Abstract Alcohol use disorder (AUD) is a heterogeneous condition resulting from the interplay of neurobiological, genetic, and environmental factors. There is pressing need to develop new and, potentially, broadly effective medications. Alcohol is a highly pro-inflammatory molecule, which is key in the pathogenesis of alcohol- induced tissue damage. Work by the applicants and collaborators has identified 3 candidate drugs for repositioning for AUD that are likely to act at least in part via reduction of neuroinflammation. They include inhibitors of the pannexin1 channel, which has emerged as a major driver of neuroinflammation, and modulators of glucocorticoid signaling, that has a complex action on inflammation. In fact, chronic glucocorticoids result in neuroinflammation and neuronal damage that contribute to both AUD and neurodegenerative diseases. Collectively, these considerations support targeting inflammation and the associated tissue damage for AUD. However, some inflammatory signaling mechanisms recruited by alcohol, such as the Toll-like receptor 4, have proven not to modify alcohol intake. Thus, it is paramount to delineate the inflammatory mechanisms of motivational and therapeutic significance. To this end, Specific Aim 1 in the present proposal will test the effects of representative anti-inflammatory drugs including direct and indirect inflammasome inhibitors with different mechanisms of action in an established rat paradigm of non-dependent and dependent alcohol intake, which is characterized by escalated alcohol drinking and is highly translational as it proved sensitive to the action of virtually all drugs that have shown promise in human AUD. Interlinked studies in Specific Aim 2 will dissect the effects of alcohol and the therapeutics under study on neuroinflammation, inflammasome regulation and astrocyte and microglia regulation to identify key indicators of alcohol-induced neuroinflammation as well as the mechanisms of action of the drugs under testing to determine the molecular bases of their effectiveness or lack thereof as well as to uncover potential new therapeutic targets for AUD. Altogether, the results of this study will advance our understanding of the mechanisms behind treatment responsiveness or lack thereof as well as of alcohol-induced tissue damage of therapeutic significance, and will point to new therapeutic targets for more specific and effective medications to ameliorate neuroinflammation and tissue damage in the setting of AUD and reduce excessive alcohol consumption.

Public Health Relevance Work by the applicants and collaborators has identified 3 candidate drugs for repositioning for alcohol use disorder (AUD) that are currently in different stages of clinical testing and that are likely to act at least in part via modulation of neuroinflammation. Using these 3 candidate drugs for AUD and a panel of selected anti- inflammatory drugs with different mechanisms of actions, we aim to reverse engineer the effects of alcohol on neuroinflammation to identify mechanisms behind alcohol-induced tissue damage and therapeutic efficacy. This approach is expected to highlight specific alcohol-induced inflammatory pathways of motivational significance and that their delineation will point to new and more effective therapeutic targets and medications for AUD.