Sex Differences in GPER-1 Modulation of Reward and Dopamine Release

Abstract

Sex differences in motivation for drugs can be linked to differences in the organizational and activational effects of gonadal hormones, like estradiol (E2), in males and females. The majority of studies examining E2 find evidence that it enhances the motivation properties of drugs of abuse in females but not males. However, recent studies have found that activation of G-Protein Coupled Estradiol Receptor 1 (GPER-1), an E2 receptor subtype, attenuates male reward preference. I propose that the mechanisms underlying this difference involve the sex-specific effects of GPER-1 signaling on dopamine (DA) signaling in the dorsolateral striatum (DLS). Chapter 2 establishes a concentration-effect curve for the GPER-1 agonist G1 within the DLS. While I could not find a dose of intra-DLS G1 that affected reward preference in females, I did establish that systemic administration of G1 can attenuate a cocaine-induced conditioned place preference in both males and females. I next sought to link the behavioral effects of G1 administration to changes in electrically stimulated dopamine release in the dorsolateral striatum using fast-scan cyclic voltammetry. However, first, in Chapter 3, I assessed whether the repeated electrical stimulation would sensitize dopamine neurons, increasing dopamine release over time in castrated (CAST) males and ovariectomized (OVX) females. I found that repeated stimulation increased stimulated dopamine release over four weeks, as well as a reduction in dopamine reuptake in females. In Chapter 4, I tested whether GPER-1 activity mediates the effects seen in Chapter 2 by attenuating stimulated dopamine release in the dorsolateral striatum. Surprisingly, G1 treatment increased DA release in males, but only at the highest stimulation parameter. DA release initially dropped before rebounding at the same parameter in G1-treated OVX females. The results presented here highlight a previously unknown role of GPER-1 signaling in motivated behavior and DA release in both sexes. These findings contribute to the field's goal of understanding the mechanisms underlying sex differences in reward processing and, ultimately, the development of sex-specific pharmacotherapeutics.