The goal of this project is to characterize the physiological significance of the sexual dimorphism in corticosteroid binding in the hypothalamus and hippocampus of rats, and to relate regional binding differences to sex-dependent differences in stress responsiveness. Glucocorticoids bind with high affinity to intracellular receptors in discrete regions of the rodent and primate brain. However, the physiological implications of this binding have been poorly understood since it has been difficult to separate the effects of glucocorticoids form those of other hormones involved in stress responses. Preliminary studies using 3H-corticosterone and 3H-dexamethasone have indicated that the number of cytosolic glucocorticoid receptors present in these brain regions is sexually dimorphic and that differences persist following gonadectomy. A nuclear uptake study also has shown a sex difference. Proposed studies will first further characterize three aspects of the dimorphism in the hippocampus and hypothalamus: verification that the dimorphic binding proteins have the characteristics of cytosolic glucocorticoid receptors; determination of whether the dimorphism results from an organizational effect of gonadal steroids on the brain during development; and determination of whether the dimorphism in cytosolic binding capacity results in a sex difference in the in vivo nuclear uptake of corticosterone in castrated animals. The remainder of the project is focused on the role played by brain glucocorticoid receptors in mediating pituitary-adrenal feedback inhibition. Nuclear and cytosolic receptor occupancy will be determined in the hypothalamus, hippocampus, and anterior pituitary in rats with varying degrees of pituitary activation: basal, mildly stressed, and severely stressed. Plasma levels of ACTH and corticosterone will also be determined. The hypothesis that the degree of 'fast' feedback inhibition is proportional to receptor number in the hypothalamus and hippocampus will be tested in a series of three experiments involving the time course of the animal's response to stress.
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