The purpose of this project is to analyze the neuroendocrine components of homeostatic regulation, with emphasis on the mechanisms of adaptation to stress. In studies on the hypothalamic control of corticotropin (ACTH) release, the receptors and actions of corticotropin releasing factor (CRF) have been characterized in the pituitary gland and nervous system. Increases in ACTH secretion following adrenalectomy were accompanied by marked increases in basal ACTH release in isolated cells, and by decreases in pituitary CRF receptors and CRF-stimulated adenylate cyclasse activity. Studies are in progress to determine the mechanisms of receptor desensitization and maintenance of elevated ACTH secretion after adrenalectomy and stress. Analysis of the secretion of CRF and vasopressin (VP) from median eminences in vitro showed a decrease in CRF release and an increase in VP release after adrenalectomy, suggesting that VP is a major factor in the control of ACTH release. Autoradiographic analysis of frozen brain sections has shown that CRF receptors are prominently located in the cerebral cortex and limbic system related areas. Brain CRF receptors were also coupled to adenylate cyclase, and in contrast to the pituitary receptors were not down-regulated following adrenalectomy. In addition, functional CRF receptors were found in sympathetic ganglia, and in the adrenal medulla, indicating that CRF is involved in the peripheral response to stress. Studies are also being conducted in the pituitary corticotroph to elucidate the mechanisms of action of the several factors involved in the regulation of ACTH secretion. These findings have revealed that CRF exerts receptor-mediated actions within the nervous system at sites involved in the behavioral and autonomic responses to stress, as well as on the pituitary-adrenal secretion of stress hormones.
