substance addiction behavior directly.…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…The results from our sleep time study, together with the results from the motor activity analysis, lend credence the notion that a decrease in β2 protein expression translates to a functional loss of the GABA A receptor activity. Blednov et al (2003) showed a significant decrease in etomidateinduced sleep times in β2 knockout mice when compared to wild-type mice, although another study did not observe this effect (O'Meara et al, 2004). The reasons for the discrepancy between the studies are unclear but might be related to differences in the doses and route of administration and dose (40 mg/kg intraperitoneal vs. 5-5 mg/kg intravenous).…”

Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

“…deletions of particular GABA A receptor subunits (Blednov et al, 2003;Kralic et al, 2003). To address this possibility and confirm that DKO mice did not show increased sleep time after activation of GABA A receptors, we measured sleep time after administration of THIP, a direct agonist of the GABA A receptor.…”