Journal Mobile Options
Table of Contents
Vol. 78, No. 1, 2003
Issue release date: July 2003
Neuroendocrinology 2003;78:12–22

Antidepressants Differentially Influence the Transcriptional Activity of the Glucocorticoid Receptor in vitro

Herr A.S. · Tsolakidou A.F. · Yassouridis A. · Holsboer F. · Rein T.
Max Planck Institute for Psychiatry, Munich, Germany

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Functional normalization of the hypothalamic-pituitary-adrenal axis in depressive patients by successful treatment with antidepressants is associated with increased efficiency of corticosteroid signal transduction. Accordingly, some antidepressants have been shown to influence the activity of the glucocorticoid receptor (GR) in cultured cells. It is not clear, however, whether this is a common principle for all antidepressants throughout all classes. Therefore, we screened a range of 18 antidepressants of different classes for their effect on GR signaling in a reporter gene assay using the mouse hippocampal cell line HT22. We evaluated GR-mediated gene transcription after short-time incubation (24 h) with different concentrations of each antidepressant (1 or 10 µM) in the presence or absence of the synthetic steroid dexamethasone (0.01 or 1 µM). The majority of antidepressants had a tendency to enhance steroid-induced GR-mediated gene transcription at high concentrations of antidepressant and low concentrations of steroid. Some antidepressants reduced the steroid-independent background activity of GR. This reduction was not due to unspecific inhibition of GR by oxidative stress, since no induction of intracellular peroxides was detectable in the concentration range of antidepressants used in our study. Furthermore, no significant change in GR activity was observed by concomitant treatment of HT22 cells with the antioxidant α-tocopherol (vitamin E). In conclusion, we report that many antidepressants enhance GR signaling in an in vitro neuronal system at clinically relevant concentrations. Those not showing an effect in vitro apparently use different mechanisms to influence GR activity that require an in vivo setting.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000;23:477–501.

    External Resources

  2. Manji HK, Drevets WC, Charney DS: The cellular neurobiology of depression. Nat Med 2001;7:541–547.
  3. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett AL: Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry 1987;44:328–336.
  4. Rubin RT, Phillips JJ, Sadow TF, McCracken JT: Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry 1995;52:213–218.
  5. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W: Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226:1342–1344.
  6. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M: Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988;45:577–579.
  7. Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF: Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60:436–444.
  8. Strickland PL, Deakin JF, Percival C, Dixon J, Gater RA, Goldberg DP: Bio-social origins of depression in the community. Interactions between social adversity, cortisol and serotonin neurotransmission. Br J Psychiatry 2002;180:168–173.
  9. Cowen PJ: Cortisol, serotonin and depression: All stressed out? Br J Psychiatry 2002;180:99–100.
  10. Zhou DF, Shen YC, Shu LN, Lo HC: Dexamethasone suppression test and urinary MHPG X SO4 determination in depressive disorders. Biol Psychiatry 1987;22:883–891.
  11. Heuser I, Yassouridis A, Holsboer F: The combined dexamethasone/CRH test: A refined laboratory test for psychiatric disorders. J Psychiatr Res 1994;28:341–356.
  12. Rybakowski JK, Twardowska K: The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res 1999;33:363–370.
  13. von Bardeleben U, Holsboer F: Effect of age on the cortisol response to human corticotropin-releasing hormone in depressed patients pretreated with dexamethasone. Biol Psychiatry 1991;29:1042–1050.
  14. Rupprecht R, Wodarz N, Kornhuber J, Wild K, Schmitz B, Braner HU, Muller OA, Riederer P, Beckmann H: In vivo and in vitro effects of glucocorticoids on lymphocyte proliferation in depression. Eur Arch Psychiatry Clin Neurosci 1991;241:35–40.
  15. Bauer ME, Papadopoulos A, Poon L, Perks P, Lightman SL, Checkley S, Shanks N: Altered glucocorticoid immunoregulation in treatment resistant depression. Psychoneuroendocrinology 2003;28:49–65.
  16. Holsboer F, Liebl R, Hofschuster E: Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinical improvement. J Affect Disord 1982;4:93–101.
  17. Greden JF, Gardner R, King D, Grunhaus L, Carroll BJ, Kronfol Z: Dexamethasone suppression tests in antidepressant treatment of melancholia. The process of normalization and test-retest reproducibility. Arch Gen Psychiatry 1983;40:493–500.
  18. Holsboer F, Gerken A, Stalla GK, Muller OA: ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery. Biol Psychiatry 1985;20:276–286.
  19. Pfeiffer A, Barden N: Glucocorticoid receptor gene expression in rat pituitary gland intermediate lobe following ovariectomy. Mol Cell Endocrinol 1988;55:115–120.
  20. Przegalinski E, Budziszewska B: The effect of long-term treatment with antidepressant drugs on the hippocampal mineralocorticoid and glucocorticoid receptors in rats. Neurosci Lett 1993;161:215–218.
  21. Przegalinski E, Budziszewska B, Siwanowicz J, Jaworska L: The effect of repeated combined treatment with nifedipine and antidepressant drugs or electroconvulsive shock on the hippocampal corticosteroid receptors in rats. Neuropharmacology 1993;32:1397–1400.
  22. Seckl JR, Fink G: Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology 1992;55:621–626.
  23. Reul JM, Stec I, Soder M, Holsboer F: Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993;133:312–320.
  24. Shelton RC: Intracellular Mechanisms of antidepressant drug action. Harv Rev Psychiatry 2000;8:161–174.
  25. Brady LS, Whitfield HJJ, Fox RJ, Gold PW, Herkenham M: Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest 1991;87:831–837.
  26. Rossby SP, Nalepa I, Huang M, Perrin C, Burt AM, Schmidt DE, Gillespie DD, Sulser F: Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant. Brain Res 1995;687:79–82.
  27. Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, Engelmann M, Reul JM, Landgraf R, Holsboer F: Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol 1995;7:841–845.
  28. Pepin MC, Pothier F, Barden N: Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 1992;355:725–728.
  29. Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJJ: The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res 1992;572:117–125.
  30. Budziszewska B, Siwanowicz J, Przegalinski E: The effect of chronic treatment with antidepressant drugs on the corticosteroid receptor levels in the rat hippocampus. Pol J Pharmacol 1994;46:147–152.
  31. Pariante CM, Miller AH: Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment. Biol Psychiatry 2001;49:391–404.
  32. Pariante CM, Pearce BD, Pisell TL, Owens MJ, Miller AH: Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. Mol Pharmacol 1997;52:571–581.
  33. Pepin MC, Govindan MV, Barden N: Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. Mol Pharmacol 1992;41:1016–1022.
  34. Budziszewska B, Jaworska-Feil L, Kajta M, Lason W: Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription – a possible mechanism. Br J Pharmacol 2000;130:1385–1393.
  35. Glotzbach RK, Preskorn SH: Brain concentrations of tricyclic antidepressants: Single-dose kinetics and relationship to plasma concentrations in chronically dosed rats. Psychopharmacology (Berl) 1982;78:25–27.
  36. Hrdina PD, Dubas TC: Brain distribution and kinetics of desipramine in the rat. Can J Physiol Pharmacol 1981;59:163–167.
  37. Miyake K, Fukuchi H, Kitaura T, Kimura M, Sarai K, Nakahara T: Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline. J Pharm Sci 1990;79:288–291.
  38. Post A, Crochemore C, Uhr M, Holsboer F, Behl C: Differential induction of NF-kappaB activity and neural cell death by antidepressants in vitro. Eur J Neurosci 2000;12:4331–4337.
  39. Makino Y, Yoshikawa N, Okamoto K, Hirota K, Yodoi J, Makino I, Tanaka H: Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. J Biol Chem 1999;274:3182–3188.
  40. Bodwell JE, Holbrook NJ, Munck A: Evidence for distinct sulfhydryl groups associated with steroid- and DNA-binding domains of rat thymus glucocorticoid receptors. Biochemistry 1984;23:4237–4242.
  41. Makino Y, Okamoto K, Yoshikawa N, Aoshima M, Hirota K, Yodoi J, Umesono K, Makino I, Tanaka H: Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system. J Clin Invest 1996;98:2469–2477.
  42. Hutchison KA, Matic G, Meshinchi S, Bresnick EH, Pratt WB: Redox manipulation of DNA binding activity and BuGR epitope reactivity of the glucocorticoid receptor. J Biol Chem 1991;266:10505–10509.
  43. Chakraborti PK, Garabedian MJ, Yamamoto KR, Simons SS: Role of cysteines 640, 656, and 661 in steroid binding to rat glucocorticoid receptors. J Biol Chem 1992;267:11366–11373.
  44. Morimoto BH, Koshland DEJ: Induction and expression of long- and short-term neurosecretory potentiation in a neural cell line. Neuron 1990;5:875–880.
  45. Herr A, Wochnik GM, Rosenhagen MC, Holsboer F, Rein T: Rifampicin is not an activator of the glucocorticoid receptor. Mol Pharmacol 2000;57:732–737.
  46. Hollenberg SM, Evans RM: Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell 1988;55:899–906.
  47. Behl C, Davis JB, Lesley R, Schubert D: Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 1994;77:817–827.
  48. Raber J: Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. From obesity to memory deficits. Mol Neurobiol 1998;18:1–22.
  49. Born J, Fehm HL: Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. Exp Clin Endocrinol Diabetes 1998;106:153–163.
  50. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M: Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301.
  51. Pariante CM, Makoff A, Lovestone S, Feroli S, Heyden A, Miller AH, Kerwin RW: Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. Br J Pharmacol 2001;134:1335–1343.
  52. Okugawa G, Omori K, Suzukawa J, Fujiseki Y, Kinoshita T, Inagaki C: Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones. J Neuroendocrinol 1999;11:887–895.
  53. Reul JM, Labeur MS, Grigoriadis DE, De Souza EB, Holsboer F: Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide. Neuroendocrinology 1994;60:509–519.
  54. Steckler T, Rammes G, Sauvage M, van Gaalen MM, Weis C, Zieglgansberger W, Holsboer F: Effects of the monoamine oxidase A inhibitor moclobemide on hippocampal plasticity in GR-impaired transgenic mice. J Psychiatr Res 2001;35:29–42.
  55. Bjartmar L, Johansson IM, Marcusson J, Ross SB, Seckl JR, Olsson T: Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat. Psychopharmacology (Berl) 2000;151:7–12.
  56. Sillaber I, Montkowski A, Landgraf R, Barden N, Holsboer F, Spanagel R: Enhanced morphine-induced behavioural effects and dopamine release in the nucleus accumbens in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: influence of long-term treatment with the antidepressant moclobemide. Neuroscience 1998;85:415–425.
  57. Then Bergh F, Kumpfel T, Grasser A, Rupprecht R, Holsboer F, Trenkwalder C: Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial. J Clin Endocrinol Metab 2001;86:1610–1615.
  58. Alpsoy E, Ozcan E, Cetin L, Ozgur O, Er H, Yilmaz E, Karaman T: Is the efficacy of topical corticosteroid therapy for psoriasis vulgaris enhanced by concurrent moclobemide therapy? A double-blind, placebo-controlled study. J Am Acad Dermatol 1998;38:197–200.
  59. Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H: Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry 2003;60:24–28.
  60. Schüle C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G: The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects. Psychopharmacology (Berl) 2002;163:95–101.
  61. Sapolsky RM, Krey LC, McEwen BS: The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;7:284–301.
  62. Brown ES, Rush AJ, McEwen BS: Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology 1999;21:474–484.

    External Resources

  63. Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, Schatzberg AF: An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002;52:386–392.
  64. Gold P, Drevets W, Charney D: New insights into the role of cortisol and the glucocorticoid receptor in severe depression. Biol Psychiatry 2002;52:381.
  65. Uhr M, Holsboer F, Muller MB: Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins. J Neuroendocrinol 2002;14:753–759.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50