The role of Phosphodiesterase type 4 in ethanol drinking

项目总结

Project Summary Alcohol Use Disorders (AUD) have a devastating impact on individuals and their families, and exert a high cost to society. Of the >88,000 annual deaths attributed to alcohol use, approximately half are due to binge drinking, making it the third leading cause of preventable death in the United States. Binge drinking is a strong predictor of AUD diagnosis and is associated with deleterious health consequences, including dysregulated sleep/wake patterns and drastic changes in biological and circadian rhythms. Changes in these patterns, such as mutations in circadian genes, are associated with both increased ethanol intake and the motivation to consume ethanol. To help treat individuals with AUDs, our research focuses on understanding molecular determinants of binge drinking and the motivation to drink ethanol. The goal of this application is to test the importance of phosphodiesterase 4 (PDE4) as a molecular determinant in 1) the regulation of circadian genes following chronic ethanol intake and 2) the motivational aspects of binge-like ethanol drinking. PDE4 inhibits the activity of cyclic-AMP (cAMP), an important second messenger for both circadian- and motivation-related cell signaling events. Pharmacotherapies which inhibit PDE4, such as apremilast (which is FDA approved to treat psoriasis), have proven efficacious in reducing binge-like ethanol intake and ethanol preference, suggesting a high translational value in the treatment of AUD. We have recently shown that two PDE4 inhibitors (rolipram and apremilast) reduce binge-like drinking in 3 high drinking strains of mice. Moreover, apremilast reduced binge drinking when administered directly in the nucleus accumbens (NAc), a brain region central to ethanol reinforcement. PDE4 inhibitors are also known to increase the amplitude of circadian gene expression, suggesting therapeutic potential in rescuing the maladaptive loss of rhythmic circadian gene expression following chronic ethanol drinking. Therefore, we propose to test whether the PDE4 inhibitor, apremilast, can rescue the reduction in circadian gene expression in the NAc following chronic binge-like ethanol drinking. Further, we will test whether apremilast treatment reduces the reinforcing effects of ethanol in mice using operant self-administration. This approach directly tests a major component of human AUDs; the motivation to drink. In changes the progressive inhibition components aim 1, we will determine whether treatment with apremilast ameliorates ethanol-induced in rhythmic circadian gene expression in the NAc. In aim 2, we will t est whether apremilast educes reinforcing and motivational effects of alcohol hrough the use of operant self-administration on a order of reinforcement . These studies have the potential to determine mechanisms by which PDE4 decreases drinking behaviors and rescues maladaptive circadian gene changes, important of alcohol use with face validity in human AUDs. r t