Abstract

Ethanol intoxication results partly from actions of ethanol at specific ligand-gated ion channels. One such channel is the GABA_A receptor complex, although ethanol's effects on GABA_A receptors are variable. For example, we found that hippocampal neurons from selectively bred mice and rats with high hypnotic sensitivity to ethanol have increased GABA_Areceptor-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 GABA_A receptor sensitivity to ethanol. We examined acute effects of ethanol on GABA_Areceptor-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^+/+). GABA_A 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 GABA_A 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 GABA_A receptor function and hypnotic sensitivity to ethanol.