Estrogen modulation of the forebrain dopamine systems: Neurochemical and behavioral studies.

Abstract

This thesis focuses on neurochemical, neuropharmacological and behavioral aspects of estrogen's action in forebrain dopamine (DA) systems of female rats. It is proposed that estrogen acts in the striatum via a novel receptor-mediated mechanism distinct from the classic estrogen receptor. To characterize the pharmacological specificity of the estrogen binding site, the first part of the project employs a superfusion method to examine relative potencies of estrogen agonists and antagonists on amphetamine (AMPH)-induced DA release from striatal tissue of ovariectomized rats. The results indicate that the action of estrogen depends on the steroidal structure of estrogen compounds and the hydroxyl groups on A-ring and D-ring. Moreover, the estrogen binding site seems to be located on the extracellular surface of the neuronal membrane. Second, in vivo microdialysis methods are used to determine extracellular striatal DA concentrations and AMPH-induced DA release in intact and gonadectomized, estrogen-treated male and female rats. The results demonstrate sex differences and estrous cycle-dependent variation in extracellular striatal DA concentrations. Exogenous estrogen enhances AMPH-induced DA release and associated behavior in the absence of gonadal steroids in female, but not male rats. Finally, effects of estrogen in the striatum and the nucleus accumbens (NAc) on female rat pacing behavior are investigated using intracranial implantation methods. Pacing consists of a sensorimotor and a motivational component. The former serves to coordinate sensory inputs with appropriate motor response following each sexual stimulus, and the latter to initiate sexual contact at certain intervals. Estrogen in the striatum and NAc differentially facilitates these two components. Implants with an steroidal antiestrogen produce opposite effects to those of estrogen. Hence, it suggests that distinct neural substrates mediates the effects of estrogen on sensorimotor vs. motivational components of female sexual behavior. These results also support the idea that estrogen modulates striatal DA activity via a specific receptor-mediated mechanism. Furthermore, the action of estrogen in forebrain DA systems may contribute to the hormonal modulation of female rat sexual behavior.