EVIDENCE FOR MINERALOCORTICOID RECEPTOR FACILITATION OF GLUCOCORTICOID RECEPTOR-DEPENDENT REGULATION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXISACTIVITY

These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticos teroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid re ceptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal cort icosterone levels in the morning, but had no effect on basal corticost erone levels in the evening or on restraint stress corticosterone leve ls at either time of day. Acute treatment with the selective glucocort icoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basa l or restraint stress corticosterone levels at either time of day. How ever, combined treatment with RU28318 and RU40555 produced an elevatio n of evening basal corticosterone levels land morning basal on one occ asion) and produced an increase in corticosterone levels during and af ter 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 c orticosteroid receptor measures, the RU28318 treatment was estimated t o selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selective ly occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary an d sufficient to maintain low basal corticosterone levels during the ci rcadian trough, whereas glucocorticoid receptor activation is necessar y to constrain corticosterone secretion during the circadian peak or d uring acute stress. However, even during the circadian peak or acute s tress, mineralocorticoid receptor activation plays an important role i n facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.