The dual incretin agonist tirzepatide blunts nicotine‐induced behaviours and neurochemistry in male mice

Abstract Background and Purpose Nicotine dependence remains one of the leading causes of morbidity and mortality worldwide, with high relapse rates and post‐cessation weight gain representing persistent barriers to sustained abstinence. The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) have emerged as novel treatment targets, as they appear to influence both reward‐related behaviours associated with addictive substances and body weight regulation. Whether recently developed multi‐receptor incretin agonists such as tirzepatide, a long‐acting dual GIP/GLP‐1 receptor agonist, affect nicotine‐induced behaviours remains unstudied. Experimental Approach We investigated whether tirzepatide affects nicotine‐induced behaviours (locomotor stimulation and expression of locomotor sensitisation, expression and reinstatement of conditioned place preference) and related neurochemistry (in vivo microdialysis and ex vivo tissue neurochemical analysis) in male mice. Key Results Tirzepatide attenuated nicotine‐induced locomotor stimulation in a dose‐related manner, and reduced nicotine‐induced place preference, and in vivo accumbal dopamine release. Furthermore, tirzepatide suppressed reinstatement of nicotine place preference and prevented the expression of locomotor sensitisation, indicating effects beyond acute reward processing. Ex vivo neurochemical analysis of addiction‐related brain regions in nicotine‐sensitised mice revealed that tirzepatide blocked nicotine‐induced dopamine elevations in the nucleus accumbens, ventral tegmental area and lateral septum. Furthermore, tirzepatide restored levels of multiple neurotransmitter systems, such as GABA, in a brain region‐specific manner, suggesting possible effects beyond dopaminergic signalling alone. Conclusions and Implications Collectively, these findings indicate that tirzepatide attenuates nicotine‐induced locomotor stimulation and dopamine release, as well as the expression and reinstatement of place preference, and the expression of locomotor sensitisation, in mice.