title: Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.
abstract: Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Alboni
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: R M
authors.initials: RM
authors.lastname: van Dijk
authors.affiliation: Department of Cell Biology and Neurosciences, Section of Behavioural Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Poggini
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Milior
authors.affiliation: IRCCS Neuromed, Pozzilli IS, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Perrotta
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Drenth
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Brunello
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.|Institute of Human Movement Sciences and Sport, ETH Zurich, Switzerland.
authors.forename: D P
authors.initials: DP
authors.lastname: Wolfer
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.|IRCCS Neuromed, Pozzilli IS, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Limatola
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Amrein
authors.affiliation: Department of Cell Biology and Neurosciences, Section of Behavioural Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cirulli
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.|Department of Cell Biology and Neurosciences, Section of Behavioural Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Branchi
mesh_terms: D000339:Affect / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D003865:Major Depressive Disorder / Q000188:drug therapy; D058068:Endophenotypes; D004777:Environment; D005473:Fluoxetine / Q000378:metabolism* / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors