PROJECT 3: Animal model of sex differences in stress-related cellular function in alcohol use disorder

PROJECT 3 ABSTRACT The role of Project 3 is to identify and translate the neurobiological mechanisms underlying the ‘dark side of addiction’ studied across Projects 1 and 2. Problematic alcohol use continues to increase, with stress and negative emotions playing a particularly influential role in women. Understanding the neural pathways involved in negative reinforcement drinking (NRD) is therefore a public health priority. We have developed and validated a paradigm for evaluating NRD in mice in a modified “drinking-in-the-dark” (DiD) protocol. Both male and female mice escalate ethanol (EtOH) intake and preference over time in this paradigm. In addition, we have found that exposure to a physical stressor coupled with repeated exposure to the previously stress- paired environment induces stress-induced binge-drinking in female, but not male, mice. A common intracellular signaling pathway underlying effects of alcohol, stress and neuroinflammation is the cAMP pathway. Emerging studies in animal models and human clinical subjects have demonstrated beneficial effects of blocking cAMP breakdown using the phosphodiesterase 4 inhibitor Apremilast on alcohol intake. Our preliminary studies in mice show promising results indicating that Apremilast decreases EtOH intake as well as the stress-induced binge escalation seen in female mice. We propose to determine the effect of PDE4 inhibition on interactions between stress and ethanol intake in male and female mice, to identify downstream signaling pathways recruited by PDE4 inhibition that regulate alcohol drinking and to determine whether increasing cAMP signaling through a GLP1 agonist can mimic the effects of PDE4 inhibition in the stress- induced alcohol drinking paradigm in male and female mice. These studies will support the identification of pathways important for effects of stress on alcohol-related behaviors, potentially aiding in development of novel medications and combinations thereof that will be particularly effective in helping women quit drinking.