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0026-895X/97/040588-09$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 51:588-596 (1997).

Gene Knockout of the alpha 6 Subunit of the gamma -Aminobutyric Acid Type A Receptor: Lack of Effect on Responses to Ethanol, Pentobarbital, and General Anesthetics

Gregg E. Homanics, Carolyn Ferguson, Joseph J. Quinlan, Jodi Daggett, Kimberly Snyder, Carl Lagenaur, Zhi-Ping Mi, Xiao-Hui Wang, Dennis R. Grayson, and Leonard L. Firestone

Departments of Anesthesiology/Critical Care Medicine (G.E.H., C.F., J.J.Q., J.D., K.S., L.L.F.) and Neurobiology (C.L., Z.-P.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and Neurosciences Research Center, Allegheny-Singer Research Institute, and Departments of Psychiatry and Neurobiology and Anatomy, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212 (X.-H.W., D.R.G.)

The alpha 6 subunit of the gamma -aminobutyric acid type A receptor (GABAA-R) has been implicated in mediating the intoxicating effects of ethanol and the motor ataxic effects of general anesthetics. To test this hypothesis, we used gene targeting in embryonic stem cells to create mice lacking a functional alpha 6 gene. Homozygous mice are viable and fertile and have grossly normal cerebellar cytoarchitecture. Northern blot and reverse transcriptase-polymerase chain reaction analyses demonstrated that the targeting event disrupted production of functional alpha 6 mRNA. Autoradiography of histological sections of adult brains demonstrated that diazepam-insensitive binding of [3H]Ro15-4513 to the cerebellar granule cell layer of wild-type mice was completely absent in homozygous mice. Cerebellar GABAA-R density was unchanged in the mutant mice; however, the apparent affinity for muscimol was markedly reduced. Sleep time response to injection of ethanol after pretreatment with vehicle or Ro15-4513 did not differ between genotypes. Sleep time response to injection of pentobarbital and loss of righting reflex and response to tail clamp stimulus in mice anesthetized with volatile anesthetics also did not differ between genotypes. Thus, the alpha 6 subunit of the GABAA-R is not required for normal development, viability, and fertility and does not seem to be a critical or unique component of the neuronal pathway mediating the hypnotic effect of ethanol and its antagonism by Ro15-4513 in mice. Similarly, the alpha 6 subunit does not seem to be involved in the behavioral responses to general anesthetics or pentobarbital.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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