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Vol. 304, Issue 1, 30-36, January 2003

Deletion of the alpha 1 or beta 2 Subunit of GABAA Receptors Reduces Actions of Alcohol and Other Drugs

Yuri A. Blednov, S. Jung, H. Alva, D. Wallace, T. Rosahl, P.-J. Whiting and R. Adron Harris

Waggoner Center for Alcohol and Addiction Research and Section of Neurobiology, University of Texas at Austin, Austin, Texas (Y.A.B., S.J., H.A., D.W., R.A.H.); and Neuroscience Research Center, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, United Kingdom (T.R., P.-J.W.).

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 (alpha 1 and beta 2) subunits of GABAA 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 GABAA 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 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 alpha 1 or beta 2 subunits 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.

0022-3565/03/3041-0030$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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