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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.

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