Project Summary/Abstract Addiction is a major public health concern. Approximately 8.3% of the population needed treatment for addiction in 2013. Cocaine is one commonly used illicit drug that is abused by 10-12% of the population and is highly addictive. During adolescents, equivalent numbers of males and females are abusing or dependent on cocaine. In adults aged 18 and older, the prevalence is double in males compared to females. It is important that we identify why twice as many males are continuing to use after adolescence, and identify novel potential treatment targets that can be beneficial to males. While our lab has historically studied sex differences and especially the characteristics of female drug taking, the studies proposed focus on a novel mechanism that may mitigate drug taking in males. In the proposed work, we investigate a novel mechanism through which the preference and motivation for cocaine is differentially affected in males, but not females. Estradiol (E2) is an important hormone in the brains of both females and males. In males, E2 in the brain is synthesized from testosterone via the enzyme aromatase. In both sexes, E2 acts by binding to one of three types of E2 receptors (ER)s: alpha (α), beta (β), or G-protein receptor -1 (GPER-1). Previous studies have found that E2 potentiates cocaine-induced DA in the dorsal striatum (dSTR) and enhances acquisition of drug taking in females only. The studies proposed will identify how ER activation of GPER-1 differentially influences preference and motivation for cocaine in male and female rats. Our preliminary data show that activation of GPER-1 in the dSTR of male rats blocks conditioned place preference (CPP) for cocaine, but has no effect on CPP in females. Additional preliminary results find that activating GPER-1 attenuates cocaine-induced DA increases within the dSTR of males, but not females. Together, these results suggest that GPER-1 activation may have a protective effect against the rewarding effects of cocaine in male rats, but not females. The experiments proposed will investigate: 1) whether sex differences in GPER-1 receptor activation in the dSTR are related to the preference for cocaine; 2) the effect of GPER-1 on cocaine-induced DA release in male and female rats; and 3) the effect of GPER-1 on the motivation for cocaine in male and female rats during acquisition and after acquisition. Addiction treatment needs targeted treatment for males and females. This work will open new avenues for prevention and treatment of addiction by providing a sex-specific understanding of gonadal hormones the neurobiological mechanisms mediating the rewarding properties of psychostimulants.