RT Journal Article SR Electronic T1 Ethanol Differentially Enhances Hippocampal GABAAReceptor-Mediated Responses in Protein Kinase Cγ (PKCγ) and PKCε Null Mice JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 264 OP 270 DO 10.1124/jpet.102.045450 VO 305 IS 1 A1 W. R. Proctor A1 W. Poelchen A1 Barbara J. Bowers A1 Jeanne M. Wehner A1 R. O. Messing A1 T. V. Dunwiddie YR 2003 UL http://jpet.aspetjournals.org/content/305/1/264.abstract AB Ethanol intoxication results partly from actions of ethanol at specific ligand-gated ion channels. One such channel is the GABAA receptor complex, although ethanol's effects on GABAA receptors are variable. For example, we found that hippocampal neurons from selectively bred mice and rats with high hypnotic sensitivity to ethanol have increased GABAAreceptor-mediated synaptic responses during acute ethanol treatment compared with mice and rats that display low behavioral sensitivity to ethanol. Here we investigate whether specific protein kinase C (PKC) isozymes modulate hypnotic and GABAA receptor sensitivity to ethanol. We examined acute effects of ethanol on GABAAreceptor-mediated inhibitory postsynaptic currents (IPSCs) in mice lacking either PKCγ (PKCγ−/−) or PKCε (PKCε−/−) isozymes and compared the results to those from corresponding wild-type littermates (PKCγ+/+ and PKCε+/+). GABAA receptor-mediated IPSCs were evoked in CA1 pyramidal neurons by electrical stimulation in stratum pyramidale, and the responses were recorded in voltage-clamp mode using whole-cell patch recording techniques. Ethanol (80 mM) enhanced the IPSC response amplitude and area in PKCγ+/+mice, but not in the PKCγ−/− mice. In contrast, ethanol markedly potentiated IPSCs in the PKCε−/− mice, but not in PKCε+/+ littermates. There was a positive correlation between ethanol potentiation of IPSCs and the ethanol-induced loss of righting reflex such that mice with larger ethanol-induced increases in GABAA receptor-mediated IPSCs also had higher hypnotic sensitivity to ethanol. These results suggest that PKCγ and PKCε signaling pathways reciprocally modulate both ethanol enhancement of GABAA receptor function and hypnotic sensitivity to ethanol. U.S. Government