The circadian Per1 and Per2 genes influence alcohol reinforcement, and blood alcohol levels

Background: Perturbations in the function of core circadian clock components such as the Period (Per) family of genes are associated with alcohol use disorder, and disruptions in circadian cycles may contribute to alcohol abuse and relapse. This study tested ethanol consumption, reinforcement, and metabolism in mice containing functional mutations in Per1 and/or Per2 genes on an ethanol-preferring background, C57BL/6J mice. Methods: Mice were tested in: (A) free-access intake with ascending concentrations of ethanol (2-16%, v/v), (B) conditioned place preference using ethanol (2 g/kg for males; 2.5 g/kg for females) vs. saline injections, (C) recovery of the righting reflex following a 4 g/kg bolus of ethanol, and (D) blood ethanol levels 1 h after a 2 g/kg bolus of ethanol. Results: All Per mutant (mPer) mice showed increased ethanol intake and condition place preference compared to controls. There were also genotypic differences in blood ethanol concentration: in males, only mPer1 mice showed a significantly higher blood ethanol concentration than WT mice, but in females, all mPer mice showed higher blood ethanol levels than WT mice. Conclusions: Mutation of either Per1 or Per2, as well as mutations of both genes, increases ethanol intake and reinforcement in an ethanol-preferring mouse model. In addition, this increase in ethanol seeking behavior seems to result both from a change in ethanol metabolism and a change in reward responding to ethanol, but not from any change in sensitivity to ethanol's sedating effects. (C) 2013 Elsevier B.V. All rights reserved.