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

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.

Activation of G-protein Coupled Estradiol Receptor 1 in the Dorsolateral Striatum Enhances Motivation for Cocaine and Drug-Induced Reinstatement in Female Rats

BackgroundEstradiol 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. MethodsGonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on an fixed-ratio 1 schedule of reinforcement. For four 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-GPER1 activation on drug-induced reinstatement after extinction was subsequently determined. ResultsActivation of GPER1, via G1 administration intra-DLS 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.

G-protein coupled estradiol receptor 1 in dorsolateral striatum modulates cocaine preference in male rats

There are sex differences in susceptibility to addiction. Cultural influences play a role in drug seeking behaviors; however, sex differences are found in rodent models of addiction as well, suggesting that there are also neurobiological factors involved. Extensive research has shown that estradiol facilitates enhanced motivation and drug seeking in female but not male rodents. Estradiol treatment also potentiates cocaine induced dopamine overflow in the dorsolateral striatum (DLS) of females. Together, these findings suggest that estradiol potentiates the rewarding effects of cocaine in females only. However, testosterone is aromatized to estradiol in the male brain but thus far, it’s action in males is not well understood. These studies used pharmacological treatments to manipulate ERα, ERβ and GPER1 in the DLS to investigate how estradiol receptors regulate preference for cocaine in both sexes. Antagonism of ERα or ERβ did not alter cocaine CPP in males, but GPER1 activation blocked cocaine preference and inhibition of GPER1 enhanced cocaine CPP in males. Surprisingly, there was no effect of GPER1 activation in females. There were no sex differences in relative mRNA expression of ERα, ERβ and GPER1 in the dorsal striatum. Together, these results indicate that estradiol is playing differential roles in males and females such that it may be protective against drug seeking in male rats while enhancing it in females.Significance StatementDrug addiction effects men and women differently but the way we treat addiction is not tailored by sex like it should be. Apart from cultural influence, one reason for sex differences in drug taking could be due to differences in neurobiological function and actions of gonadal hormones. This research article identifies a novel, protective, role for estradiol receptor, GPER1, in male rats only. This discovery could lead to sex-specific therapeutic targets for addiction treatment.