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Cited by 53Stress Responses and CortisolAdrenal Hormones and DisordersHormonal Regulation and Hypertension

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. +1 more·2007·Journal of Neuroendocrinology
DOI 10.1111/j.1365-2826.2007.01605.x
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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.

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Crossref · 10.1111/j.1365-2826.2007.01605.x

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  • Experimental data demonstrate significant changes in the amplitude of ultradian activity over the course of a 24 hour period.

    “Experimental data demonstrate significant changes in the amplitude of ultradian activity over the course of a 24 hour period (figure 5b).”

    From Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis (2010) · cites this paper as Spiga et al. 2007

  • Following 5 days of treatment with the GR antagonist Org 34850, mean corticosterone levels were elevated over the 24 hour cycle in rats.

    “These theoretical observations are consistent with experimental studies on the rat (Spiga et al. 2007), where following 5 days of treatment with the GR antagonist Org 34850, mean corticosterone levels were elevated over the 24 hour cycle (figure 6a).”

    From Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis (2010) · cites this paper as Spiga et al. 2007

  • The general elevation in corticosterone after Org 34850 was the result of an underlying increase in both the amplitude and frequency of the ultradian pulses.

    “Furthermore, this general elevation was the result of an underlying increase in both the amplitude and frequency of the ultradian pulses.”

    From Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis (2010) · cites this paper as Spiga et al. 2007

  • Org 34850 had its greatest effect during the peak of the circadian rhythm.

    “In the same study, analysis of the corticosterone rhythm revealed that Org 34850 had its greatest effect during the peak of the circadian rhythm.”

    From Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis (2010) · cites this paper as Spiga et al. 2007

  • The model predicts a transient dynamic response to an OGTT following sub-chronic treatment with a cortisol antagonist.

    “The model also predicts a transient dynamic response to an OGTT following sub-chronic treatment with a CORT antagonist ( 54 ) (Supplementary Material).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [54]

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Authors
Spiga, F., Harrison, L. R., Wood, S. A., Atkinson, H. C., MacSweeney, C. P., Thomson, F., Craighead, M., Grassie, M., & Lightman, S. L.
Affiliations
University of Bristol (GB)
Corresponding author
Spiga, F.
ORCID
Venue
Journal of Neuroendocrinology
Publisher
Wiley
Published
2007-08-20
Volume
19
Issue
11
Pages
891-900
ISSN
  • 0953-8194 (ISSN-L)
  • 1365-2826
DOI
10.1111/j.1365-2826.2007.01605.x
OpenAlex
W2005344166
Cited by
53
References
54
Citations by year
2026: 2 · 2022: 2 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 3
FWCI
2.42
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
glucocorticoid receptor antagonist, corticosterone secretion, hypothalamic-pituitary-adrenal axis, glucocorticoid negative feedback, pulsatile hormone secretion, diurnal cycle, mineralocorticoid receptor, methylprednisolone, ACTH, hippocampus, paraventricular nucleus, anterior pituitary, depression treatment
MeSH terms
Adrenocorticotropic Hormone, Animals, Circadian Rhythm, Corticosterone, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, Steroids, Stress, Psychological, Sulfones, Rats, Sprague-Dawley, In Situ Hybridization, Rats

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