Currently, no pharmaceutical treatments exist for cocaine use disorder, which is characterized by dysregulated motivation, intense drug craving, compulsive drug-seeking behavior, and relapse during abstinence. While short-acting glucagon-like peptide-1 receptor (GLP-1R) reduces cocaine-related behaviors, its impact is limited by low affinity towards GLP-1R. Semaglutide may be beneficial in this context as it is long-acting with greater potency and affinity for the GLP-1R. Its superiority is substantiated in studies on alcohol and alcohol use disorder (AUD) as it profoundly reduces alcohol intake in animals and patients with AUD, whereas exendin-4 (Ex4) slightly reduces alcohol intake in rats, whereas it does not alter alcohol intake in AUD patients. However, it remains to be explored whether its beneficial effects extend to more complex cocaine-related behaviors, the aim of the present study. Using the cocaine self-administration paradigm in male rats, we tested the efficacy of different doses of semaglutide to reduce voluntary cocaine taking, the motivation to consume cocaine, and the reinstatement of cocaine-seeking behavior. Furthermore, we explored the effects of semaglutide on cocaine-evoked dopamine levels in the nucleus accumbens (NAc). Semaglutide decreased cocaine self-administration, the motivation to consume cocaine, and cocaine reinstatement in male rats. Moreover, semaglutide attenuated cocaine-induced elevation of dopamine levels in mice and rats. Additionally, neither of the tested doses altered kaolin intake, a measurement of malaise, in cocaine-experienced rats. These findings further support the role of GLP-1R in cocaine taking and imply that semaglutide should be tested as a candidate for treating cocaine use disorder.
