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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 11, 2003; DOI: 10.1124/jpet.102.048124

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Vol. 305, Issue 2, 600-607, May 2003

Deletion of GABAA Receptor alpha 1 Subunit-containing Receptors Alters Responses to Ethanol and Other Anesthetics

J. E. Kralic , M. Wheeler, K. Renzi, C. Ferguson, T. K. O'Buckley, A. C. Grobin, A. L. Morrow and G. E. Homanics

Departments of Pharmacology (J.E.K., A.L.M.) and Psychiatry (A.C.G., A.L.M.), Bowles Center for Alcohol Studies (J.E.K., T.K.O., A.L.M.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Departments of Anesthesiology (M.W., K.R., C.F., G.E.H.) and Pharmacology (G.E.H.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

GABAA receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of alpha 1 subunit-containing receptors. The objective of this study was to determine the contribution of alpha 1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABAA receptor alpha 1 subunit knockout mice. Deletion of alpha 1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following alpha 1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl- uptake were unaltered in alpha 1-/- mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in alpha 1-/- mice. Thus, GABAA receptor alpha 1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABAA receptor subtypes or other targets altogether.

0022-3565/03/3052-0600$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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