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.
Bajo
Michal
M
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.
Cruz
Maureen T
MT
Siggins
George R
GR
Messing
Robert
R
Roberto
Marisa
M
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