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bioRxiv · 10.64898/2026.10.16.759697

Semaglutide Increases Striatal Leptin Sensitivity, Impacting Dopaminergic Response to Cocaine

Muldowney, J. J.·Umlauf, M. C.·Bocarsly, M. E.
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Abstract

There is accumulating evidence that the GLP-1 analog, semaglutide, might effectively curb intake of cocaine via brain dopaminergic functioning, despite limited brain penetrance. However, there is currently no established mechanism elucidating how chronic semaglutide treatment regulates the dopaminergic response to cocaine. Cocaine is a highly addictive substance that produces rewarding effects primarily through antagonism of the dopamine transporter (DAT). Therapeutics for cocaine use disorder (CUD) have long targeted DAT in the hope of reducing cocaine intake. Metabolic hormones such as leptin and insulin have been shown to influence DAT, and for that reason have been explored for the regulation of cocaine reward and behavior. Interestingly, while semaglutide does not penetrate the brain, it does peripherally modulate metabolic hormones that enter the brain. Through fast-scan cyclic voltammetry and behavioral experimentation, we examined the effects of chronic semaglutide treatment on dopamine signaling, cocaine-induced dopamine release, and locomotor sensitivity. We determined that chronic semaglutide inhibits dopaminergic reward induced by cocaine. Surprisingly, semaglutides effects on cocaine reward were blunted in mice fasted overnight, suggesting a mechanistic dependence on metabolic hormones. Semaglutide administration generated significant reductions in fasting blood leptin, as well as enhanced striatal leptin sensitivity compared to vehicle controls. Preceding cocaine exposure, application of leptin to fasted mice restored semaglutides regulation of cocaine. Our results exhibit a potential mechanism for semaglutide-induced cocaine reward inhibition, emphasizing the potential of central leptin signaling as a therapeutic target for CUD.

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Muldowney, J. J., Umlauf, M. C., Bocarsly, M. E.. 2026-10-22. Semaglutide Increases Striatal Leptin Sensitivity, Impacting Dopaminergic Response to Cocaine. https://doi.org/10.64898/2026.10.16.759697

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