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Contribution of the Opioid System to the Antidepressant Effects of Fluoxetine

  • Elena Carazo-Arias
    Affiliations
    Department of Biological Sciences, Columbia University, New York State Psychiatric Institute, New York, New York

    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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  • Phi T. Nguyen
    Affiliations
    Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York

    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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  • Marley Kass
    Affiliations
    Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York

    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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  • Hyun Jung Jee
    Affiliations
    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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  • Katherine M. Nautiyal
    Affiliations
    Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire
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  • Valerie Magalong
    Affiliations
    Program in Developmental Neurogenetics, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California
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  • Lilian Coie
    Affiliations
    Department of Neuroscience, Columbia University, New York State Psychiatric Institute, New York, New York
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  • Valentine Andreu
    Affiliations
    Department of Neuroscience, Columbia University, New York State Psychiatric Institute, New York, New York
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  • Mark M. Gergues
    Affiliations
    Department of Psychology, Rutgers University, New Brunswick, New Jersey
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  • Huzefa Khalil
    Affiliations
    Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan

    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan
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  • Huda Akil
    Affiliations
    Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan

    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan
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  • Danusa Mar Arcego
    Affiliations
    Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Centre, McGill University, Montreal, Québec, Canada
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  • Michael Meaney
    Affiliations
    Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Centre, McGill University, Montreal, Québec, Canada

    Sackler Program for Epigenetics and Psychobiology, Douglas Hospital Research Centre, McGill University, Montreal, Québec, Canada

    Singapore Institute for Clinical Sciences, Singapore
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  • Christoph Anacker
    Affiliations
    Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York
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  • Benjamin A. Samuels
    Affiliations
    Department of Psychology, Rutgers University, New Brunswick, New Jersey
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  • John E. Pintar
    Affiliations
    Department of Neuroscience & Cell Biology, Rutgers University, New Brunswick, New Jersey
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  • Irina Morozova
    Affiliations
    Center for Genome Technology and Biomolecular Engineering, Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Chemical Engineering, Columbia University, New York State Psychiatric Institute, New York, New York
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  • Sergey Kalachikov
    Affiliations
    Center for Genome Technology and Biomolecular Engineering, Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Chemical Engineering, Columbia University, New York State Psychiatric Institute, New York, New York

    Data Science Institute, Columbia University, New York State Psychiatric Institute, New York, New York
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  • Rene Hen
    Correspondence
    Address correspondence to Rene Hen, Ph.D.
    Affiliations
    Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Neuroscience, Columbia University, New York State Psychiatric Institute, New York, New York

    Department of Pharmacology, Columbia University, New York State Psychiatric Institute, New York, New York

    Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York
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      Abstract

      Background

      Selective serotonin reuptake inhibitors such as fluoxetine have a limited treatment efficacy. The mechanism by which some patients respond to fluoxetine while others do not remains poorly understood, limiting treatment effectiveness. We have found the opioid system to be involved in the responsiveness to fluoxetine treatment in a mouse model for anxiety- and depressive-like behavior.

      Methods

      We analyzed gene expression changes in the dentate gyrus of mice chronically treated with corticosterone and fluoxetine. After identifying a subset of genes of interest, we studied their expression patterns in relation to treatment responsiveness. We further characterized their expression through in situ hybridization and the analysis of a single-cell RNA sequencing dataset. Finally, we behaviorally tested mu and delta opioid receptor knockout mice in the novelty suppressed feeding test and the forced swim test after chronic corticosterone and fluoxetine treatment.

      Results

      Chronic fluoxetine treatment upregulates proenkephalin expression in the dentate gyrus, and this upregulation is associated with treatment responsiveness. The expression of several of the most significantly upregulated genes, including proenkephalin, is localized to an anatomically and transcriptionally specialized subgroup of mature granule cells in the dentate gyrus. We have also found that the delta opioid receptor contributes to some, but not all, of the behavioral effects of fluoxetine.

      Conclusions

      These data indicate that the opioid system is involved in the antidepressant effects of fluoxetine, and this effect may be mediated through the upregulation of proenkephalin in a subpopulation of mature granule cells.

      Keywords

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