Conditional rescue of protein kinase C epsilon regulates ethanol preference and hypnotic sensitivity in adult mice.
Conventional gene targeting is a powerful tool to study the influence of specific genes on behavior. However, conclusions relevant for adult animals are limited by consequences of gene loss during development. Mice lacking protein kinase C epsilon (PKCepsilon) consume less alcohol and show greater acute sensitivity to alcohol than do wild-type mice. There are no selective inhibitors of PKCepsilon that can be administered systemically and cross the blood-brain barrier to test whether these phenotypes result from loss of PKCepsilon during development or in adulthood. Here we used conditional expression of PKCepsilon in the basal forebrain, amygdala, and cerebellum to rescue wild-type responses to alcohol in adult PKCepsilon(-/-) mice. Subsequent suppression of transgenic PKCepsilon restored PKCepsilon(-/-) behaviors. These findings establish that PKCepsilon signaling in the adult brain regulates alcohol consumption and sensitivity. If this extends to humans, then PKCepsilon inhibitors might prove useful as novel therapeutics for alcoholism.
Choi
Doo-Sup
DS
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
Wang
Dan
D
Dadgar
Jahan
J
Chang
Wesley S
WS
Messing
Robert O
RO
D000367:Age Factors; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics; D000679:Amygdala / Q000201:enzymology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002531:Cerebellum / Q000201:enzymology; D002755:Choice Behavior / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000201:enzymology; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D019076:Transgenes / Q000187:drug effects
D007527:Isoenzymes; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D004318:Doxycycline