Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala

doi:10.1073/pnas.0802302105

Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala

*Molecular and Integrative Neurosciences Department,
^‡Committee on Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;
^§Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, CA 94608; and
^¶Pearson Center for Alcoholism and Addiction Research, 10550 North Torrey Pines Road, La Jolla, CA 92037

Edited by Erminio Costa, University of Illinois, Chicago, IL, and approved April 23, 2008
↵ ^†M.B. and M.T.C. contributed equally to this work. (received for review March 6, 2008)

Abstract

In the central amygdala (CeA), ethanol acts via corticotrophin-releasing factor (CRF) type 1 receptors to enhance GABA release. Amygdala CRF mediates anxiety associated with stress and drug dependence, and it regulates ethanol intake. Because mutant mice that lack PKCε exhibit reduced anxiety-like behavior and alcohol consumption, we investigated whether PKCε lies downstream of CRF₁ receptors in the CeA. Compared with PKCε^+/+ CeA neurons, PKCε^−/− neurons showed increased GABAergic tone due to enhanced GABA release. CRF and ethanol stimulated GABA release in the PKCε^+/+ CeA, but not in the PKCε^−/− CeA. A PKCε-specific inhibitor blocked both CRF- and ethanol-induced GABA release in the PKCε^+/+ CeA, confirming findings in the PKCε^−/− CeA. These results identify a PKCε signaling pathway in the CeA that is activated by CRF₁ receptor stimulation, mediates GABA release at nerve terminals, and regulates anxiety and alcohol consumption.

Footnotes

^‖To whom correspondence should be addressed. E-mail: mroberto{at}scripps.edu
Author contributions: M.R. designed research; M.B., M.T.C., and M.R. performed research; M.B., M.T.C., G.R.S., R.M., and M.R. analyzed data; and G.R.S., R.M., and M.R. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0802302105/DCSupplemental.