Chronic binge drinking negatively impacts public health and is a leading cause of preventable deaths. In addition, alcohol disrupts daily rhythms, physiological processes, and reduces expression of circadian genes, which continues into sobriety and contributes to the likelihood of relapse. Circadian genes not only regulate sleep-wake cycles, they also regulate expression of genes important for cell signaling, immune function, metabolism, and neurotransmission (all of which are altered with alcohol). We tested whether apremilast treatment in mice could reduce binge drinking and ameliorate the effects of chronic drinking on expression of circadian genes in the ventral tegmental area (a brain region important for motivating behavior and circadian rhythms). Apremilast is a phosphodiesterase type 4 (PDE4) inhibitor, and previous work has shown that PDE4 inhibitors increase levels of cyclic adenosine monophosphate (cAMP) and expression of circadian genes. Therefore, we hypothesize that apremilast will reduce drinking and increase circadian gene expression. Male and female High Drinking in the Dark mice were allowed to binge drink for 6 weeks. During weeks 7 and 8, mice received apremilast (40mg/kg) or vehicle treatment prior to drinking. After the final day of drinking, mice were euthanized at zeitgeber time (ZT) 3 or ZT 15, to account for the peaks and troughs of circadian rhythms (n=11-12/sex/treatment/ZT). We found that apremilast treatment robustly reduced binge drinking in weeks 7 and 8, as compared with vehicle. Data collection is currently underway to measure circadian gene expression. Results of this experiment will tell us whether pharmacologically targeting PDE4 can reduce the effects of harmful drinking on circadian rhythms.
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"Effects of Apremilast on Binge Drinking and Circadian Gene Expression in High Drinking in the Dark Mice,"
PSU McNair Scholars Online Journal:
1, Article 5.