[R01] Evaluation of GLP-1 receptor agonists on alcohol-related behaviors
Ente: National Institute on Alcohol Abuse and Alcoholism
Scadenza: 2031-01-31
Importo max: 444.576 EUR
Paese: US
Descrizione
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 reduce the interoceptive effects of alcohol and will shift drinking
away from an alcohol reinforcer, and that these behavioral outcomes are related to blunted activity of the
salience network and salience network circuitry. These reverse translational studies will provide important
information regarding the effects of GLP-1RAs on key themes emerging from patient reports (alcohol
subjective/interoceptive effects and alcohol reinforcement) which is a highly innovative strategy to help inform
future clinical studies.
Istituzione: UNIV OF NORTH CAROLINA CHAPEL HILL
PI: Joyce Besheer
Progetto: 1R01AA032683-01
Settori: National Institute on Alcohol Abuse and Alcoholism
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