Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol inPKC epsilon-deficient mice

There is increasing evidence that individual protein kinase C (PKC) isozyme s mediate specific effects of ethanol on the nervous system. In addition, m ultiple lines of evidence suggest that the mesoaccumbens dopamine reward sy stem is critically involved in the rewarding and reinforcing effects of eth anol. Yet little is known about the role of individual PKC isozymes in etha nol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKC epsilon ) show reduced operant ethanol self-administration and an absence of ethano l-induced increase in extracellular dopamine levels in the nucleus accumben s. PKC epsilon null mice exhibited a 53% decrease in alcohol-reinforced ope rant responses under basal conditions, as well as following ethanol depriva tion. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKC epsilon null mice demon strated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis exper iments showed that, in contrast to wild-type mice, PKC epsilon null mice ex hibited no change in extracellular levels of dopamine in the nucleus accumb ens following acute administration of ethanol (1 and 2 g/kg i.p.), while me solimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (1 00 mm) in these mice were comparable with that of wild-types. These data pr ovide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKC epsilon may be useful in the treatmen t of alcohol dependence.