Progesterone attenuates the effects of cocaine on hypermobility and dopaminergic transmission in the nucleus accumbens

Currently there is no pharmacological treatment for cocaine use disorder. Previous studies have shown that progesterone can mitigate the behavioral effects induced by cocaine in both animal models and humans. However, the underlying mechanisms through which progesterone exerts this effect remain poorly understood. While it was already known that exogenous progesterone can decrease dopamine release in the nucleus accumbens (NAc) of male rats, it remains unclear whether progesterone could also reduce the cocaine-induced increase in extracellular dopamine levels. Here we evaluated if exogenous progesterone could reduce cocaine-induced increases in mobility, locomotion, ultrasonic vocalizations and electrically-evoked change in dopamine levels in the NAc of adult male and female rats. Progesterone decreased electrically-evoked dopamine levels, locomotion and mobility in both males and females, being more effective in female rats. Moreover, progesterone attenuated the cocaine-induced increase in the electrically-evoked dopamine concentration in the NAc. Rats exhibited stimulant euphoric-like and rewarding effects of cocaine through increased mobility, locomotion, and 50-kHz ultrasonic vocalization (USV) calls. We also found that progesterone attenuates these effects of cocaine in female, but not male, rats, suggesting that progesterone may dampen the rewarding, euphoric, and psychostimulant effects of cocaine, but with sex differences.