Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodentsShow others and affiliations
2026 (English)In: eBioMedicine, E-ISSN 2352-3964, Vol. 124, article id 106119Article in journal (Refereed) Published
Abstract [en]
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 < 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P < 0.001), prevented binge (P < 0.01) and relapse-like drinking (P < 0.001), and maintained efficacy during repeated administration (P < 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P < 0.05) and further altered histone regulatory proteins in this region (P < 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P < 0.001), adipose tissue mass (P < 0.01), hepatic triglycerides (P < 0.01) and circulating pro-inflammatory cytokines (P < 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.
Place, publisher, year, edition, pages
Elsevier, 2026. Vol. 124, article id 106119
Keywords [en]
Addiction, Alcohol, Dopamine, Ethanol, GIP, GLP-1, Reward, adrenalin plus lidocaine, alpha aminoadipic semialdehyde synthase, carprofen, glucagon like peptide 1 receptor, glucose dependent insulinotropic polypeptide receptor agonist, histone regulatory protein, interleukin 10, interleukin 1beta, interleukin 6, kaolin, microtubule associated protein 1A, proline rich transmembrane protein 2, reticulon 3, taurine transporter, tirzepatide, tooth cement, tumor necrosis factor, unclassified drug, adipose tissue, adult, alcohol consumption, animal experiment, animal model, animal tissue, Article, body weight, controlled study, depression, diabetes mellitus, drinking behavior, electrophysiological procedures, electrophysiology, female, gonadal white adipose tissue, intrascapular brown adipose tissue, knowledge, lateral septal nucleus, local anesthesia, locomotion, male, microdialysis, mouse, nonhuman, obesity, place preference, proteomics, rat, relapse, rodent, stimulation, subcutaneous white adipose tissue
National Category
Pharmaceutical Sciences Neurosciences Physiology and Anatomy
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-26127DOI: 10.1016/j.ebiom.2025.106119ISI: 001663989000001PubMedID: 41506148Scopus ID: 2-s2.0-105027630044OAI: oai:DiVA.org:his-26127DiVA, id: diva2:2033464
Funder
Swedish Research Council, 2023-2600Swedish Research Council, 2020-00559Swedish Research Council, 2020-01463Swedish Research Council, 2024-03054NIH (National Institutes of Health), P50 AA010761NIH (National Institutes of Health), U01 AA014095Herbert och Karin Jacobssons Stiftelse, 2024-Forskning-225Adlerbertska Research Foundation, 2024-791Wilhelm och Martina Lundgrens Vetenskapsfond, 2024-SA-4698Åke Wiberg Foundation, M24-0216Diabetesfonden, DIA 2024-898Mary von Sydow Foundation, 2024-36Mary von Sydow Foundation, 2024-185
Note
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: elisabet.jerlhag@pharm.gu.se
The study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 & 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 & U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&D I01BX000813 & IK6BX006299), Herbert & Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm & 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 & 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.
2026-01-292026-01-292026-02-02Bibliographically approved