Low Doses of Dexamethasone Can Produce a Hypocorticosteroid State in the Brain

Abstract

The synthetic glucocorticoid dexamethasone (dex) blocks stress-induced hypothalamic-pituitary-adrenal (HPA) activation primarily at the level of the anterior pituitary because multidrug resistance P-glycoprotein hampers its penetration in the brain. Here, we tested the hypothesis that central components of the HPA axis would escape dex suppression under conditions of potent peripheral glucocorticoid action. We subchronically treated rats with low or high doses of dex. The animals were subjected on the last day of treatment for 30 min to a restraint stressor after which central and peripheral markers of HPA axis activity were measured. Basal and stress-induced corticosterone secretion, body weight gain, adrenal and thymus weight, as well as proopiomelanocortin mRNA in the anterior pituitary were reduced in a dose-dependent manner by dex administered either 5 d sc or 3 wk orally. In the brain, the highest dose dex suppressed CRH mRNA and CRH heteronuclear RNA in the paraventricular nucleus (PVN). However, in the peripherally active low-dose range of dex CRH mRNA and heteronuclear RNA showed resistance to suppression, and CRH mRNA expression in the PVN was in fact enhanced under the long-term treatment condition. In the PVN, c-fos mRNA was suppressed by the highest dose of dex, but this effect showed a degree of resistance after long-term oral treatment. c-fos mRNA responses in the anterior pituitary followed those in PVN and reflect central drive of the HPA axis even if corticosterone responses are strongly reduced. The results support the concept that low doses of dex can create a hypocorticoid state in the brain.

Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats

“…It has been reported that DEX, at the 0.01 mg/kg dose used in this study produces its inhibitory effects on plasma CORT primarily by inhibiting POMC gene expression in the anterior pituitary gland (Birnberg et al, 1983) without producing significant inhibition of CRH mRNA in the PVN (Karssen et al, 2005). Although we failed to observe effects of cocaine SA on pituitary GR in the present study, we previously found that GR mRNA was reduced specifically in the anterior lobe of the pituitary (i.e., the site of POMC/ACTH producing corticotrophs) at a similar withdrawal time in rats with a history of long-access SA compared to rats with more limited cocaine exposure (Mantsch et al, 2003).…”

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

“…One large study used body weightbased low doses of dexamethasone in men and women, and found no evidence of diminished suppression of the ACTH-adrenal axis, although it was larger in women than in men (45). However, dexamethasone has limited access to the brain and binds to low-capacity glucocorticoid receptors in the pituitary in contrast to the natural glucocorticosteroid in humans, which binds to the glucocorticoid receptors in the brain (46,47). Administration of physiological amounts of cortisol to obese and lean men showed that ACTH inhibition during the nocturnal period was diminished, but comparable with controls during waking hours (33).…”

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

“…In situ hybridizations were performed as described in ref. 41 by using 35 S-UTP labeled riboprobes against mouse MR exon 2, GR exon 2 (courtesy Dr. T. Cole), a 1 kb fragment of the CRH gene (courtesy Dr. G. Dent), and a 505-bp fragment of the mouse CRH intron (courtesy of Dr. A. Seasholtz). Final stringency of posthybridization washes was at 0.1 x standard sodium citrate at 65°C.…”