NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

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This project has focused on the mechanism of regulation of hypothalamic and pituitary function during stress. Increases in vasopressin (VP) expression in parvicellullar neurons of the PVN, as well as pituitary VP (V1b) receptor upregulation are important determinants of the increased ACTH responsiveness observed in several chronic stress paradigms. Further evidence for the importance of VP was provided by studies during adjuvant induced arthritis in rats, showing elevation in VP mRNA in the parvicellular PVN and increases in pituitary VP receptors accompaning marked activation of the hypothalamic-pituitary-adrenal (HPA) axis. Studies on the regulation of pituitary VP receptors were extended to investigate the mechanism of regulation of V1b receptor expression. Adrenalectomy causes parallel decreases in VP binding and V1b receptor mRNA, an effect which was prevented by glucocorticoid replacement. Similar changes following adrenalectomy were found in Brattleboro VP deficient rats indicating that the decreased V1b receptor expression was not due to adrenalectomy-induced increases in parvicellular VP. Increasing pituitary exposure VP by surgical shunting of magnocellular VP to the hypophyseal portal circulation caused pituitary VP receptor downregulation without changes in V1b receptor mRNA levels. Dexamethasone administration in intact rats was without effect on V1b receptor mRNA levels. These data suggest that V1b receptor mRNA levels are directly regulated by glucocorticoids or by hypothalamic factors other than VP. Studies to elucidate the mechanism by which stress induces CRH receptors in the hypothalamic paraventricular nucleus (PVN) focused on the role of glucocorticoids and neural pathways. While adrenalectomy transiently induced CRH receptors in the parvicellular PVN, glucocorticoid administration or withdrawal had no effect on stress induced receptor expression. Surgical hemisections of ascending neural pathways induced CRH receptor mRNA in lower brainstem/spinal cord projecting neurons of the PVN, but had no effect on basal or stress-induced CRH receptor mRNA in hypophyseotrophic parvicellular subdivision. These data show that while glucocorticoids and neural imputs from the brain stem and spinal cord influence CRH receptor expression in the PVN, other factors and neural pathways are responsible for stress-induced CRH receptor expression.