Rev-erb alpha Knockout Reduces Ethanol Consumption and Preference in Male and Female Mice

Alcohol use is a contributor in the premature deaths of approximately 3 million people annually. Among the risk factors for alcohol misuse is circadian rhythm disruption; however, this connection remains poorly understood. Inhibition of the circadian nuclear receptor REV-ERB alpha is known to disrupt molecular feedback loops integral to daily oscillations, and impact diurnal fluctuations in the expression of proteins required for reward-related neurotransmission. However, the role of REV-ERB alpha in alcohol and substance use-related phenotypes is unknown. Herein, we used a Rev-erb alpha knockout mouse line and ethanol two-bottle choice preference testing to show that disruption of Rev-erb alpha reduces ethanol preference in male and female mice. Rev-erb alpha null mice showed the lowest ethanol preference in a two-bottle choice test across all genotypes, whereas there were no ethanol preference differences between heterozygotes and wildtypes. In a separate experiment, alcohol-consuming wildtype C57B1/6N mice were administered the REV-ERB alpha/beta inhibitor SR8278 (25 mg/kg or 50 mg/kg) for 7 days and alcohol preference was evaluated daily. No differences in alcohol preference were observed between the treatment and vehicle groups. Our data provides evidence that genetic variation in REV-ERB alpha may contribute to differences in alcohol drinking.