Involvement of Regulator of G-protein Signaling 9-2 in estrogenic augmentation of reward behavior

Abstract

Research indicates the gonadal hormone 17-beta estradiol enhances dopamine-mediated behaviors, which makes women and female rats more sensitive to the effects of the psychostimulant drug, amphetamine. Therefore, a strong emphasis has been placed on the effect of estradiol in the mesolimbic dopamine pathway. The studies described herein provided an analysis on a novel protein family termed the Regulators of G-protein Signaling (RGS) proteins. Preliminary data analyzed the effects of estradiol treatment and amphetamine administration on the expression of RGS9-2, RGS4 and RGS2 mRNA by employing ovariectomized female rats replaced with 17-beta estradiol by either Silastic implant (5-mm) or daily subcutaneous injections (80 mug/kg). After determining estradiol did indeed reduce the mRNA and protein expression of RGS9-2 we explored estradiol mediated enhanced amphetamine-induced conditioned place preference behavior (1.0 mg/kg). Enhanced amphetamine-induced place preference was observed and associated with reductions in RGS9-2 protein expression. Next, in order to demonstrate the direct interaction of the estradiol mediated enhanced place preference behavior and reductions in RGS9-2 we employed the well-established methodology of viral mediated transgene overexpression by herpes simplex virus (HSV) vectors. Overexpression of RGS9-2 in the nucleus accumbens shell by microinjection of HSV successfully increased the expression of RGS9-2 in the nucleus accumbens of treated rats and reversed the estradiol enhancement of amphetamine-induced place preference. The final series of experiments investigated the impact of a single microinjection of saline or pertussis toxin, which depletes Galphai, in the nucleus accumbens shell on estradiol-potentiated place preference behavior and RGS9-2 expression. In summary, twenty years of research involving estradiol enhancements of dopamine-mediated behaviors have been repeatedly reported. Yet, these studies are ambiguous regarding the involvement of dopamine and its receptors. The current research has investigated a novel mechanism by which estradiol may be acting to enhance behavior. The data that are complied in this dissertation demonstrate that reductions in RGS9-2 expression may underlie the mechanism of estradiol enhanced behavior. Thus, providing a great deal of evidence for its role in augmented behavioral responses that might be related to the enhanced susceptibility of addictive behavior in women.