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      Serotonin, 5-HT 1A Serotonin Receptors and Proliferation of Lymphocytes in Major Depression Patients

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          Abstract

          Serotonin receptors are present in lymphocytes and might be related to the functionality of these cells in health and in pathology. The serotonergic system is affected in the brain and in peripheral immune cells of depressed patients. The objectives of this work were to evaluate the basal proliferation of lymphocytes, the response to the mitogen concanavalin A, and the role of serotonin 5-HT<sub>1A</sub> receptors. Twenty-nine patients, 19–52 years old, were diagnosed for a major depression episode with the Statistical and Diagnostic Manual-IV of the American Psychiatric Association, approved by ethic committees and gave written consent. The Hamilton depression score was 30.60 ± 2.65. An apparently healthy group without a family history of psychiatric illness was included. Blood peripheral lymphocytes were isolated by density gradients with Ficoll/Hypaque and differential adhesion to plastic, cultured in 96-well plaques with RPMI-1640 medium with or without 4 µg/ml of concanavalin A. 8-Hydroxy-2-(di- n-propylamino)tetralin (5–40 n M) and WAY-100,478 (0.1–100 µ M), agonist and antagonist of 5-HT<sub>1A</sub> receptors, serotonin (12.5–100 n M) or imipramine (0.1–100 µ M) were also added. Proliferation was evaluated at 72 h with 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide, and the optical density was 570 nm. Basal proliferation was three times higher in depressed patients than in controls, whereas no response to mitogen was obtained, and 5-HT<sub>1A</sub> receptors significantly reacted to the agonist, with increases of about 31–54% at 10, 20 and 40 n M of the specific agonist, indicating initial activation probably in relation to autoimmunity and overreactivity of these receptors in depression. The antagonist reduced proliferation in mitogen-stimulated lymphocytes, 50% in controls and 70% in depressed patients, with a differential concentration dependency; probably, these receptors are more sensitive in depression due to increased 5-HT<sub>1A</sub> receptor transduction. The antagonist also reduced the stimulation produced by the 5-HT<sub>1A</sub> agonist. Imipramine caused biphasic effects according to concentrations, showing a possible dual role for serotonin, although all values were significantly higher in depressed subjects. The described alterations might be of relevance in the pathophysiology of depression.

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          Most cited references 35

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          Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression.

          Glucocorticoids play an essential role in the response to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine and immune reactions. A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids (glucocorticoid resistance), which is believed to be related in part to impaired functioning of the glucocorticoid receptor (GR). Glucocorticoid resistance, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. Recent data indicate that glucocorticoid resistance may be a result of impaired GR function secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress. Indeed, inflammatory cytokines and their signaling pathways including mitogen-activated protein kinases, nuclear factor-kappaB, signal transducers and activators of transcription, and cyclooxygenase have been found to inhibit GR function. Mechanisms include disruption of GR translocation and/or GR-DNA binding through protein-protein interactions of inflammatory mediators with the GR itself or relevant steroid receptor cofactors as well as alterations in GR phosphorylation status. Interestingly, cAMP signal transduction pathways can enhance GR function and inhibit cytokine signaling. Certain antidepressants have similar effects. Thus, further understanding the effects of cytokines on GR signaling and the mechanisms involved may reveal novel therapeutic targets for reversal of glucocorticoid resistance and restoration of glucocorticoid-mediated inhibition of relevant bodily/immune responses during stress and immune challenge.
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            Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop.

            CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-beta by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-alpha or interferon-gamma. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function.
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              PET imaging of serotonin 1A receptor binding in depression.

              The serotonin-1A (5HT1A) receptor system has been implicated in the pathophysiology of major depression by postmortem studies of suicide victims and depressed subjects dying of natural causes. This literature is in disagreement, however, regarding the brain regions where 5HT1A receptor binding differs between depressives and controls and the direction of such differences relative to the normal baseline, possibly reflecting the diagnostic heterogeneity inherent within suicide samples. PET imaging using the 5HT1A receptor radioligand, [11C]WAY-100635, may clarify the clinical conditions under which 5HT1A receptor binding potential (BP) is abnormal in depression. Regional 5HT1A receptor BP values were compared between 12 unmedicated depressives with primary, recurrent, familial mood disorders and 8 healthy controls using PET and [carbonyl-11C]WAY-100635. Regions-of-interest (ROI) assessed were the mesiotemporal cortex (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies suggested 5HT1A receptor binding is abnormal in depression. The mean 5HT1A receptor BP was reduced 41.5% in the raphe (p < .02) and 26.8% in the mesiotemporal cortex (p < .025) in the depressives relative to the controls. Post hoc comparisons showed the abnormal reduction in 5HT1A receptor BP was not limited to these regions, but extended to control ROI in the occipital cortex and postcentral gyrus as well. The magnitude of these abnormalities was most prominent in bipolar depressives (n = 4) and unipolar depressives with bipolar relatives (n = 4). Serotonin-1A receptor BP is abnormally decreased in the depressed phase of familial mood disorders in multiple brain regions. Of the regions tested, the magnitude of this reduction was most prominent in the midbrain raphe. Converging evidence from postmortem studies of mood disorders suggests these reductions of 5HT1A receptor BP may be associated with histopathological changes involving the raphe.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2007
                August 2007
                15 August 2007
                : 14
                : 1
                : 8-15
                Affiliations
                aLaboratorio de Neuroquímica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, and bServicio de Psiquiatría, Hospital Vargas de Caracas, Caracas, Venezuela
                Article
                107283 Neuroimmunomodulation 2007;14:8–15
                10.1159/000107283
                17700035
                © 2007 S. Karger AG, Basel

                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. 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 government 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.

                Page count
                Figures: 4, References: 55, Pages: 8
                Categories
                Original Paper

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