title: Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment.
abstract: It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alboni
authors.affiliation: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Poggini
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Garofalo
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC UMR S1127, Institut du Cerveau et de la Moelle épinière, Paris 75013, France.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Milior
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Hassan
authors.initials: H
authors.lastname: El Hajj
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lecours
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Girard
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gagnon
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Boisjoly-Villeneuve
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Brunello
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: David P
authors.initials: DP
authors.lastname: Wolfer
authors.affiliation: Pasteur Institute Rome-Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli, IS, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, 2705, boulevard Laurier, Québec, Canada.
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Tremblay
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy; Institute of Anatomy, University of Zurich, Zurich, Switzerland. Electronic address: igor.branchi@iss.it.
authors.forename: Igor
authors.initials: I
authors.lastname: Branchi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003863:Depression; D004660:Encephalitis / Q000378:metabolism*; D004777:Environment; D005473:Fluoxetine / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013315:Stress, Psychological
chemical_list: D016207:Cytokines; D005473:Fluoxetine; D018836:Inflammation Mediators; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Antidepressant; Cytokines; Environment; Inflammation; Major depression; Microglia; Plasticity; SSRI; Serotonin; Undirected susceptibility to change hypothesis