Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion.

Abstract

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.

• Authors: F Spiga, L R Harrison, S A Wood, H C Atkinson, C P MacSweeney, F Thomson, M Craighead, M Grassie, S L Lightman
• Journal: Journal of neuroendocrinology (J Neuroendocrinol) Vol. 19 Issue 11 Pg. 891-900 (Nov 2007) ISSN: 0953-8194 [Print] United States
• PMID: 17927667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Org 34850
• Receptors, Glucocorticoid
• Steroids
• Sulfones
• Adrenocorticotropic Hormone
• Corticosterone

Topics

• Adrenocorticotropic Hormone (metabolism)
• Animals
• Circadian Rhythm (drug effects, physiology)
• Corticosterone (metabolism)
• Hypothalamo-Hypophyseal System (drug effects, physiology)
• In Situ Hybridization
• Male
• Pituitary-Adrenal System (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glucocorticoid (antagonists & inhibitors)
• Steroids (metabolism, pharmacology)
• Stress, Psychological
• Sulfones (metabolism, pharmacology)