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Background  Estradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and, more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G protein-coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study, the effects of activating GPER1 in the DLS on drug-seeking are investigated.    Methods  Gonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on a fixed-ratio 1 schedule of reinforcement. For 4 weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-DLS GPER1 activation on drug-induced reinstatement after extinction were subsequently determined.    Results  Activation of GPER1, via intra-DLS G1 administration, potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females; however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males.    Conclusions  These results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

biology of sex differences

Activation of G protein-coupled estradiol receptor 1 in the dorsolateral striatum enhances motivation for cocaine and drug-induced reinstatement in female but not male rats