PT  - JOURNAL ARTICLE
AU  - Yuri A. Blednov
AU  - S. Jung
AU  - H. Alva
AU  - D. Wallace
AU  - T. Rosahl
AU  - P.-J. Whiting
AU  - R. Adron Harris
TI  - Deletion of the α1 or β2 Subunit of GABA<sub>A</sub>Receptors Reduces Actions of Alcohol and Other Drugs
AID  - 10.1124/jpet.102.042960
DP  - 2003 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 30--36
VI  - 304
IP  - 1
4099  - http://jpet.aspetjournals.org/content/304/1/30.short
4100  - http://jpet.aspetjournals.org/content/304/1/30.full
SO  - J Pharmacol Exp Ther2003 Jan 01; 304
AB  - Enhancement of the activation of GABAA receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABAA 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 GABAA 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 GABAA 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 GABAA receptors. Our results show that removal of either α1 or β2subunits of GABAA receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABAA receptor in mechanisms mediating sedative/hypnotic effects. The American Society for Pharmacology and Experimental Therapeutics