γ-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions

Abstract

γ-Aminobutyric acid A (GABA A) receptors are believed to mediate a number of alcohol's behavioral actions. Because the subunit composition of GABA A receptors determines receptor pharmacology, behavioral sensitivity to alcohol (ethanol) may depend on which subunits are present (or absent). A number of knock-out and/or transgenic mouse models have been developed (α1, α2, α5, α6, β2, β3, γ2S, γ2L, δ) and tested for behavioral sensitivity to ethanol. Here we review the current GABA A receptor subunit knock-out and transgenic literature for ethanol sensitivity, and integrate these results into those obtained using quantitative trait loci (QTL) analysis and gene expression assays. Converging evidence from these three approaches support the notion that different behavioral actions of ethanol are mediated by specific subunits, and suggest that new drugs that target specific GABA A subunits may selectively alter some behavioral actions of ethanol, without altering others. Current data sets provide strongest evidence for a role of α1-subunits in ethanol-induced loss of righting reflex, and α5-subunits in ethanol-stimulated locomotion. However, three-way validation is hampered by the incomplete behavioral characterization of many of the mutant mice, and additional subunits are likely to be linked to alcohol actions as behavioral testing progresses.