Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Enhancement of serotonin uptake by cortisol: A possible link between stress and depression

  • 4225 Accesses

  • 48 Citations


Stress and depression are characterized by elevation of circulating cortisol, as well as by changes in physiological functions. In this study, we addressed the possibility that elevated cortisol is also associated with the origin and development of depression. We report here that cortisol at the nM-μM concentration range induces a substantial increase in serotonin uptake both in vitro, by human peripheral blood lymphocytes (PBLs) and cortical neuronal cells, and in vivo, by rabbit PBLs, owing to promotion of synthesis of the serotonin transporter. These findings offer a novel molecular mechanism for depression associated with stress. Accordingly, the elevated cortisol induced by stress increases serotonin uptake, under both rest and nerve stimulation, which is overtly expressed in symptoms of depression.


  1. Abramson, L. Y., Seligman, M. E., & Teasdale, J. D. (1978). Learned helplessness in humans: Critique and reformulation. Journal of Abnormal Psychology, 87, 49–74.

  2. Akil, H. A., & Morano, M. I. (1995). Stress. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 773–785). New York: Raven.

  3. Amara, S. G., & Kuhar, M. J. (1993). Neurotransmitter transporters: Recent progress. Annual Reviews in Neuroscience, 16, 73–93.

  4. Amsterdam, J. D., Winokur, A., Caroff, S. N., & Conn, J. (1982). The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects. American Journal of Psychiatry, 139, 287–291.

  5. Antoni, F.A. (1986). Hypothalamic control of adrenocorticotropin secretion: Advances since the discovery of 41-residue corticotropinreleasing factor. Endocrine Reviews, 7, 351–378.

  6. Axelrod, J., & Reisine, T. D. (1984). Stress hormones: Their interaction and regulation. Science, 224, 452–459.

  7. Barden, N., Reul, J. M., & Holsboer, F. (1995). Do antidepressants stabilize mood through actions on the hypothalamic-pituitaryadrenocortical system? Trends in Neurosciences, 18, 6–11.

  8. Barker, E. L., & Blakely, R.D. (1995). Norepinephrine and serotonin transporters: Molecular targets of antidepressant drugs. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation (pp. 321–334). New York: Raven.

  9. Beato, M. (1989). Gene regulation by steroid hormones. Cell, 56, 335–344.

  10. Beato, M., Chalepakis, G., Schauer, M., & Slater, E. P. (1989). DNA regulatory elements for steroid hormones. Journal of Steroid Biochemistry, 32, 737–747.

  11. Block, E. R., & Edwards, D. (1987). Effect of plasma membrane fluidity on serotonin transport by endothelial cells. American Journal of Physiology, 253, C672-C678.

  12. Carroll, B. J., Curtis, G. C., & Mendels, J. (1976). Cerebrospinal fluid and plasma free cortisol concentrations in depression. Psychological Medicine, 6, 235–244.

  13. Chaouloff, F. (1993). Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain Research Review, 18, 1–32.

  14. Charles, G., Ansseau, M., Sulon, J., Demey-Ponsart, E., Meunier, J. C., Wilmotte, J., & Legros, J. J. (1986). Free cortisol and the dexamethasone suppression test. Biological Psychiatry, 21, 549–552.

  15. Chrousos, G. P., & Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. Journal of the American Medical Association, 267, 1244–1252.

  16. Dallman, M. F., Akana, S. F., Levin, N., Walker, C. D., Bradbury, M. J., Suemaru, S., & Scribner, K. S. (1994). Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. In E. R. de Kloet, E. C. Azmitia, & P. W. Landfield (Eds.), Brain corticosteroid receptors: Studies on the mechanism, function, and neurotoxicity of corticosteroid action (Annals of the New York Academy of Sciences, Vol. 746, pp. 22–31). New York: New York Academy of Sciences.

  17. Dallman, M. F., Makara, G.B., Roberts, J.L., Levin, N., & Blum, M. (1985). Corticotrope response to removal of releasing factors and corticosteroids in vivo. Endocrinology, 117, 2190–2197.

  18. Deakin, J. F. W. (1998). The role of serotonin in panic, anxiety, and depression. International Clinical Psychopharmacology, 13 (Suppl. 4) S1-S5.

  19. Dunn, K. J., Perez-Polo, J. R., & Wood, T. G. (1996). Rapid neurite formation in a human cortical neuronal cell line. International Journal of Developmental Neuroscience, 14, 61–68.

  20. Evans, R.M. (1988). The steroid and thyroid hormone receptor superfamily. Science, 240, 889–895.

  21. Faraj, B. A., Olkowski, Z. L., & Jackson, R. T. (1991). Binding of [3H]-dopamine to human lymphocytes: Possible relationship to neurotransmitter uptake sites. Pharmacology, 42, 135–141.

  22. Faraj, B.A., Olkowski, Z. L., & Jackson, R. T. (1994). Expression of a high-affinity serotonin transporter in human lymphocytes. International Journal of Immunopharmacology, 16, 561–567.

  23. Faraj, B. A., Olkowski, Z. L., & Jackson, R. T. (1997). Prevalence of high serotonin uptake in lymphocytes of abstinent alcoholics. Biochemical Pharmacology, 53, 53–57.

  24. Gerritsen, M. E., Schwarz, S. M., & Medow, M. S. (1991). Glucocorticoid-mediated alterations in fluidity of rabbit cardiac muscle microvessel endothelial cell membranes: Influences on eicosanoid release. Biochimica et Biophysica Acta, 1065, 63–68.

  25. Gold, P.W., Goodwin, F. K., & Chrousos, G. P. (1988a). Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress. New England Journal of Medicine, 319, 348–353.

  26. Gold, P.W., Goodwin, F. K., & Chrousos, G. P. (1988b). Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress. New England Journal of Medicine, 319, 413–420.

  27. Grodzicki, J., Pardo, M., Schved, G., Schlosberg, A., Fuchs, S., & Kanety, H. (1990). Differences in [3H]-spiperone binding to peripheral blood lymphocytes from neuroleptic responsive and nonresponsive schizophrenic patients. Biological Psychiatry, 27, 1327–1330.

  28. Halbach, M., & Henning, U. (1989). Abnormal glucocorticoid dependent increase of spiperone binding sites on lymphocytes from schizophrenics in vitro. Pharmacopsychiatry, 22, 169–173.

  29. Havenaar, R., Meijer, J. C., Morton, D. B., Ritskes-Hoitinga, J., & Zwart, P. (1993). Biology and husbandry of laboratory animals. In L. F. M. Van Zutphen, V. Baumans, & A. C. Beynen (Eds.), Principles of laboratory animal science (pp. 17–74). Amsterdam: Elsevier.

  30. Henninger, G. R. (1995).The role of serotonin in clinical disorders. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 471–482). New York: Raven.

  31. Herman, J. P., Schafer, M. K., Young, E. A., Thompson, R., Douglass, J., Akil, H., & Watson, S. J. (1989). Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamopituitary-adrenocortical axis. Journal of Neuroscience, 9, 3072–3082.

  32. Hoffman, B. J., Mezey, E., & Brownstein, M. J. (1991). Cloning of a serotonin transporter affected by antidepressants. Science, 254, 579–580.

  33. Holsboer, F. (1995). Neuroendocrinology of mood disorders. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 957–969). New York: Raven.

  34. Kanner, B. I., & Schuldiner, S. (1987). Mechanism of transport and storage of neurotransmitters. CRC Critical Reviews in Biochemistry, 22, 1–38.

  35. Keller-Wood, M. E., & Dallman, M. F. (1984). Corticosteroid inhibition of ACTH secretion. Endocrine Reviews, 5, 1–24.

  36. Kelly, W. F., Checkley, S. A., & Bender, D. A. (1980). Cushing’s syndrome, tryptophan and depression. British Journal of Psychiatry, 136, 125–132.

  37. LeDoux, J. E., Iwata, J., Cicchetti, P., & Reis, D. J. (1988). Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. Journal of Neuroscience, 8, 2517–2529.

  38. Le Fur, G., Phan, T., & Uzan, A. (1980). Identification of stereospecific [3H]spiroperidol binding sites in mammalian lymphocytes. Life Sciences, 26, 1139–1148.

  39. Lesch, K. P., Balling, U., Gross, J., Strauss, K., Wolozin, B. L., Murphy, D. L., & Riederer, P. (1994). Organization of the human serotonin transporter gene. Journal of Neural Transmission, 95, 157–162.

  40. Lesch, K. P., Wolozin, B. L., Murphy, D. L., & Reiderer, P. (1993). Primary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. Journal of Neurochemistry, 60, 2319–2322.

  41. Maes, M., & Meltzer, H.Y. (1995). The serotonin hypothesis of major depression. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 933–943). New York: Raven.

  42. Mann, J. J., Brown, R. P., Halper, J. P., Sweeney, J. A., Kocsis, J. H., Stokes, P. E., & Bilezikian, J. P. (1985). Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. New England Journal of Medicine, 313, 715–720.

  43. McEwen, B. S., & Brinton, R. E. (1987). Neuroendocrine aspects of adaptation. Progress in Brain Research, 72, 11–26.

  44. McEwen, B. S., & Sapolsky, R.M. (1995). Stress and cognitive function. Current Opinion in Neurobiology, 5, 205–216.

  45. Meltzer, H.Y., & Lowy, M. T. (1987). The serotonin hypothesis of depression. In H. Meltzer (Ed.), Psychopharmacology: The third generation of progress (pp. 513–526). New York: Raven.

  46. Mokrani, M. C., Duval, F., Crocq, M.A., Bailey, P., & Macher, J. P. (1997). HPA axis dysfunction in depression: Correlation with monoamine system abnormalities. Psychoneuroendocrinology, 22(Suppl. 1), S63-S68.

  47. Munck, A., Guyre, P. M., & Holbrook, N. J. (1984). Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endrocrine Reviews, 5, 25–44.

  48. Murphy, B. E. (1991). Steroids and depression. Journal of Steroid Biochemistry and Molecular Biology, 38, 537–559.

  49. Murphy, B. E. (1997). Antiglucocorticoid therapies in major depression: A review. Psychoneuroendocrinology, 22(Suppl. 1), S125-S132.

  50. Murphy, B. E., Dhar, V., Ghadirian, A. M., Chouinard, G., & Keller, R. (1991). Response to steroid suppression in major depression resistant to antidepressant therapy. Journal of Clinical Psychopharmacology, 11, 121–126.

  51. Oitzl, M. S., van Haarst, A. D., & De Kloet, E. R. (1997). Behavioral and neuroendocrine responses controlled by the concerted action of central mineralocorticoid (MRS) and glucocorticoid receptors (GRS). Psychoneuroendocrinology, 22(Suppl. 1), S87-S93.

  52. Owens, M. J., & Nemeroff, C. B. (1994). Role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clinical Chemistry, 40, 288–295.

  53. Peeters, B. W., & Broekkamp, C. L. (1994). Involvement of corticosteroids in the processing of stressful life-events: A possible implication for the development of depression. Journal of Steroid Biochemistry & Molecular Biology, 49, 417–427.

  54. Post, R. M. (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. American Journal of Psychiatry, 149, 999–1010.

  55. Ramamoorthy, S., Bauman, A. L., Moore, K. R., Han, H., Yang-Feng, T., Chang, A. S., Ganapathy, V., & Blakely, R. D. (1993). Antidepressant- and cocaine-sensitive human serotonin transporter: Molecular cloning, expression, and chromosomal localization. Proceedings of the National Academy of Sciences, 90, 2542–2546.

  56. Reichel, R. R., & Jacob, S. T. (1993). Control of gene expression by lipophilic hormones. Federation of American Societies for Experimental Biology Journal, 7, 427–436.

  57. Reus, V. I., Wolkowitz, O. M., & Frederick, S. (1997). Antiglucocorticoid treatments in psychiatry. Psychoneuroendocrinology, 22(Suppl. 1), S121-S124.

  58. Ronnett, G. V., Hester, L. D., Nye, J. S., Connors, K., & Snyder, S. H. (1990). Human cortical neuronal cell line: Establishment from a patient with unilateral megalencephaly. Science, 248, 603–605.

  59. Scheidereit, C., Krauter, P., Von Der Ahe, D., Janich, S., Rabenau, O., Cato, A. C., Suske, G., Westphal, H.M., & Beato, M. (1986). Mechanism of gene regulation by steroid hormones. Journal of Steroid Biochemistry & Molecular Biology, 24, 19–24.

  60. Selye, H. (1946). The general adaptation syndrome and the diseases of adaptation. Journal of Clinical Endocrinology, 6, 117–130.

  61. Selye, H. (1950). Stress and the general adaptation syndrome. British Medical Journal, 1, 1383–1392.

  62. Shinitzky, M. (1984). Membrane fluidity and cellular functions. In M. Shinitzky (Ed.), Physiology of membrane fluidity (pp. 1–52). Boca Raton, FL: CRC Press.

  63. Shinitzky, M., & Barenholz, Y. (1978). Fluidity parameters of lipid regions determined by fluorescence polarization. Biochimica et Biophysica Acta, 515, 367–394.

  64. Smelik, P. G. (1987). Adaptation and brain function. Progress in Brain Research, 72, 3–9.

  65. Starkman, M. N., Schteingart, D. E., & Schork, M.A. (1981). Depressed mood and other psychiatric manifestations of Cushing’s syndrome: Relationship to hormone levels. Psychosomatic Medicine, 43, 3–18.

  66. Teasdale, J. D. (1978). Effects of real and recalled success on learned helplessness and depression. Journal of Abnormal Psychology, 87, 155–164.

  67. Thase, M. E., & Rush, A. J. (1995). Treatment-resistant depression. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 1081–1097). New York: Raven.

  68. Truss, M., & Beato, M. (1993). Steroid hormone receptors: Interaction with deoxyribonucleic acid and transcription factors. Endocrine Reviews, 14, 459–479.

  69. Wolkowitz, O. M., Reus, V. I., Manfredi, F., Ingbar, J., Brizendine, L., & Weingartner, H. (1993). Ketoconazole administration in hypercortisolemic depression. American Journal of Psychiatry, 150, 810–812.

Download references

Author information

Correspondence to Meir Shinitzky.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tafet, G.E., Toister-Achituv, M. & Shinitzky, M. Enhancement of serotonin uptake by cortisol: A possible link between stress and depression. Cognitive, Affective, & Behavioral Neuroscience 1, 96–104 (2001). https://doi.org/10.3758/CABN.1.1.96

Download citation


  • Cortisol
  • Serotonin
  • Serotonin Transporter
  • Serotonin Uptake
  • Human Peripheral Blood Lymphocyte