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

Spiga, F., Harrison, L.R., Wood, S.A., Atkinson, H.C., MacSweeney, C.P., Thomson, F. , Craighead, M., Grassie, M. and Lightman, S.L. (2007) Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion. Journal of Neuroendocrinology, 19(11), pp. 891-900. (doi:10.1111/j.1365-2826.2007.01605.x) (PMID:17927667)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Dr Fiona
Authors: Spiga, F., Harrison, L.R., Wood, S.A., Atkinson, H.C., MacSweeney, C.P., Thomson, F., Craighead, M., Grassie, M., and Lightman, S.L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Neuroendocrinology
Publisher:Wiley
ISSN:0953-8194
ISSN (Online):1365-2826
Published Online:20 August 2007

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