Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 2002 Dec;22(5-6):797–804. doi: 10.1023/A:1021869310702

Serotonin Transporter Modulation in Blood Lymphocytes from Patients with Major Depression

Lucimey Lima 1, Mary Urbina 1
PMCID: PMC11533775  PMID: 12585696

Abstract

1. Serotonin is a neurotransmitter in the central nervous system which has been implicated in the aetiology and pathogenesis of affective disorders. The serononergic system also plays several roles in the immune system through the expression of a number of its receptor subtypes in the immune cells.

2. Following release serotonin is inactivated by reuptake into neurons and other cells by a specific serotonin sodium and chloride-dependent transporter molecule, whose structure has been elucidated.

3. Measurement [3H]paroxetine binding showed that human lymphocytes contain a high-affinity serotonin transporter.

4. To assess the serotonin function in major depression, we investigated serotonin transporter density in blood lymphocytes from patients with this disorder and selected according to the interview of the American Psychiatric Association.

5. Patients were divided into two groups and treated with two different antidepressant drugs, one group receiving fluoxetine, a selective serotonin reuptake inhibitor, and another mirtazapine, an antagonist of α2-adrenergic auto and heteroreceptors, for a period of 6 weeks.

6. Blood samples were obtained before and after the treatment, lymphocytes were isolated by Ficoll/Hypaque gradient, subjected to differential adhesion to plastic, and cell membranes were prepared for binding assay of [3H]paroxetine.

7. Lymphocytes serotonin transporter number was significantly reduced, while the affinity was unchanged, in patients with major depression disorder as compare to controls.

8. In addition, there was a partial recovery in lymphocytes serotonin(5HT) transporter number in the period posterior to the antidepressants administration, accompanied with clinical and depression rating scales improvement. Serotonin was determined in platelet-poor plasma and in lymphocytes before and after drugs administration, showing a significant decrease in the patients treated compared to untreated and controls.

9. These results are evidence of the potential interaction between the nervous and immune systems. The mechanisms underlying this interaction are under study, and might be related to modifications in the expression or function of the serotonin transporters in lymphocytes of depressed patients.

Keywords: lymphocytes, major depression, serotonin, serotonin transporter

REFERENCES

  1. Aghajanian, G. K., and Sanders-Busch, E. (2002). Serotonin. In Davis, K. L., Charney, D., Coyle, J. T., and Nemeroff, C. (eds.), Neuropsychopharmacology, The Fifth Generation of Progress, Lippincott Wiliams & Wilkins, New York, pp. 15–34. [Google Scholar]
  2. American Psychiatric Association (1994). Diagnostic and Statistical Manual for Mental Disorders (DSMIV), American Psychiatric Association, Washington, DC. [Google Scholar]
  3. American Psychiatric Association (2000). Handbook of Psychiatric Measurements (HPM), 1st edn., American Psychiatric Association, Washington, DC. [Google Scholar]
  4. Baccichet, E., and Peña, S. (2001). El transportador de serotonina en linfocitos de sangre periférica de pacientes con trastorno depresivo mayor antes y después del tratamiento con mirtazapina, Trabajo Especial de Investigación, Universidad Central de Venezuela e Instituto Venezolano de Investigaciones Científicas.
  5. Bakish, D. (2001). New standard of depression treatment: Remission and full recovery. J. Clin. Psychiatry26:5–9. [PubMed] [Google Scholar]
  6. Barker, E. L., and Blakely, R. D. (1995). Norepinephrine and Serotonin transporters. Molecular targets of antidepressant drugs. In Bloom, F. E., and Kupfer, D. F. (eds.), Psychopharmacology: The Fourth Generation of Progress, Vol. 28, Raven Press, New York, pp. 321–333. [Google Scholar]
  7. Blakely, R. D. (2001). Physiological genomics of antidepressant targets: keeping the periphery in mind. J. Neurosci.21:8319–8323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blakely, R.D., Berson, H. E., and Fremeau, R.T. J. (1991). Cloning and expression of a functional serotonin transporter from rat brain. Nature354:66–70. [DOI] [PubMed] [Google Scholar]
  9. Cedeño, N., Lima, L., Obregón, F., and Urbina, M. (2001). Síntesis of serotonin in peripheral blood lymphocytes of rats. Scand. J. Immunol. 54:1325. [Google Scholar]
  10. Duncan, G. E., Little, K. Y., Kirkman, J. A., Kaldas, R. S., Stumpf, W. E., and Breese, G. R. (1992). Autoradiographic characterization of imipramine and citalopram binding in rat and human brain: Species differences and relationships to serotonin innervation patterns. Brain Res.591:181–197. [DOI] [PubMed] [Google Scholar]
  11. Fajardo, O., and Galeno, J. (2000). Receptores 5HT1Aen linfocitos de sangre periférica de pacientes con trastorno depresivo mayor, Trabajo Especial de Investigación, Universidad Central de Venezuela e Instituto Venezolano de Investigaciones Científicas.
  12. Faraj, B. A., Olkowski, L., and Jackson, R. T. (1994). Expression of high-affinity serotonin transporter in human lymphocytes. Int. J. Immunopharmacol.16:561–567. [DOI] [PubMed] [Google Scholar]
  13. Ferrière, F., Khan, N., Meyniel, J., and Deschaux, P. (1999). Characterization of serotonin transport mechanisms in rainbow trout peripheral blood lymphocytes: Role in PHA-induced proliferation. Dev. Comp. Immunol. 23:37–50. [DOI] [PubMed] [Google Scholar]
  14. Fozard, J. (1989). Peripheral Actions of 5-hydroxytryptamine, Oxford University Press, New York. [Google Scholar]
  15. González, A., and Mata, S. (2001). La detección de la patología psiquiátrica menor en una consulta de neurología mediante el Cuestionario de Salud General (GHQ). Arch. Hosp. Vargas43:165–172. GraphPad Prism, Version 2.0 (1998). San Diego, CA. [Google Scholar]
  16. Heils, A., Mossner, R., and Lesch, K. P. (1997).The human serotonin transporter gene polymorphism-basic research and clinical implications. J. Neural Transm.104:1005–1014. [DOI] [PubMed] [Google Scholar]
  17. Hernández, E., Lastra, S., Urbina, M., Carreira, I., and Lima L. (2002). Serotonin, 5-hydroxyindoleacetic acid and serotonin transporter in blood peripheral lymphocytes of patients with generalized anxiety disorder. Int. Immunopharmacol. 2:893–900. [DOI] [PubMed] [Google Scholar]
  18. Hoffman, B. J., Mezey, E., and Brownstein, M. J. (1991). Cloning of a serotonin transporter affected by antidepressants. Science254:579–580. [DOI] [PubMed] [Google Scholar]
  19. Irwin, M. (1999). Immune correlates of depression. Adv. Exp. Med. Biol.461:1–24. [DOI] [PubMed] [Google Scholar]
  20. Keltner, N. L., and Folks, D. G. (2001). Psychotropic Drugs, 3rd. edn., Mosby, London. [Google Scholar]
  21. Lenox, R. H., and Frazer, A. (2002). Mechanism of action of antidepressants and mood stabilizers. In Davis, K. L., Charney, D., Coyle, J. T., and Nemeroff, C. (eds.), Neuropsychopharmacology, The Fifth Generation of Progress, Lippincott Wiliams & Wilkins, New York, pp. 1139–1163. [Google Scholar]
  22. Lesch, K. P., Wolozin, B. L., Murphy, D. L., and Reiderer, P. (1993). Primary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. J. Neurochem.60:2319–2322. [DOI] [PubMed] [Google Scholar]
  23. Lima, L., Radtke, I., and Drujan, B. (1992). [3H]serotonin binding sites in goldfish retinal membranes. Neurochem. Res.17:991–996. [DOI] [PubMed] [Google Scholar]
  24. Lima, L., and Schmeer, C. (1994). Characterization of serotonin transporteer in goldfish retina by biding of [3H]paroxetine and the uptake of [3H]serotonin: Modulation by light. J. Neurochem. 62:528–535. [DOI] [PubMed] [Google Scholar]
  25. Lima, L., Schmeer, C., and Urbina, M. (1994). 8-[3H]Hydroxy-2-(Di-n-propylamino) tetralin binding sites in goldfish retina. Neurochem. Res. 19:249–255. [DOI] [PubMed] [Google Scholar]
  26. Maddock, C., and Pariante, C. M. (2001). How does stress affect you? An overview of stress, immunity, depression and disease. Epidemiol. Psichiatr.10:153–162. [DOI] [PubMed] [Google Scholar]
  27. Mossner, R., and Lesch, K. (1998). Role of serotonin in the immune system and neuroimmune interactions. Brain Behav. Immun.12:249–271. [DOI] [PubMed] [Google Scholar]
  28. Motulsky, H. (1995). Intuitive Biostatistics, Oxford University Press, New York. [Google Scholar]
  29. Murphy, D. L., Li, Q., Engel, S., Wichems, C., Andrews, A., Lesch, K.-P., and Uhl, G. (2001). Genetic perspectives on the serotonin transporter. Brain Res. Bull.56:487–494. [DOI] [PubMed] [Google Scholar]
  30. Nakao, M., Yamanaka, G., and Kuboki, T. (2001). Major depression and somatic symptoms in mind/body medicine clinic. Psychopathology34:230–235. [DOI] [PubMed] [Google Scholar]
  31. Osborne, N. N. (1982). Uptake localization and release of serotonin in chick retina. J. Physiol. 331:17–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Owens, M. J., and Nemeroff, C. B. (1994). The role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clin. Chem.40:288–295. [PubMed] [Google Scholar]
  33. Pacholczyk,T., Blakely, R.D., and Amara S.G. (1991). Expression cloning of a cocaine and antidepressantsensitive human noradrenaline transporter. Nature350:350–354. [DOI] [PubMed] [Google Scholar]
  34. Patten, S. B., Sedmak, B., and Russell, M. L. (2001). Major depression: Prevalence, treatment utilization and age in Canada. Can. J. Clin. Pharmacol. 8:133–138. [PubMed] [Google Scholar]
  35. Ramamoorthy, S., Bauman, A. L., and Moore, K. R. (1993). Antidepressant-and cocaine-sensitive human serotonin transporter: Molecular cloning, expression, and chromosomal localization. Proc. Nactl. Acad. Sci. U.S.A.90:2542–2546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ravna, A. W., and Edvardsen, O. (2001). A putative three-dimensional arrangement of the human serotonin transporter transmembrane helices: A tool to aid experimental studies. J. Mol. Graph. Model.20:133–144. [DOI] [PubMed] [Google Scholar]
  37. Stefulj, J., Jernej,B., Cicin-Sain, L., Rinner, I., and Schauenstein, K. (2000).mRNAespression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav. Immun.14:219–224. [DOI] [PubMed] [Google Scholar]
  38. Uhl, G. R., and Hartig, P. (1992). Transporter explosion: Update on uptake. Trends Pharmacol. 13:4221–422. [DOI] [PubMed] [Google Scholar]
  39. Urbina, M., Pineda, S., Piñango, L., Carreira, I., and Lima, L. (1999). [3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with major depression before and after treatment with fluoxetine. Int. J. Immunopharmacol.21:631–646. [DOI] [PubMed] [Google Scholar]
  40. World Health Organization (1993). International Classification of Diseases (ICD-10), World Health Organization, Geneva. [Google Scholar]
  41. Zaharia, M. D., Ravindran, A. V., Griffiths, J., Merali, Z., and Anisman, H. (2000). Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features. J. Affect. Disord.58:1–10. [DOI] [PubMed] [Google Scholar]
  42. Zhou, F. C., Tao-Cheng, J. H., Segu, L., Patel, T., and Wang, Y. (1998). Serotonin transporters are located on the axons beyond the synaptic junctions: Anatomical and functional evidence. Brain Res.805:241–254. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES