Steroid-Independent Translocation of the Glucocorticoid Receptor by the Antidepressant Desipramine
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322
Abstract
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1–10 μm) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24–96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression.
Footnotes
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Send reprint requests to: Andrew H. Miller, MD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, GA 30322. E-mail:amill02{at}emory.edu
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↵1 Current affiliation: Maudsley Hospital, London, UK.
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↵2 Plotsky, P. M., personal communication.
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↵3 Written by Wayne S. Rasband (National Institutes of Health, Bethesda, MD); available over the Internet by anonymous FTP (zippy.nimh.nih.gov).
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This work was supported by National Institute of Mental Health Grants MH00680 and MH47674 (A.H.M.); University of Cagliari, Italy (C.M.P.); and Italian Consiglio Nazionale delle Ricerche Grants AI95.00290.04 and AI96.00156.04 (C.M.P.).
- Abbreviations:
- HPA
- hypothalamic-pituitary-adrenal
- ACTH
- adrenocorticotropic hormone
- BSA
- bovine serum albumin
- CAT
- chloramphenicol acetyltransferase
- CRF
- corticotropin-releasing factor
- Dex
- dexamethasone
- ROI
- region of interest
- DMI
- desipramine
- DMEM
- Dulbecco’s modified Eagle’s medium
- FITC
- fluorescein isothiocyanate
- GR
- glucocorticoid receptor
- HBSS
- Hanks’ balanced salt solution
- MMTV
- mouse mammary tumor virus
- NDS
- normal donkey serum
- PBS
- phosphate-buffered salt solution
- TBS
- Tris-buffered saline
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- hsp
- heat shock protein
- GRE
- glucocorticoid response element
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- Received March 27, 1997.
- Accepted June 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
