Project Summary Alcohol use disorder (AUD) is a pressing public health issue and treatments are much needed. Glucagon-like peptide-1 receptor agonist (GLP-1RA) compounds (e.g., Ozempic, Wegovy, Mounjaro) have been receiving tremendous media attention for their dramatic weight loss effects. With this popularity have come media and anecdotal reports from clinicians and individuals using these medications of decreased alcohol use and changes in sensitivity to the subjective effects of alcohol. The rapid market expansion of GLP-1RA compounds and their derivatives presents an opportunity to identify which may be most efficacious for clinical trials in individuals with AUD. Therefore, in this application we developed a preclinical screening pipeline focused on two key aspects of alcohol drinking with translational importance – alcohol subjective/interoceptive effects and alcohol reinforcement in the context of an alternate reward choice. We will evaluate the long-acting and FDA approved compounds semaglutide (GLP-1RA; which is currently in clinical trials for AUD) and dual GLP-1RA and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide, and the triple (GIP, GLP-1R and glucagon) agonist retatrutide. Additionally, the mechanisms by which GLP-1RAs reduce drinking remain poorly understood, with the salience network and activity in its key hubs emerging as promising targets for investigation. In this application, we will evaluate the effects of GLP-1RAs on alcohol interoceptive effects (Aim 1) and drinking behavior in the context of an alcohol vs. sucrose concurrent choice self-administration procedure (Aim 2). Finally, we will use functional MRI to assess the effects of the most efficacious GLP-1RA on salience network activity with and without alcohol, and fiber photometry to measure neural activity in salience network circuitry during the alcohol vs. sucrose choice self-administration procedure (Aim 3). Overall, we hypothesize that GLP-1RA compounds will r