title: All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation.
abstract: 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.
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: P
authors.initials: P
authors.lastname: Hu
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: X-R
authors.initials: XR
authors.lastname: Qi
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: C-C
authors.initials: CC
authors.lastname: Qi
authors.affiliation: Swammerdam Institute for Life Science, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lucassen
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: J-N
authors.initials: JN
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000139:chemically induced / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014212:Tretinoin / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D005938:Glucocorticoids; D006727:Hormone Antagonists; C000607073:Rara protein, rat; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015735:Mifepristone; D014212:Tretinoin; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D006854:Hydrocortisone