FROM EXPRESSION TO BEHAVIOR: SEX-DEPENDENT ROLE OF TRPV1 AND ITS ANTAGONISM ON COCAINE REINFORCEMENT

Cocaine use disorder (CUD) is a chronic condition characterized by compulsive drug-seeking behavior and high relapse rates, mostly triggered by stress, with currently no effective treatments. Experimental findings show that the endocannabinoid system (ECS) plays a pivotal role in modulating reward pathways involved in the addictive processes of CUD. In particular, transient receptor potential vanilloid 1 (TRPV1), well known as a molecular integrator of painful stimuli and part of the extended ECS, remains unexplored in brain regions related to stress, reward, and motivation. This study aimed to map TRPV1 protein in the brain of naïve mice and examine how TRPV1 antagonism influences cocaine self-administration (SA), motivation, and cue-induced seeking. Immunohistochemistry revealed TRPV1 protein expression in midbrain and hypothalamic area strongly linked to stress and reward, including the ventral tegmental area, Edinger-Westphal nucleus, and dorsal hypothalamus providing one of the first descriptions of TRPV1 protein in this context. Moreover, western blot analysis showed that TRPV1 expression is significantly increased in the medial prefrontal cortex of only female mice that received non-contingent cocaine injections compared to saline-injected controls. In a cocaine SA paradigm, the selective TRPV1 antagonist SB366791 reduced cue-induced cocaine-seeking in males and modulated the motivation to obtain cocaine under progressive ratio test. Complementary, gene expression analyses in mesocorticolimbic areas indicated region- and sex-dependent regulation of TRPV1. Taken together, these findings identify midbrain TRPV1 as a previously undercharacterized node within reward-responsive circuits and demonstrate that TRPV1 signaling modulates cocaine reinforcement and relapse vulnerability in a sex-dependent manner.