Estradiol enhances psychostimulant responses in females, however the neurobiological mechanisms underlying this effect are largely unknown. Recently our lab demonstrated that in ovariectomized female rats, estradiol treatment enhances cocaine-induced locomotor sensitization through an mGluR5-dependent mechanism. These data are in agreement with our model that within the female striatum, estradiol activation of membrane-localized ERa leads to transactivation of mGluR5. Interestingly, previous work has shown that both estradiol treatment and mGluR5 can each independently mobilize endogenous cannabinoids (endoCBs) within the nervous system. Given that the endoCB system is emerging as key mediator of drug related behaviors, we hypothesized that estradiol recruits the endoCB system to enhance psychostimulant responses in female rats via mGluR5. Consistent with previous studies, we found that five days of experimenter-administered cocaine (15mg/kg) induced locomotor sensitization in estradiol-, but not in oil-treated, ovariectomized animals. Consistent with our hypothesis, this locomotor sensitizationin estradiol-treated females was attenuated by pretreatment with a cannabinoid receptor type 1 (CB1r) inverse agonist, AM251 (1mg/kg). Unexpectedly, cocaine-induced locomotor sensitization was observed in ovariectomized females that received AM251 treatment in the absence of estradiol. We are currently investigating whether structural plasticity within the striatum following these pharmacological treatments will explain these behavioral data.