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. 2025 Jul 23.
doi: 10.1007/s00213-025-06854-3. Online ahead of print.

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

McKinley Windram  1 , Dennis F Lovelock  1 , Joseph M Carew  1 , Caroline G Krieman  1 , Christian S Hendershot  1   2   3 , Joyce Besheer  4   5
Affiliations

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

McKinley Windram et al. Psychopharmacology (Berl). .

Abstract

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.

Keywords: Alcohol; Drug discrimination; GIP; GLP-1; Glucagon; Interoception; Retatrutide; Semaglutide; Subjective; Tirzepatide.

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Conflict of interest statement

Declarations. Ethical approval: All procedures were carried out in accordance with the NIH Guide for Care and Use of Laboratory Animals and institutional guidelines. All protocols were approved by the UNC Institutional Animal Care and Use Committee (IACUC). UNC-Chapel Hill is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Consent to participate: N/A. Consent to publish: N/A. Competing interests: None.

References

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