Abstract
Several of the actions of ethanol are mediated by γ-aminobutyrate type A (GABAA) 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 GABAA receptors. GABAA 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 GABAA 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 GABAA receptor function to treat other disorders such as anxiety and epilepsy.
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Acknowledgements
This work was supported by funds from the State of California for Alcohol and Drug Abuse Research to C.W.H. and R.O.M. and by a grant from the Alcoholic Beverage Medical Research Foundation to C.W.H.
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Hodge, C., Mehmert, K., Kelley, S. et al. Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε. Nat Neurosci 2, 997–1002 (1999). https://doi.org/10.1038/14795
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DOI: https://doi.org/10.1038/14795
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