Deletion ofPrkczIncreases Intermittent Ethanol Consumption in Mice

Abstract

Background Prkcz has been identified as a gene whose expression is positively correlated with ethanol consumption in mice and is also induced by ethanol. Two proteins are produced from Prkcz: protein kinase M zeta (PKMζ), which is expressed in the nervous system and protein kinase C zeta (PKCζ), which is expressed in other tissues. We examined Prkcz−/− mice that lack PKCζ and PKMζ to investigate the role of this gene in behavioral responses to ethanol. Methods Male Prkcz−/− and wild-type littermates were tested for ethanol consumption using four procedures: 24-hour intermittent access, 4-hour limited intermittent access, 4-day drinking-in-the-dark (DID), and 24-hour continuous access. We also assessed the acute hypnotic effect of ethanol, ethanol reward, and taste preference for sweet-, bitter-, salty-, and umami-flavored solutions. Finally, we determined whether ethanol could increase PKMζ and PKCζ transcripts and protein expression in wild-type mice using quantitative PCR and western blot analysis. Results Prkcz−/− mice consumed more ethanol than their wild-type littermates in both intermittent access procedures, but not in the DID or 24-hour continuous access procedures. Ethanol exposure increased Prkcz transcripts in cultured PC12 cells and intermittent ethanol consumption increased PKMζ protein in the ventral striatum of wild-type mice. Conclusions Absence of PKMζ in the brain is associated with increased ethanol intake during procedures that incorporate intermittent consumption sessions every other day. Our data suggest that ethanol induces PKMζ, which acts in a negative feedback loop to limit binge-like ethanol consumption.

Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice

“…Alcohol intake was compared under continuous access two-bottle choice conditions for 4 days at each concentration as described (Lee et al 2013). Analysis of ethanol consumption revealed a main effect of concentration ( F (4,76) * = 18.6, p < 0.001) and interaction ( F (4,84) * = 6.9, p < 0.001), but no significant main effect of genotype (Fig.…”

“…In order to determine if any of the novelty seeking measures correlated with ethanol drinking (Manzo et al 2014; Parkitna et al 2013), mice from the first two (of four) cohorts that underwent the novelty seeking battery ( n = 8 WT, n = 9 ob/ob) were singly housed, then exposed to ethanol in a continuous access two-bottle choice paradigm as described (Lee et al 2013). Mice had access to food at all times and were exposed to each concentration of ethanol (3, 6, 10, 14, and 20 %) in ascending order for 4 days each.…”

Molecular mechanisms underlying alcohol-drinking behaviours

“…The expression of PKMζ, which is an isoform of PKC, is increased in the NAc of mice in response to consumption of alcohol and a period of 24 hours of withdrawal, and global knockout of Prkcz (which encodes PKMζ) in mice increases alcohol intake in models of excessive alcohol intake (20%IA2BC and 20%LA paradigms) 130 . The biological function of PKMζ in the CNS is a matter of controversy 131, 132 , and the possibility that this kinase contributes to stop mechanisms should be further explored.…”

Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice

“…The ethanol-induced loss of the righting reflex was examined as described in prior work (Choi et al, 2002, Hodge et al, 1999, Lee et al, 2014, Wallace et al, 2007). …”