Semaglutide, tirzepatide, and retatrutide attenuate the interoceptive effects of alcohol in male and female rats.

RATIONALE: Alcohol use disorder (AUD) remains a major public health challenge, yet effective pharmacotherapies are limited. As such, there is growing interest in repurposing medications with novel mechanisms of action. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for type 2 diabetes, have emerged as promising candidates due to effects on intake regulation and reward processing. GLP-1 receptor agonists, including semaglutide, reduce alcohol intake and relapse-like behaviors in rodent and non-human primate models, and a recent clinical trial found that semaglutide decreased alcohol craving and drinking in adults with AUD. Modulation of the subjective/interoceptive effects of alcohol may contribute to the therapeutic potential of GLP-1 receptor agonists. OBJECTIVES: This study used operant drug discrimination in male and female rats to assess how acute and repeated semaglutide treatment affects alcohol's discriminative stimulus (interoceptive) effects. We hypothesized that GLP-1 receptor activation would disrupt alcohol's interoceptive effects. We also evaluated acute treatment with tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) receptor agonist, and retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, to determine whether broader receptor activity would differentially influence alcohol's subjective effects. RESULTS: Acute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, suggesting modulation of subjective alcohol effects. Repeated semaglutide maintained efficacy across the 15-day treatment period; alcohol discrimination returned to control levels three days after treatment cessation. CONCLUSIONS: Building on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics.