Knockout mice and isozyme-selective peptide inhibitors have been also useful in identifying roles for PKC isozymes in effects of ethanol in vivo. Thus, ethanol-induced dopamine release in the NAc appears to require PKCε as it is attenuated in PKCε knockout mice.196 Acute ethanol treatment increases glycine currents in rat VTA neurons; a peptide inhibitor of PKCε reduces this effect.197 Acute ethanol exposure also potentiates GABAA receptor-mediated inhibitory postsynaptic currents in hippocampal pyramidal cells, an effect that is increased in neurons from PKCε knockout mice and abolished in neurons from PKCγ knockout mice.198 PKCγ can be co-immunoprecipitated with α1 and α4 GABAA receptor subunits,199 suggesting that PKCγ interacts directly with GABAA receptors to mediate its effect on receptor function. The PKCγ substrates that mediate this response are not known. On the other hand, PKCε regulates GABAA receptor function by phosphorylating γ2 subunits of synaptic receptors at Ser-327, which results in a diminished enhancement of GABA-stimulated current by ethanol.200
