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NEUROPHARMACOLOGY

Knockin Mice with Ethanol-Insensitive 1-Containing -Aminobutyric Acid Type A Receptors Display Selective Alterations in Behavioral Responses to Ethanol

Departments of Pharmacology (D.F.W., G.E.H.) and Anesthesiology (G.E.H.), University of Pittsburgh, Pittsburgh, Pennsylvania; Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, Texas (Y.A.B., C.M.B., R.A.H.); Departments of Physiology and Pharmacology (O.J.A., Y.S., E.L., J.L.W.) and Program in Neuroscience (J.L.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Psychology, University of Memphis, Memphis, Tennessee (R.B.B., D.B.M.); C.V. Starr Laboratory for Molecular Neuropharmacology, Departments of Anesthesiology and Pharmacology, Weill Medical College, Cornell University, New York, New York (N.L.H.)

Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABA_A-Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The 1 subunit of the GABA_A-R is the most abundant subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an 1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the 1 subunit are important for specific ethanol-induced behavioral effects.

Address correspondence to: Dr. Gregg E. Homanics, University of Pittsburgh, Department of Anesthesiology, W1356 Biomedical Science Tower, Pittsburgh, PA 15261. E-mail: homanicsge{at}anes.upmc.edu

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