Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels.

Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered corticosteroid receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in corticosteroid receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization caused a significant increase in CRH, but not AVP, mRNA levels in the parvocellular PVN in sham rats. The ADX + CORT group showed significantly greater increases in both CRH and AVP mRNA levels in the PVN compared to sham rats. These data indicate that PVN AVP mRNA levels are more sensitive to glucocorticoid negative feedback than are the levels of CRH mRNA. In repeated stress, the sham groups showed robust increases in PVN CRH and AVP mRNA levels despite high levels of plasma CORT. The rise in AVP mRNA levels was greater than that in CRH mRNA. Type II glucocorticoid receptor mRNA in the hippocampus and PVN was decreased in the repeatedly stressed sham group. These data suggest a decrease in the CORT negative feedback restraint of PVN CRH and AVP mRNA levels repeated stress and a persistence of relatively greater responsiveness of AVP mRNA levels to CORT negative feedback. After repeated stress in ADX+CORT rats, both PVN CRH and AVP mRNA levels showed robust responses, with a relatively greater increase in AVP mRNA. These data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress. Similarly, we postulate that the relative shift from CRH to AVP in the PVN after repeated stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and CORT-independent mechanisms.