NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

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Research has focused on the mechanism of regulation of hypothalamic and pituitary function during stress. The studies have shown that the level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators corticotropin releasing hormone (CRH) and vasopressin (VP) and the sensitivity of the glucocorticoid feedback. While the inhibition of the HPA axis during osmotic is associated with stimulation of VP secretion by magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, physical-psychological stress paradigms associated with corticotroph hyperresponsiveness show activation of CRH and CRH/VP parvicellular neurons in the PVN. Binding studies using [3H]VP and anterior pituitary membranes from rats under osmotic stress (water deprivation and 2% saline intake) or physical-psychological stress (immobilization or i.p. hypertonic saline injection) showed a good correlation between changes in pituitary VP receptors and corticotroph responsiveness. Northern blot analysis of VP receptor mRNA in pituitaries from chronically stressed rats revealed changes in mRNA levels parallel to those in VP binding. In contrast to the findings in chronic stress, continuous exposure of the pituitary to increased levels of VP by surgical shunting of magnocellular VP to the hypophyseal portal circulation caused corticotroph desensitization and pituitary VP receptor downregulation. These data suggest that regulation of VP receptor number plays a critical role in the regulation of corticotroph responsiveness during chronic stress. Studies on the expression of CRH receptors in the brain revealed that while CRH binding and CRH receptor mRNA are undetectable in the PVN under basal conditions, they markedly increase during stress with expression in parvicellular cells after physical psychological stress and in magnocellular cells after osmotic stimulation. These data suggest an autoregulatory role for CRH in the control of PVN function.