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Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake

  • Author Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Michel M.M. Verheij
    Correspondence
    Address correspondence to Michel M.M. Verheij, Ph.D., Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Kapittelweg 29, 6525 EN Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
    Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands

    Department of Molecular and Animal Physiology, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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  • Author Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Candice Contet
    Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Affiliations
    Department of Molecular and Animal Physiology, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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  • Peter Karel
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
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  • Judith Latour
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
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  • Rick H.A. van der Doelen
    Affiliations
    Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
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  • Bram Geenen
    Affiliations
    Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
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  • Josephus A. van Hulten
    Affiliations
    Department of Neuroscience, Scripps Research Institute, La Jolla, California
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  • Francisca Meyer
    Affiliations
    Department of Neuroscience, Scripps Research Institute, La Jolla, California
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  • Tamas Kozicz
    Affiliations
    Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
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  • Olivier George
    Affiliations
    Department of Molecular and Animal Physiology, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
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  • Author Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    George F. Koob
    Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Affiliations
    Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
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  • Author Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Judith R. Homberg
    Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
    Affiliations
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands
    Search for articles by this author
  • Author Footnotes
    1 MMMV and CC contributed equally to this work, and GFK and JRH contributed equally to this work.
Published:November 20, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.10.031

      Abstract

      Background

      Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes.

      Methods

      We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking.

      Results

      SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown.

      Conclusions

      Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.

      Keywords

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