Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala.
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 PKCepsilon exhibit reduced anxiety-like behavior and alcohol consumption, we investigated whether PKCepsilon lies downstream of CRF(1) receptors in the CeA. Compared with PKCepsilon(+/+) CeA neurons, PKCepsilon(-/-) neurons showed increased GABAergic tone due to enhanced GABA release. CRF and ethanol stimulated GABA release in the PKCepsilon(+/+) CeA, but not in the PKCepsilon(-/-) CeA. A PKCepsilon-specific inhibitor blocked both CRF- and ethanol-induced GABA release in the PKCepsilon(+/+) CeA, confirming findings in the PKCepsilon(-/-) CeA. These results identify a PKCepsilon signaling pathway in the CeA that is activated by CRF(1) receptor stimulation, mediates GABA release at nerve terminals, and regulates anxiety and alcohol consumption.
Molecular and Integrative Neurosciences Department, Committee on Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Michal
M
Bajo
Maureen T
MT
Cruz
George R
GR
Siggins
Robert
R
Messing
Marisa
M
Roberto
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001007:Anxiety / Q000201:enzymology* / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000502:physiology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D051744:Protein Kinase C-epsilon