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Mu Opioid Receptor Activation Mediates (S)-ketamine Reinforcement in Rats: Implications for Abuse Liability

  • Marjorie R. Levinstein
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Meghan L. Carlton
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Tommaso Di Ianni
    Affiliations
    Neuroradiology Division, Department of Radiology, Stanford University School of Medicine, Stanford, California
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  • Emilya N. Ventriglia
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Arianna Rizzo
    Affiliations
    Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L’Hospitalet de Llobregat, Catalonia, Spain

    Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat, Catalonia, Spain
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  • Juan L. Gomez
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Reece C. Budinich
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Yavin Shaham
    Affiliations
    Neurobiology of Relapse Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland
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  • Raag D. Airan
    Affiliations
    Neuroradiology Division, Department of Radiology, Stanford University School of Medicine, Stanford, California
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  • Carlos A. Zarate Jr.
    Affiliations
    Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland
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  • Jordi Bonaventura
    Correspondence
    Address correspondence to Jordi Bonaventura, Ph.D
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland

    Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L’Hospitalet de Llobregat, Catalonia, Spain

    Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat, Catalonia, Spain
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  • Michael Michaelides
    Correspondence
    Michael Michaelides, Ph.D.
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Published:December 24, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.12.019

      Abstract

      Background

      (S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown.

      Methods

      We investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability.

      Results

      We found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine–induced activation of the nucleus accumbens, a key brain reward region. A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and activity and decreased heroin reinforcement without producing changes in NMDA receptor or kappa opioid receptor density.

      Conclusions

      These results suggest that (S)-ketamine’s abuse liability in humans is mediated in part by brain MORs.

      Keywords

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