PPAR-GAMMA SEX-DEPENDENTLY MODULATES COCAINE-SEEKING AND TAKING BEHAVIOURS BY TARGETING MOTIVATIONAL OR COGNITIVE PROCESSES

Currently, there are no effective pharmacological treatments for cocaine-use disorder (CUD). Sex differences are also reported in its development, negative effects, and impulsivity. Here, we propose PPAR-gamma as a molecular target against CUD as it modulates key areas from the mesocorticolimbic pathway where cocaine increases dopaminergic transmission. The aim is to evaluate the sex-dependent role of PPAR-gamma in different phases of cocaine addiction in mice using the paradigm of intravenous cocaine self-administration (SA). To assess this, male and female mice were treated with pioglitazone, a PPAR-gamma agonist, at 10 mg/kg during acquisition of SA, before a motivational task like progressive ratio or during a period of forced-abstinence. To evaluate differences in the modulation of cognitive or motivational processes, we performed cognitive tests like Y-maze alternation and novel object recognition (NOR) test, followed by assessment of hippocampal neurogenesis using the BrdU assay and gene expression analyses. Overall, behavioural and molecular results display significant differences in the processes modulated by PPAR-gamma between sexes. Acquisition ratio after SA is lower in females treated with pioglitazone without impairing drug-seeking of acquired animals. Moreover, higher exploration time during NOR training is reported in non-acquired VEH- treated females, but not for pioglitazone, suggesting impairment in learning processes. On the other hand, pioglitazone reduces drug-seeking in motivational tasks like progressive ratio or cue-induced seeking test only in males. In conclusion, PPAR-gamma modulates several processes involved in reward codification in a sex-dependent manner, reducing motivation for drug-seeking in males and impairing learning of reward related memories in females.