Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents

Abstract

Background: Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Methods: Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioural assays (locomotor activity and conditioned place preference), alcohol intake paradigms (intermittent access two-bottle choice, drinking in the dark and the alcohol deprivation effect), and molecular analyses (microdialysis, electrophysiology and proteomics) in rodents. Findings: First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release (P &lt; 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P &lt; 0.001), prevented binge (P &lt; 0.01) and relapse-like drinking (P &lt; 0.001), and maintained efficacy during repeated administration (P &lt; 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P &lt; 0.05) and further altered histone regulatory proteins in this region (P &lt; 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P &lt; 0.001), adipose tissue mass (P &lt; 0.01), hepatic triglycerides (P &lt; 0.01) and circulating pro-inflammatory cytokines (P &lt; 0.05). Interpretation: Together, our findings suggest tirzepatide modulates alcohol-related behaviours through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatide's established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications.CC BY 4.0© 2025 The Author(s)Correspondence Address: E. Jerlhag; Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Medicinaregatan 13, SE-405 30, Sweden; email: [email protected] study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 &amp; 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 &amp; U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&amp;D I01BX000813 &amp; IK6BX006299), Herbert &amp; Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm &amp; Martina Lundgren’s Research Foundation (2024-SA-4698), Åke Wibergs Foundation (M24-0216), Swedish Diabetes Foundation (DIA 2024-898) and Mary von Sydow Foundation (2024-36 &amp; 2024-185). Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg.</p