EXCEED THE SPACEPROVIDED.Gonadal neurosteroids are important modulators of behavior and have been shown to impact a range of clinicallysignificant conditions, including sexual behavior, sleep, cognition, drug and alcohol abuse, affective disorders,pain sensitivity, epileptic seizure disorders and stress reactivity. Recent molecular and cellular studies as well asdata from whole animal behavioral models indicate that gonadal neurosteroids influence behavior through thedirect regulation of neuronal activity, as well as the modulation of classical neurotransmitter function, through avariety of both genonic and nongenomic mechanisms. To date, the effects of estrogen and progesterone onneurotransmitter function in humans have received almost no attention. We, and others, have successfully useddrug discriminationand functional neuroimaging methodologies to examine the manner in which psychoactivedrugs alter classical neurotransmitter function (i.e., clinical neuropharmacological effects of drugs), as well as theneuroanatomical locations of these effects. This basic science project will be among the first to apply thesemethodologies within the same individuals to examine the manner and anatomical locations in which estrogen andprogesterone modulate clinical neurotransmitter function in humans. One series of studies will examine the effectsof estradiol on dopaminergic activity. It is hypothesized that estradiol will enhance dopamine function selectivelyin women. A second series of studies will examine the neuropharmacological effects of progesterone. It ishypothesized that progesterone and its metabolites will engender direct interoceptive effects via modulation ofmultiple receptor sites, includingGABAA, sigma and NMDA, in both men and women. This information will beinvaluable for expanding our understanding of the neurobiologicalbasis of gender differences in mood andbehavior regulation. These studies will have important applied significance in helping future development ofgender-specific medications having selective effects at steroidal receptor sites and/or tailored to work incombination with endogenous neurosteroids. It is also likely that these studies will inform and enhance ongoingefforts to develop and evaluate steroid-based medications. Finally, this project will promote the mentoring,development and promotion of our junior and early career colleagues' academic interests in the clinicalneurobiology of women's health.
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