Creating teetotaler mice

The GABA_A receptor mediates the sedative and anxiety-reducing effects of ethanol. Although ethanol can potentiate GABA_A receptor function, the effects are variable, and it has been suggested that the receptor's sensitivity to ethanol may depend on its phosphorylation state. In this issue (pages 997–1002), Hodge and colleagues show that one isoform of protein kinase C (PKCε) mediates both the behavioral and biochemical response to ethanol by phosphorylation of the GABA_A receptor. The authors found that mutant mice lacking PKCε show markedly reduced ethanol self-administration compared to wild-type mice, and are much more sensitive to the acute behavioral effects of ethanol. Biochemically, these effects are associated with an increased GABA_A receptor sensitivity. Because the mutant mice consume less ethanol, the authors suggest that inhibitors of PKCε may be useful for treating alcoholism. Interestingly, the mutants also showed normal locomotor activity and did not appear to be sleepy or sedated. Inhibitors of PKCε could therefore also be a non-sedating alternative to enhance GABA_A function when treating disorders such as anxiety or epilepsy.