Tirzepatide attenuates dopamine reward signaling and suppresses alcohol drinking and relapse-like behaviors in rodents

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. 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 behavioral assays, alcohol intake paradigms, and molecular analyses in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release. Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption, prevented binge and relapse-like drinking, and maintained efficacy during repeated administration. Finally, tirzepatide induced sustained synaptic depression in the lateral septum and further altered histone regulatory proteins in this region, suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight, adipose tissue mass, hepatic triglycerides and circulating pro-inflammatory cytokines. Together, our findings suggest tirzepatide modulates alcohol-related behaviors through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatides established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. SIGNIFICANCE STATEMENTExisting treatments for alcohol use disorder show limited effectiveness, leaving patients without viable therapeutic options. We demonstrate that tirzepatide, a long-acting gut peptide-based drug already approved for diabetes and obesity, substantially reduces alcohol consumption and prevents relapse-like behavior across multiple preclinical models. Tirzepatide appears to work by influencing brain reward systems while simultaneously affecting metabolic complications common in alcohol disorders. Given tirzepatides clinical availability, these findings suggest repurposing a recently approved drug to tackle one of medicines more persistent treatment challenges.