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Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model

  • Daniele Caprioli
    Correspondence
    Address correspondence to Daniele Caprioli, Ph.D., IRP/NIDA/NIH, Behavioral Neuroscience Branch, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224.
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Marco Venniro
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland

    Neuropsychopharmacology Laboratory, Section of Pharmacology, Department Public Health and Community Medicine, University of Verona, Verona, Italy
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  • Tamara Zeric
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Xuan Li
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Sweta Adhikary
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Rajtarun Madangopal
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Nathan J. Marchant
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland

    Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia
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  • Federica Lucantonio
    Affiliations
    The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Geoffrey Schoenbaum
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Jennifer M. Bossert
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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  • Yavin Shaham
    Affiliations
    Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland
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Published:February 23, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.02.018

      Abstract

      Background

      Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence.

      Methods

      We trained rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 hours/day) or 50 sessions (3 hours/day). We then assessed cue-induced methamphetamine seeking in extinction tests after 1 or 21 abstinence days. Between tests, the rats underwent either forced abstinence (no access to the food- or drug-paired levers) or voluntary abstinence (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day) for 19 days. We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 day or 21 days after forced or voluntary abstinence.

      Results

      Under both training and abstinence conditions, cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day (incubation of methamphetamine craving). AZD8529 decreased cue-induced methamphetamine seeking on day 21 but not day 1 of forced or voluntary abstinence.

      Conclusions

      We introduce a novel animal model to study incubation of drug craving and cue-induced drug seeking after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Our data suggest that positive allosteric modulators of metabotropic glutamate receptor 2 should be considered for relapse prevention.

      Keywords

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      Linked Article

      • Metabotropic Glutamate Receptor 2 Positive Allosteric Modulators: Closing the Gate on Drug Abuse?
        Biological PsychiatryVol. 78Issue 7
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          Abnormally high levels of extracellular glutamate, the principal excitatory neurotransmitter in the central nervous system, have been implicated in elevated drug seeking and taking as well as drug addiction (1). Presynaptic metabotropic glutamate receptors (mGluRs) can limit glutamate release by acting as autoreceptors on glutamatergic terminals (2). Among the eight subtypes of mGluRs, group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR7, and mGluR8) are known to act as autoreceptors at excitatory synapses in the mammalian brain.
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