INCREASED EXPRESSION OF TYPE-1 ANGIOTENSIN-II RECEPTORS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS FOLLOWING STRESS AND GLUCOCORTICOID ADMINISTRATION

Double staining in situ hybridization studies have shown that angiotensin II (AII) type 1 receptors (AT1) in the hypothalamic paraventricular nucleus (PVN) are located primarily in corticotropin releasing hormone (CRH) neurons of the parvicellular subdivision, The purpose of these studies was to investigate the role of AII regulating the hypothalamic-pituitary adrenal (HPA) axis, by correlating AT(1) receptor expression levels in the PVN with the known changes in activity of the HPA axis under different stress paradigms, and manipulation of circulating glucocorticoids. AT(1) receptor mRNA was measured by in situ hybridization using S-35-labelled cRNA probes and AII binding by autoradiography using I-125[Sar(1),Ile(8)]AII in slide mounted hypothalamic sections. AT(1) receptor mRNA levels and AII binding in the PVN were reduced by about 20% 18 h after adrenalectomy remaining at these levels up to 6 days after. This effect was prevented by corticosterone administration in the drinking water, or dexamethasone injection (100 mg, s.c., daily). Conversely, dexamethasone injection in intact rats caused a 20% increase in AT(1) receptor mRNA in the PVN. AT(1) receptor mRNA and binding in the PVN increased 4 h after exposure to stress paradigms associated with activation of the HPA axis (immobilization for 1 h, or i.p. injection of 1.5 M NaCl), and remained elevated after repeated daily stress for 14 days. Unexpectedly, two osmotic stress models associated with inhibition of the HPA axis (60 h water deprivation or 12 days of 2% saline intake) also resulted in increased AT(1) receptor mRNA levels and AII binding in the parvicellular PVN. In intact rats, the stimulatory effect of acute stress on AT(1) receptor mRNA in the PVN was significantly enhanced by dexamethasone administration (100 mu g, s.c., 14 h and 1 h prior to stress), while in adrenalectomized rats, with or without glucocorticoid replacement, stress reduced rather than increased, AT(1) receptor mRNA. Dexamethasone, 100 mu g, injected sc within 1 min the beginning of immobilization in adrenalectomized rats, increased AT(1) receptor mRNA in the PVN to levels significantly higher than those after dexamethasone alone, indicating that the stress induced glucocorticoid surge is required for the stimulatory effect of stress on AT(1) receptor mRNA. The data suggest that AT(1) receptor expression in the PVN is under dual control during stress: stress-activated inhibitory pathways and the stimulatory effect of glucocorticoids. The lack of specificity of the changes in AT(1) receptor expression in the PVN following stressors with opposite effects on ACTH secretion (osmotic and physical-psychological stress) does not support a role for AII as a major determinant of the response of the HPA axis during stress.