All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation

Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-α (RAR-α) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus-pituitary-adrena...

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Bibliographic Details
Published in:Translational psychiatry 2013-12, Vol.3 (12), p.e336-e336
Main Authors: Hu, P, Liu, J, Zhao, J, Qi, X-R, Qi, C-C, Lucassen, P J, Zhou, J-N
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal - drug effects
Corticosterone - metabolism
Corticosterone - secretion
Corticotropin-Releasing Hormone - drug effects
Corticotropin-Releasing Hormone - metabolism
Depression - chemically induced
Depression - metabolism
Dexamethasone - pharmacology
Feedback, Physiological - drug effects
Glucocorticoids - pharmacology
Hormone Antagonists - pharmacology
Hydrocortisone - metabolism
Hypothalamo-Hypophyseal System - drug effects
Hypothalamo-Hypophyseal System - metabolism
Mifepristone - pharmacology
Original
Paraventricular Hypothalamic Nucleus - drug effects
Paraventricular Hypothalamic Nucleus - metabolism
Pituitary-Adrenal System - drug effects
Pituitary-Adrenal System - metabolism
Rats
Receptors, Glucocorticoid - antagonists & inhibitors
Receptors, Glucocorticoid - drug effects
Receptors, Glucocorticoid - metabolism
Receptors, Retinoic Acid - metabolism
Retinoic Acid Receptor alpha
Signal Transduction
Tretinoin - adverse effects
Tretinoin - pharmacology
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Summary:Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-α (RAR-α) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus-pituitary-adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all-trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback. RA was applied to rats chronically through intracerebroventricular injection. A 19-day RA exposure induced potent HPA axis activation and typical depression-like behavior. Dexamethasone failed to suppress basal corticosterone (CORT) secretion, which is indicative of a disturbed GR negative feedback. In the hypothalamic paraventricular nucleus, increased CRH⁺ and c-fos⁺ cells were found while a negative R-2⁺/ER⁺ correlation was present between the number of RAR-α⁺ and GR⁺ cells. This was paralleled by increased RAR-α and decreased GR protein expression in the hypothalamus. Additional in vitro studies confirmed that RA abolished GR-mediated glucocorticoid-induced suppression of CRH expression, indicating a negative cross-talk between RAR-α and GR signaling pathways. Finally, the above changes could be rapidly normalized by treatment with GR antagonist mifepristone. We conclude that in addition to the 'classic' RAR-α-mediated transcriptional control of CRH expression, disturbances in GR negative feedback constitute a novel pathway that underlies RA-induced HPA axis hyperactivity. The rapid normalization by mifepristone may be of potential clinical interest in this respect.
ISSN:2158-3188
2158-3188
DOI:10.1038/tp.2013.98