Received for publication April 14, 2006.
Revised June 15, 2006.
Accepted for publication June 15, 2006.

Knock-in mice with ethanol-insensitive alpha1-containing GABA_A receptors display selective alterations in behavioral responses to ethanol

Abstract

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 -aminobutyric acid 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 alpha1 subunit of the GABA_A-R is the most abundant alpha 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 alpha1 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 knock-in 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 alpha1 subunit are important for specific ethanol-induced behavioral effects.

Key words: GABA, alcohol, electrophysiology, ethanol, gene knock-in, mutant mice

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