Circadian clock genesBmal1andPer2in the nucleus accumbens are negative regulators of alcohol-drinking behavior in mice

Abstract

ABSTRACTVoluntary alcohol consumption is influenced by a variety of environmental and genetic factors, including circadian clock genes. Even though their sex-specific role in alcohol drinking was identified through selective ablation ofBmal1andPer2from neurons of the mouse striatum, the contribution of specific striatal subregions to the observed drinking behavior remains unclear. Thus, alcohol intake and preference was investigated in male and female mice with a conditional knockout ofBmal1andPer2from cells in the nucleus accumbens (Nac). Mood- and anxiety-related behaviors were assessed prior to alcohol drinking to exclude potential confounding effects of the animal’s behavioral state on alcohol consumption. Alcohol consumption and preference were increased in male and female mice with a conditional knockout ofBmal1, whereas the same effect was only found in males with a deletion ofPer2. Because affective behaviors were only mildly influenced by the conditional gene knockouts, observed alcohol-drinking phenotypes can be directly associated with the Nac-specific clock gene deletion. The results thus suggest an inhibitory role ofBmal1andPer2in the Nac on alcohol consumption in male mice. In females, the inhibitory effect ofBmal1is strictly localized to the Nac, because striatal-wide deletion ofBmal1caused a suppression of alcohol consumption. This sex-dependent stimulatory effect ofBmal1on alcohol drinking is probably mediated through other striatal subregions such as the dorsal striatum.