Tirzepatide attenuates mesolimbic cocaine-evoked dopamine levels and reduces cocaine taking, motivation and seeking behaviours in male rodents.

BACKGROUND: Cocaine use disorder (CUD) remains among the most treatment-resistant addictions, characterised by high relapse rates even following extended abstinence periods. Dopamine signalling in mesocorticolimbic circuits contributes to cocaine's reinforcing effects and remains an important target for therapeutic intervention. Growing evidence suggests appetite-regulating peptides may influence central dopamine transmission. Whether recently approved incretin polyagonists can modulate cocaine-related behaviours through their capacity to simultaneously engage multiple appetite-regulating peptide receptor pathways remains unexplored. METHODS: Here we investigated whether tirzepatide, a clinically approved long-acting dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide 1 (GLP-1) receptor agonist, alters cocaine-related behavioural and neurochemical responses in male rodents. FINDINGS: We found that tirzepatide produced dose-dependent reductions in cocaine self-administration (P < 0.001) and diminished cocaine-evoked dopamine responses, as evidenced by attenuated locomotor stimulation (P < 0.001), conditioned place preference (P < 0.001), and accumbal dopamine levels (P < 0.01) across two cocaine doses. Tirzepatide also reduced the motivation to self-administer cocaine (P < 0.05) and attenuated the reinstatement of cocaine-seeking behaviour in animal models of relapse (P < 0.001). Beyond these effects, tirzepatide prevented the expression of cocaine-induced locomotor sensitisation (P < 0.001), suggesting it may have broader neuroadaptive effects. Neurochemical analyses revealed that tirzepatide normalised cocaine-induced dopamine elevations in mesocorticolimbic circuits (P < 0.001) and the lateral septum (P < 0.001), consistent with the behavioural attenuation and our accumbal microdialysis data. We also observed effects on GABA (P < 0.01) and glutamate (P < 0.01) signalling in these regions, suggesting possible multi-neurotransmitter mechanisms. Principal component analysis indicated that tirzepatide affects neural substrates regulating mesocorticolimbic function, potentially contributing to the observed effects on accumbal dopamine release. INTERPRETATION: When considering our findings alongside tirzepatide's clinical availability, the evidence suggests this incretin polyagonist merits investigation as a potential treatment approach for CUD. FUNDING: The study is supported by grants (EJ) from the Swedish Research Council (2023-2600 and 2025-07154), LUA/ALF (grant no. 723941) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren's Research Foundation (2024-SA-4698) and Mary von Sydow Foundation (2024-36). This work was also supported by the following grants from the National Institutes of Health (NIH): R01 DA037897 and R01 DA061799 (H.D.S.) 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.