Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKC
Clyde W. Hodge, Kristin K. Mehmert, Stephen P. Kelley, Thomas McMahon, Ashley Haywood, M. Foster Olive, Dan Wang, Ana Maria Sanchez-Perez
& Robert O. Messing
Department of Neurology and Ernest Gallo Clinic and Research Center, University of California San Francisco, 1001 Potrero Avenue; Building 1, Room 101, San Francisco, California 94110, USA
Several of the actions of ethanol are mediated by -aminobutyrate type A (GABAA) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKC) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABAA receptors. GABAA receptors in membranes isolated from the frontal cortex of PKC 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 PKC increases sensitivity of GABAA receptors to ethanol and allosteric modulators. Pharmacological agents that inhibit PKC may be useful for treatment of alcoholism and may provide a non-sedating alternative for enhancing GABAA receptor function to treat other disorders such as anxiety and epilepsy.
-aminobutyrate type A (GABAA) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKC
) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABAA receptors. GABAA receptors in membranes isolated from the frontal cortex of PKC
