REGULATION OF PITUITARY ACTH-SECRETION DURING CHRONIC STRESS

Maintenance of adequate levels of response of the hypothalamic-pituita ry-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimul us, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and h yperresponsiveness to a novel stress, as occurs during repeated painfu l stress and insulin hypoglycemia; and (c) small and transient increas es in ACTH, but sustained elevations of plasma corticosterone and dimi nished ACTH responses. The level of response of the pituitary corticot roph is determined by differential regulation of the hypothalamic regu lators, corticotropin-releasing hormone (CRH) and vasopressin (VP), an d the sensitivity of the negative glucocorticoid feedback. While osmot ic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chro nic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, p redominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in main taining the secretory capacity of the pituitary corticotroph during ch ronic stimulation. Decreased sensitivity of the glucocorticoid feedbac k, probably due to interaction of glucocorticoid receptors with transc ription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid l evels during chronic stress. Although both CRH and VP receptors are ac tivated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pitui tary ACTH responsiveness. The inhibitory effect of chronic osmotic sti mulation on ACTH secretion in spite of high circulating levels of VP i s probably the result of diminished activity of parvicellular PVN neur ons and downregulation of pituitary VP receptors. Although the exact i nteraction between regulatory factors and the molecular mechanisms con trolling the sensitivity of the corticotroph during adaptation to chro nic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituit ary VP receptors, and the sensitivity to feedback inhibition play a cr itical role. (C) 1994 Academic Press, Inc.