Several of the actions of ethanol are mediated by γ-aminobutyrate type A (GABA A) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKCε) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABA A receptors. GABA A receptors in membranes isolated from the frontal cortex of PKCε null mice were also supersensitive to allosteric activation by ethanol and flunitrazepam. In addition, these mutant mice showed markedly reduced ethanol self-administration. These findings indicate that inhibition of PKCε increases sensitivity of GABA A receptors to ethanol and allosteric modulators. Pharmacological agents that inhibit PKCε may be useful for treatment of alcoholism and may provide a non-sedating alternative for enhancing GABA A receptor function to treat other disorders such as anxiety and epilepsy.