SEX-SPECIFIC MOLECULAR ADAPTATIONS UNDERLYING LOCOMOTOR TOLERANCE TO PSYCHOSTIMULANTS

Substance use disorders (SUD) is a major public health issue. Tolerance to psychostimulants like cocaine, driving dose escalation and overdose risk, remains an underexplored therapeutic target.
The objectives of this study are to characterize behavioral and striatal transcriptomic alterations underlying psychostimulant-induced tolerance in male and female rats. The striatum plays a central role in this process.
Building on a previous translational study showing that Lrp1b and Vps13a are associated with cocaine-induced locomotor tolerance in both male rats and humans, we investigated sex- and drug-specificity. We extended our study to female rats with the same as males 5-day binge cocaine treatment (20mg/kg, i.p.), to MDPV using a 3-day binge (3mg/kg, i.p.) treatment followed by extinction-reinstatement testing and morphine using a 4-day escalating-dose protocol (10–40 mg/kg, s.c.) in male and female. Locomotor activity was assessed to quantify tolerance.
In males, our results showed significant upregulation of Lrp1b and Vps13a expression (RTqPCR) in ventral and dorsal striatum of rats tolerant to both psychostimulants (cocaine, MDPV) and morphine. No modifications of these genes expression were detected in females rats tolerant to psychostimulants.
Despite same behavior with a similar progression of tolerance to tested drugs in both sexes, these findings highlight a sex-specific genetic dimorphism in response to drugs.
Conclusions indicate that Lrp1b and Vps13a are specifically linked to drug-induced tolerance in males. Underscoring the importance of considering sex-specific mechanisms and suggest that a better understanding of the genetics of tolerance may help to develop personalized treatments considering sex differences in SUD.