Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies

A dose of dexamethasone was determined in rats (50 mu g/kg SC) that suppres sed the corticosterone response to restraint stress by 80%. Corticosteroid receptor occupancy estimates found that the 50 mu g/kg SC dose of dexametha sone had no significant effect on available glucocorticoid receptor (GR) or mineralococrticoid receptor (MR) binding in brain regions (hypothalamus, h ippocampus and cortex); on the other hand dexamethasone produced a selectiv e and significant decrease in available GR in peripheral tissues (pituitary and spleen). Functional studies showed that the 50 mu g/kg SC dose of dexa methasone completely blocked the effects of corticotropin-releasing hormone (CRH; 0.3-3.0 mu g/kg IP) on corticosterone secretion, but did not inhibit the corticosterone response to an adrenocorticotropin hormone (ACTH; 2.5 I .U./kg IP) challenge. These studies indicate that this dose of dexamethason e exerts its inhibitory effects on the HPA axis primarily by acting at GR i n the pituitary. The plasma dexamethasone levels produced by this dose of d examethasone are similar to those present in humans the afternoon after an oral dexamethasone suppression test (DST), a time at which many depressed p atients escape from dexamethasone suppression. These results support and ex tend other studies which suggest that the DST provides a direct test of the effects of increased GR activation in the pituitary on ACTH and cortisol s ecretion. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.