Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion.
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.
Spiga
F
F
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK. F.Spiga@bristol.ac.uk
Harrison
L R
LR
Wood
S A
SA
Atkinson
H C
HC
MacSweeney
C P
CP
Thomson
F
F
Craighead
M
M
Grassie
M
M
Lightman
S L
SL
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D017403:In Situ Hybridization; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000378:metabolism* / Q000494:pharmacology; D013315:Stress, Psychological; D013450:Sulfones / Q000378:metabolism* / Q000494:pharmacology
C526063:Org 34850; D011965:Receptors, Glucocorticoid; D013256:Steroids; D013450:Sulfones; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone