Corticosterone pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis activity via multiple actions that vary with time, site of action, and de novo protein synthesis.

Glucocorticoid regulation of the hypothalamic-pituitary-adrenal (HPA) axis is believed to depend on multiple actions operative within discrete time domains. However, the underlying cellular and molecular mechanisms for those glucocorticoid actions remain undetermined. Moreover, there is absence of in vivo studies examining whether there are multiple glucocorticoid effects on HPA axis-related function within an intermediate feedback time frame (1-3  h after glucocorticoid elevation), and whether those effects depend on de novo protein synthesis. We examined in rats the effects of protein synthesis inhibition on HPA axis response to restraint (15 min) after 1 and 3  h phasic corticosterone (CORT) pretreatment. We measured HPA axis hormones (ACTH and CORT) and gene expression in the paraventricular nucleus (c-fos and crh genes), as well as gene expression in the anterior and intermediate pituitaries (c-fos and pomc genes). Both CORT pretreatment intervals produced inhibition of stress-induced ACTH secretion, but no inhibition was observed in the presence of protein synthesis inhibition. CORT pretreatment produced inhibitory effects on stress-induced gene expression that varied for each gene depending on the anatomical site, pretreatment time, and protein synthesis dependency. Taken together, the ACTH and gene expression patterns support the presence of multiple independent glucocorticoid actions initiated during the intermediate glucocorticoid negative feedback phase. Moreover, we conclude that those effects are exerted predominantly on the intrinsic anatomical elements of the HPA axis, and some of those effects depend on CORT induction of the expression of one or more regulatory gene products.