Evidence for Mineralocorticoid Receptor Facilitation of Glucocorticoid Receptor-Dependent Regulation of Hypothalamic-Pituitary-Adrenal Axis Activity *

These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitaryadrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone. (Endocrinology 139: 2718–2726, 1998) A of the hypothalamic-pituitary-adrenal (HPA) axis is tightly and dynamically regulated by corticosteroid negative feedback (1). The inhibitory effects of corticosterone on HPA axis function are believed to be transduced primarily by intracellular steroid receptor proteins that function as hormone-activated transcription factors. The existence of two different corticosteroid receptors was first suggested in pharmacological studies nearly 20 yr ago (2) and has been confirmed with the more recent cloning of the complementary DNA for these two closely related receptors (3, 4). The lower affinity corticosterone receptor, the glucocorticoid receptor (type II corticosteroid receptor), is found in fairly high concentrations throughout the brain and the pituitary (5–7). The higher affinity corticosterone receptor, the mineralocorticoid receptor (type I corticosteroid receptor), also serves as the aldosterone receptor in the kidney (8). Interestingly, the highest concentration of mineralocorticoid receptors in the body appears to be in the hippocampal formation, with substantially lower levels of mineralocorticoid receptors scattered throughout the brain and pituitary (3, 9). Thus, the two receptor subtypes for corticosterone are located in target tissues believed to contribute importantly to negative feedback regulation of HPA axis function (i.e. throughout the brain and pituitary). Two separate groups of investigators have been especially instrumental in defining the relative roles of these two receptor subtypes in mediating corticosteroid feedback regulation of the HPA axis. Dallman and colleagues have focused on the role of glucocorticoid and mineralocorticoid receptors in regulating the basal and stress-induced activity of the HPA axis and how those roles change across the circadian cycle of HPA axis basal activity (1, 10–14). de Kloet and colleagues performed many of the initial studies characterizing the distribution and hormone binding properties of mineralocorticoid and glucocorticoid receptors in brain and pituitary. They have also examined the role of corticosterone receptor subtypes in mediating corticosterone regulation of basal and stress-induced HPA axis activity during the circadian trough of activity (2, 15, 16). Based primarily on the work of these two groups of investigators, a basic model of corticosteroid receptor mediation of HPA axis regulation by corticosteroids has been put forth in which: 1) the low levels of corticosterone present during the circadian trough act via the high affinity mineralocorticoid receptors to maintain low basal activity of the HPA axis; 2) the higher levels of corticosterone present during the circadian peak or acute stress act via the lower affinity glucocorticoid receptors to constrain HPA axis activity (1, 2, 15). A recent study indicates that mineralocorticoid receptors contribute to the corticosterone maintenance of basal HPA axis activity during the circadian peak, perhaps by potentiating corticosterone effects at glucocorticoid receptors (13). Received September 19, 1997. Address all correspondence and requests for reprints to: Robert L. Spencer, Department of Psychology, Campus Box 345, University of Colorado, Boulder, Colorado 80309. E-mail: spencer@clipr. colorado.edu. * This work was supported by NIH Grants MH-54742 and DK-49143, and the University of Colorado Undergraduate Research Opportunity Program. 0013-7227/98/$03.00/0 Vol. 139, No. 6 Endocrinology Printed in U.S.A. Copyright © 1998 by The Endocrine Society