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      Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression

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          Abstract

          This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS) which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9), CMS+fluoxetine (n = 9) and the control (n = 6) groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively ( p<0.05). There was a trend of reduction of IL-6 and TNF-α concentration. This study revealed the potential therapeutic effects of fluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.

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          Most cited references36

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          Behavioural despair in rats: a new model sensitive to antidepressant treatments.

          Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
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            Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.

            This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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              A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.

              Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-α and NO production. We then investigated whether these effects might involve either β-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: Formal analysisRole: Methodology
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 October 2017
                2017
                : 12
                : 10
                : e0186700
                Affiliations
                [1 ] Department of Clinical Psychology and Psychiatry/School of Public Health, Zhejiang University College of Medicine, Hangzhou, China
                [2 ] Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                [3 ] Department of Psychological Medicine, National University Health System, Singapore
                [4 ] Shandong Provincial Key Laboratory of Cerebral Microcirculation, Taishan Medical University, Tai’an, China
                [5 ] Department of Medical Psychology, School of Basic Medical Sciences, Taishan Medical University, Tai’an, China
                [6 ] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
                [7 ] Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
                [8 ] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
                [9 ] Department of Toxicology and Pharmacology, University of Toronto, Toronto, Ontario, Canada
                Radboud University Medical Centre, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-0878-7525
                Article
                PONE-D-17-25989
                10.1371/journal.pone.0186700
                5648231
                29049348
                6907cd93-d13a-4794-84de-3fe3f0f139a2
                © 2017 Lu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 July 2017
                : 5 October 2017
                Page count
                Figures: 4, Tables: 2, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81600018
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001352, National University of Singapore;
                Award ID: 519600-X11601
                Award Recipient :
                This project was supported by National Science Funds for Young Scientist (81600018 to YL) provided by the National Natural Science Foundation of China (NSFC) and Joint Research Fund for International Cooperation (519600-X11601 to YL) provided by the National University of Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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