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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, MD 21224 USA
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  • Meghan L. Carlton
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA
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  • Tommaso Di Ianni
    Affiliations
    Department of Radiology, Neuroradiology Division, Stanford University School of Medicine, Stanford, CA 94305 USA
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  • Emilya N. Ventriglia
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA
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  • Arianna Rizzo
    Affiliations
    Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L’Hospitalet de Llobregat, Catalonia

    Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L’Hospitalet de Llobregat, Catalonia
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  • Juan L. Gomez
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA
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  • Reece C. Budinich
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA
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  • Yavin Shaham
    Affiliations
    Neurobiology of Relapse Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA
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  • Raag D. Airan
    Affiliations
    Department of Radiology, Neuroradiology Division, Stanford University School of Medicine, Stanford, CA 94305 USA
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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, MD 20892 USA
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  • Jordi Bonaventura
    Correspondence
    Corresponding authors: Jordi Bonaventura, Ph.D.
    Affiliations
    Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224 USA

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

    Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L’Hospitalet de Llobregat, Catalonia
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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, MD 21224 USA

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
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Published:December 24, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.12.019

      Abstract:

      Background

      (S)-ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, but it also binds to and activates mu (MOR) and kappa (KOR) opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown.

      Methods

      We investigated in rats the extent to which (S)-ketamine interacts with opioid receptors 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 self-administration without producing changes to NMDAR or KOR 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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