Sex- and site-specific effects of GPER-1 activation on saccharin vs cocaine preference in male and female rats

Estradiol (E2) receptor signaling has a sex-specific impact on the brain's reward pathway, enhancing cocaine reinforcement in females but not in males. Selective activation of G-Protein Coupled Estradiol Receptor 1 (GPER-1) in the dorsolateral striatum (DLS) attenuates the reinforcing effects of 0.1 % saccharin (SACC) and cocaine in males but not females. This study investigated GPER-1 activation in the DLS and systemically using the GPER-1 agonist G1 to assess its effect on SACC and cocaine preference in male and female rats. Five experiments were conducted using gonad-intact and gonadectomized animals to determine dose-response effects and the influence of circulating hormones. Intra-DLS GPER-1 activation with 20 % G1 selectively reduced SACC preference in intact males but not females, while higher and lower concentrations had no effect. Systemic G1 administration attenuated cocaine-induced conditioned place preference (CPP) in both sexes in a dose-dependent way. Interestingly, systemic administration of G1 did not alter SACC preference in either sex, regardless of the presence or absence of gonadal hormones. These findings suggest that GPER-1 activation influences reward processing in a site-, reward-, and sex-dependent manner.