Effect of Chronic Administration of Selective Glucocorticoid Receptor Antagonists on the Rat Hypothalamic–Pituitary–Adrenocortical Axis

Abstract

The effects of the selective glucocorticoid receptor (GR) antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamic-pituitary-adrenocortical (HPA) system were investigated. To assess the potency of the compounds to occupy GR in the brain and pituitary, we applied a single acute subcutaneous (s.c.) injection (10 mg/kg). ORG 34517 was most potent to occupy GR in the anterior pituitary and distinct brain areas, whereas all compounds were unable to occupy mineralocorticoid receptor (MR). Chronic administration of ORG 34850, ORG 34116, and ORG 34517 (20 mg/kg/day) for 1, 3, and 5 weeks resulted only in minor changes in brain GR levels. However, profound increases of hippocampal MR were observed virtually at all time points. Treatment with ORG 34850 and ORG 34116 elicited episodic increases in HPA axis activity, whereas ORG 34517 did not cause any changes in HPA activity. Thus, the GR antagonists exert distinct effects on the HPA axis, which may be pertinent for the proposed antidepressant activity of these compounds.

Improvements in Neurocognitive Function and Mood Following Adjunctive Treatment with Mifepristone (RU-486) in Bipolar Disorder

“…Interestingly, RU-486 was the only GR antagonist examined in a recent study to increase both mineralocorticoid receptor (MR) and GR binding in the frontal cortex (Bachmann et al, 2003). This may underpin the selective pattern of improvement in neurocognitive function seen in the present study, which was restricted to tests which have been shown to be sensitive to frontal lobe dysfunction (Owen et al, 1995).…”

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

“…Continued or repeated cortisol hypersecretion leads to over-exposure of corticosteroid receptors, which in turn may be downregulated. This premise has been the source of a number of studies evaluating the efficacy of glucocorticoid inhibitors (Belanoff et al, 2001(Belanoff et al, , 2002Jahn et al, 2004;Flores et al, 2006) and glucocorticoid receptor antagonists (Bachmann et al, 2003;Johnson et al, 2007) as anti-depressants. Thus, it is possible that there are differences in the autoregulatory feedback of GAD and comparison subjects due to corticosteroid receptor performance.…”

Altered Serotonergic Neurotransmission but Normal Hypothalamic–Pituitary–Adrenocortical Axis Activity in Mice Chronically Treated with the Corticotropin-Releasing Hormone Receptor Type 1 Antagonist NBI 30775

“…It can be argued that the selected treatment regimen, that is, oral administration of NBI 30775 via the food, may underlie the absence of behavioral and neuroendocrine (see below) effects in the present study. However, treatment regimens in which drugs have been added to the drinking water or food have successfully been used to demonstrate the effects of various antidepressants on HPA axis regulation (see Reul et al, 1993Reul et al, , 1994Bachmann et al, 2003). Although we did not study receptor occupation after chronic treatment with NBI 30775, a recent report by Gutman et al (2003) shows that even 8 h after acute intravenous administration of NBI 30775 (10 mg/kg body weight), 45% of CRH-R1 in the rat frontal cortex are still occupied by the antagonist.…”

“…This strategy has recently successfully been used to demonstrate the effects of putative antidepressant glucocorticoid receptor antagonists on HPA axis activity (Bachmann et al, 2003). Mice were adapted to eat a liquid diet starting 5 days before surgery.…”