Abstract
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.
Footnotes
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The financial support of Department of Veterans Affairs-Merit Review to T.V.D. and W.R.P.; National Institutes of Health (NIH) Grant AA03527 to T.V.D., W.R.P., J.M.W. and B.J.B.; NIH Grant AA11275 to J.M.W. and B.J.B.; NIH Grant AA00141 and a Research Career Award to J.M.W; and NIH Grant AA13588 to R.O.M. is acknowledged.
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DOI: 10.1124/jpet.102.045450
- Abbreviations:
- IPSC
- inhibitory postsynaptic current
- LORR
- loss of righting reflex
- PKCγ+/+ and PKCγ−/−
- wild-type and null mutant mouse lines for the γ-protein kinase C isoform
- PKCε+/+ and PKCε−/−
- wild-type and null mutant mouse lines for the ε-protein kinase C isoform
- aCSF
- artificial cerebrospinal fluid
- DNQX
- 6,7-dinitroquinoxaline-2,3-dione
- APV
- dl-(−)-2-amino-5-phosphonovaleric acid
- CGP 35348
- (3-aminopropyl)(diethoxymethyl)phosphinic acid
- Received October 9, 2002.
- Accepted December 17, 2002.
- U.S. Government
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