This proposal will evaluate roles of intracellular estrogen and androgen receptors in the differential hormone modulation of identified midbrain dopamine (DA) systems. Sex differences in the epidemiology of schizophrenia and Parkinson's disease, disorders with underlying DA pathology, as well as studies of hormone manipulations in rats and other mammals suggest that the mesostriatal and mesolimbic DA systems respond differently to androgen and estrogen stimulation. Although some effects may occur independently of intracellular receptors, these studies build on existing data indicating that midbrain DA systems are also subject to intracellular estrogen and androgen receptor-mediated actions. This proposal posits that these influences are anatomically segregated and differentially poised to influence DA neurons in mesostriatal verses mesolimhic pathways. To test this hypothesis, experiments will combine methods of tract-tracing, and single- double- and triple-label immunocytochemistry to localize hormone receptors to specific pathways, and will then use hormone manipulations to test the response of these pathways to receptor-mediated estrogen and androgen stimulation. These studies will concretely place hormone receptive machinery and endpoints of their stimulation in identified, non-endocrine DA pathways, and could identify novel and important neural substrates for the independent modulation of functionally and physiologically distinct DA systems that are differentially important to sensorimotor and cognitive function. ? ?
