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2006, Number 1

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Salud Mental 2006; 29 (1)

The serotoninergic system and depression. Part two

Moreno J, Campos MG, Lara C, Torner C

Language: Spanish
References: 52
Page: 44-50
PDF size: 128.80 Kb.


ABSTRACT

Nowadays there are increasing number of studies to support the crucial role of monoamines in depressive disorders. Among them are studies such as long-term treatment of antidepressants whose mechanism of action regulates monoamine metabolism, monoamine receptor density and post-mortem studies.
An acute increase in monoamine concentration at the synaptic cleft might induce desensitization of brain auto- and heteroreceptors which explains the therapeutic antidepressive response. This has been proved by monoamine depletion studies in which an antidepressant effect or a patient relapse has been observed. Likewise, the antidepressive therapeutic response occurs earlier when auto-receptors are pharmacologically blocked at nervous and somatodendritic terminals.
In the first part of this review, post-mortem studies related with the serotoninergic system were analyzed, as well as the usefulness of measuring serotonin, triptophan, and serotonin metabolite levels in different biological fluids of depressed patients. In this second part, alterations in platelet transporter and serotonin receptors are discussed as platelet is considered a neural serotoninergic model. Platelets are capable of storing and releasing serotonin in a similar manner as serotoninergic synaptosomes. Thus, platelets and serotoninergic synaptic terminals share biochemical and morphological properties.
Serotonin transporter in platelets of depressed patients Due to the difficulty to obtain human brain samples and disagreements in the post-mortem studies, platelets have been suggested as a peripheral model to study neural serotonin uptake. The model is supported by the fact that platelet properties are similar to those of neuronal serotoninergic synaptic terminals.
Serotonin studies in platelets have been useful in clinical aspects such as depressive disturbances. Radioligand studies in platelets from untreated depressed patients have shown a decrease in [3H]imipramine binding sites, compared to the binding in platelets from control subjects. Since that decrease has been consistently confirmed in studies on affective subjects, it has been proposed as a specific biomarker of depressed patients. Nevertheless, some researchers have not found similar results, and no explanation of the variability in the density of [3H]-imipramine binding sites has been proposed.
Serotonin receptor changes in depressed patients The hypothesis on receptor adaptative changes proposes that there is a depletion of monoaminergic neurotransmitters in depressed subjects which induces a compensatory regulation in the number and/or function of receptors. To explore this different techniques as the following have been developed:
••Techniques to evaluate receptor density and affinity, including post-mortem radioligand binding to serotonin receptors in brain tissue and in platelets from depressed patients.
•Techniques to evaluate receptor regulation and sensitivity by using neuroendocrine tests described below.
Somatodendritic 5HT1A autoreceptor dysfunction in depressive disorders disorders
Dysfunction of presynaptic somatodendritic 5HT1A autoreceptors has been found in behavioral changes related to anxiety, depression and alcoholism. Neuroendocrine tests after the administration of 5-HT1A agonists have been used as an index of 5-HT1A receptor function. It seems that azapirodecanediones increase plasmatic concentrations of prolactin, somatotropin, and adrenocorticotropin; they also seem to decrease body temperature.

In depressed patients, the hypothermia response, following presynaptic 5-HT1A receptor stimulation, and the neuroendocrine response, following hypothalamus postsynaptic 5-HT1A receptor stimulation, were both diminished. These findings suggest a desensitization or down-regulation of pre- and post-synaptic 5HT1A receptors in depressed patients.
Platelet 5-HT2A receptors in depressed patients
Density and affinity
Most radioligand studies have found an increase of platelet 5-HT2A receptors either in major depression patients or in attempted suicide patients. However, Rosel et al. studied platelets from depressed patients, finding an increment in the 5-HT2A platelet receptors affinity for [3H]-ketanserin, but not in the receptors density.
Functional capacity
The evaluation of receptor function and sensitivity in platelets is performed after serotonin stimulation by using neuroendocrine tests and some other functional tests, such as platelet aggregation, morphological changes, quantification of intracellular calcium, and second messengers quantification.
Despite being widely used, neuroendocrine tests are not completely reliable because they could be influenced by factors such as: stress on the hypothalamus-hypophysis axis, the lack of stereo-selective agonists and antagonists for different subtype serotonin receptors, and the effect of the drugs on other neurotransmitter systems. Other methodological aspects, such as: population heterogeneity, small samples, lack of variable control (i.e. age, sex, doses, diet, menstrual cycle), and placebo effects, are limitations to the neuroendocrine tests related to a single neurotransmitter system (serotonin).
Results from platelet functional studies are contradictory as well. Platelet aggregation assays in depressed patients suggested a down-regulation of 5-HT2A receptors, compared to platelets from healthy subjects. However, some other studies have found no differences. Other platelet function responses mediated by 5HT2A receptors, such as morphology changes, intracellular calcium, and phosphatidyl inositol hydrolysis, suggest a receptor up-regulation or hypersensitivity in depressed patients.
Despite some disagreement among the results of platelet 5HT2A receptor studies in depressed patients, most of them have reported an increase in 5-HT2A receptors density in these patients. However, suicidal behavior is clearly correlated to such an increase. Similar results have been observed in most post-mortem studies reporting an increase of 5-HT2A receptors in the prefrontal cortex. Protein synthesis and mRNA for 5-HT2A receptors are increased in prefrontal cortex and hippocampus in adolescent and adult suicide victims. These findings suggest that changes in the brain serotonergic system are related to depressive states and suicidal behavior.
Human brain imaging techniques as well as molecular genetics studies may be additional tools to support the understanding of the neurobiology of depressive states, and their treatment.


REFERENCES

  1. ARRANZ B, ERIKSSON A, MELLERUP E, PLENGE P y cols.: Brain 5-HT1A, 5-HT1D, and 45-HT2 receptors in suicide victims. Biol Psychiatry, 35:457-463, 1994.

  2. BAKISH D, CAVAZZONI P, CHUDZIK J, RAVINDRAN A y cols.: Effects of selective reuptake inhibitors on platelet serotonin parameters in major depressive disorder. Biol Psychiatry, 41:184-190, 1997.

  3. BERK M, MITCHELL VS, PLEIN H: The platelet intracellular calcium response to serotonin in subsyndromal depression. Int Clin Psychopharmacol, 13:107-110, 1998.

  4. BIEGON A, GRINSPOON A, BLUMENFELD B, BLEICH A y cols.: Increased serotonin 5-HT2 receptor binding in blood platelets of suicidal men. Psychopharmacology, 100:165167, 1990

  5. BRUSOV OS, BELIAEV BS, KATASONOV AB, ZLOBINA GP y cols.: Does platelet serotonin receptor supersensitivity accompany endogenous depression? Biol Psychiatry, 25(4):375381, 1989.

  6. BUTLER J, LEONARD BE: The platelet serotonergic system in depression and following sertraline treatment. Int Clin Psychopharmacol, 3:343-347, 1988.

  7. CASTROVIOVANNI P, DI MURO A, MARAZZITI D: Imipramine binding as a predictor of fluoxetine response in depressed patients. Neuropsychobiology, 31:64-67, 1995.

  8. CHARNEY DS, MENKES DB, HENINGER GR: Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the aetiology and therapy of depression. Arch Gen Psychiatry, 38:1160-1180, 1981.

  9. COWEN PJ. Serotonin receptor subtypes in depression: evidence from studies in neuroendocrine regulation. Clin Neuropharmacol, 16:6-18, 1993.

  10. CUENCA E, COULLAUT-JAUREGUI, LOPEZ-MUÑOZ F, ALAMO C: Serotonina y depresión. Psiquiatría Biológica, 3(2):53-70, 1996.

  11. D'ONDT P, MAES M, LEYSEN J, GOMMEREN W y cols.: Binding of 3[H]-paroxetine to platelets of depressed patients: Seasonal differences and effects of diagnostic classification. J Affective Dis, 32:27-35, l994.

  12. DELISI SM, KONOPKA LM, OCONNER FL, CRAYTON JW: Platelet cytosolic calcium responses to serotonin in depressed patients and controls: Relationship to symptomatology and medication. Biol Psychiatry, 43:327-334, 1998.

  13. DILLON KA, GROSS-ISSEROFF R, ISRAELI M, BIEGON A: Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol. Brain Res, 544:56-64, 1991.

  14. DUNN EJ, COOTE M, BROWNE G, STEINER M: Biological “markers” in dystimia. Biol Psychiatry, 39:526, 1996.

  15. ELHWUEGI AS: Central monoamines and their role in major depression. Progress Neuro-Psychopharmacology Biological Psychiatry, 28(3):435-451, 2004.

  16. ELLIS PM, SALMOND C: Is platelet imipramine binding reduced in depression? A meta analysis. Biol Psychiatry, 36:292299, 1994.

  17. FREEMAN AM, STANKOVIC SMJ, BRADLEY R, ZHANG GZ y cols.: Tritiated platelet imipramine binding and treatment response in depressed outpatiens. Depression, 1:20-23, 1993.

  18. FUKS Z, LANMAN RC, SCHANKER LS: On the membrane effects of chlorpromazine: uptake of biologic amines by the blood platelets and red cell. Int J Neuro-pharmacol, 3:623-633, 1964.

  19. GOMEZ E, CATALAN R, NAVINES R, GASTO C: Alteraciones de los receptores serotoninérgicos en la depresión: evidencias y limitaciones. Actas Esp Psiquiatr, 29(3): 186194, 2001.

  20. GOMEZ GIL E, MARTINEZ DE OSABA MJ, GASTO C: Pruebas neuroendocrinas de función serotoninérgica y estudios en depresión. Psiquiatría Biológica, 3(4):142-151, 1996.

  21. JURADO N, TORNER C, HEINZE G, LOPEZ G y cols.: Methodologic Pitfalls in measurement of 5-Hydroxytriptamine uptake transporters in human platelets by [3H]-paroxetine binding Assay. Archives Medical Research, 34:422-427, 2003.

  22. KUGAYA A, SANACORA G, STALEY JK, MALISON RT y cols.: Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry, 56(7):497-502,2004.

  23. LANGER SZ, GALZIN A-M: Studies on the serotonin transporter in platelets. Experientia, 44:127-130, 1988.

  24. LANGER SZ, JAVOY-AGID F, RACIMAN R, BRILEY M y cols.: Distribution of specific high-affinity binding sites for [3H]-imipramine in human brain. J Neurochem, 37:267271, 1981a.

  25. LANGER SZ, ZARIFIAN E, BRYLEY M, RAISMAN R y cols.: High-affinity binding of [3H]-imipramine in brain and platelets and its relevance to the biochemistry of affective disorders. Life Sci, 29:211-218, 1981b.

  26. LAWRENCE KM, FALKOWSKI J, JACOBSON RR, HORTON RW: Platelet 5-HT uptake sites in depression: three concurrent measures using [3H]imipramine and [3H]paroxetine. Psychopharmacology, 110:235-239, 1993.

  27. MALISON RT, PRICE LH, BERMAN R, VAN DYCK CH y cols.: Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 betacarbomethoxy-3 beta-(4-iodophenyl)tropane single photon emission computed tomography. Biol Psychiatry, 44(11):10901098, 1998.

  28. MCADAMS C, LEONARD BE: Changes in platelet aggregatory responses to collagen and 5-hidroxytryptamine in depressed, schizophrenic and manic patients. Int Clin Psychopharmacol, 7:81-85, 1992.

  29. MCBRIDE PA, BROWN RP, DEMEO M, KEILIP J y col.: The relationship of platelet 5-HT2 receptor indices to major depressive disorder, personality traits, and suicidal behavior. Biol Prychiatry, 35:295-308, 1994.

  30. MELLERUP E, LANGER SZ: Validity of imipramine platelet binding sites as a biological marker of endogenous depression. A world health organization collaborative study. Pharmacopsychiatry, 23:113-117, 1990.

  31. MEYER JH, KAPUR S, EISFELD B, BROWN GM y cols.: The effect of paroxetine on 5-HT(2A) receptor in depression: an [(18)F]-setoperone PET imaging study. Am J Psychiatry, 158(1):78-85, 2001.

  32. MIKUNI M, KAGAYA A, TAKAHASHI K, MELTZER HY: Serotonin but not norepinephrine-induced calcium mobilisation of platelets is enhanced in affective disorder. Psychopharmacology, 106: 311-314, 1992.

  33. MIKUNI M, KUSUMI I, KAGAYA A, KURODA Y y cols.: Increased 5-HT2 receptor function as measured by serotonin stimulated phosphoinositide hydrolysis in platelets of depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 15:49-61, 1991.

  34. OWENS MJ, NEMEROFF CB: Role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clin Chem, 40(2):288-295, 1994.

  35. OWENS MJ, NEMEROFF CB: The serotonin transporter and depression. Depression Anxiety, 8(supl)1:5-12, 1998.

  36. PANDEY GN, PANDEY SC, DWIVEDI Y, SHARMA RP y cols: Platelet serotonin-2A receptors: A potential biological marker for suicidal behaviour. Am J Psychiatry, 152:850-855, 1995.

  37. PAUL SM, REHAVI M, SKOLNICK P, BALLENGER JC y cols.: Depressed patients have decreased binding of [3H]imipramine to the platelet serotonin “transporters”. Arch Gen Psychiatry, 38:1315-1317, 1981.

  38. PIÑEYRO G, BLIER P: Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev, 51:533-591, 1999.

  39. RAO ML, HAWELLEK B, PAPASSOTIROPOULOS A, DEISTER A y cols.: Upregulation of the platelet serotonin 2A receptor and low blood serotonin in suicidal psychiatric patients. Pharmacopsychiatry, 38:84-89, 1998.

  40. ROSEL P,ARRANZ B,VALLEJO MA:Altered [3H]-imipramine and 5-HT2 but not [3H]-paroxetine binding sites in platelets from depressed patients. J Affect Disord, 52:225-233, 1999.

  41. SERRES F, AZORIN JM, VALLI M, JEANNINGROS R: Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [125I]DOI. Eur Psychiatry, 14:451-457, 1999.

  42. SHAW DM, CAMPS FE, ECCLESTON EG: 5-hydroxytryptamine in the hind brains of depressive suicides. Br J Psychiatry, 113:1.407-1.411, 1967.

  43. SHELINE YI, BARDGETT ME, JACKSON JL, NEWCORNER HW y cols.: Platelet serotonin markers and depressive symptomatology. Biol Psychiatry, 37:442-447, 1995.

  44. SNEDDON JM: Blood platelets as a model for monoamine-containing neurones. Progress Neurobiology, 1:153-198, 1972.

  45. STAIN-MALMGREN R,KJELLMAN BF, ABERG-WISTEDT A: Platelet serotonergic functions and light therapy in seasonal affective disorder. Psychiatry Res, 78:163-172, 1998.

  46. STRÜDER HK, WEICKER H: Physiology and Pathophysiology of the serotonergic System and its implications on mental and physical performance. Part 1. Int J Sports Med, 22:476481, 2001.

  47. SULSER F, VETULANI J, MOBLEY PL: Mode of action of antidepressant drugs. Biochem Pharmacol, 27:257-61, 1978.

  48. TOLLEFSON GD, HEILIGENSTEIN JH, TOLLEFSON SL, BIRKETT MA y cils.: Is there a relationship between baseline and treatment-associated changes in [3H]-IMI platelet binding and clinical response in major depression: Neuropsychopharmacology, 14:47-53, 1996.

  49. TUOMISTO J, TUKIAINEN E, AHLFORS UG: Decreased uptake of 5-hidroxytriptamine in blood platelets from patients with endogenous depression. Psychopharmacology, 65:141-147, 1979

  50. WOOD K, SWADE C, ABOU-SALEH M, COOPEN A: Peripheral serotonergic receptor sensitivity in depressive illness. J Affect Disord, 7:59-65, 1984.

  51. YAMAWAKI S, KAGAYA A, OKAMOTO Y, SHIMIZU M y cols.: Enhanced calcium response to serotonin in platelets from patients with affective disorders. J Psychol Neurosci, 21(5):321-324, 1996.

  52. ZANARDI R,ARTIGAS F,MORESCO R,COLOMBO C y cols.: Increased 5-hidroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography can study. J Clin Psychopharmacol, 21:53-58, 2001.




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