Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKC epsilon

Several of the actions of ethanol are mediated by gamma-aminobutyrate type A (GABA(A)) receptors. Here we demonstrated that mutant mice lacking protei n kinase C epsilon (PKC epsilon) were more sensitive than wildtype litterma tes to the acute behavioral effects of ethanol and other drugs that alloste rically activate GABA(A) receptors. GABA(A) receptors in membranes isolated from the frontal cortex of PKC epsilon null mice were also supersensitive to allosteric activation by ethanol and flunitrazepam. In addition, these m utant mice showed markedly reduced ethanol self-administration. These findi ngs indicate that inhibition of PKC epsilon increases sensitivity of GABA(A ) receptors to ethanol and allosteric modulators. Pharmacological agents th at inhibit PKC epsilon may be useful for treatment of alcoholism and may pr ovide a non-sedating alternative for enhancing GABA(A) receptor function to treat other disorders such as anxiety and epilepsy.