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Metabotropic Glutamate Receptor 2 Positive Allosteric Modulators: Closing the Gate on Drug Abuse?

  • Kari A. Johnson
    Correspondence
    Address correspondence to Kari A. Johnson, Ph.D., Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room TS-24, Bethesda, MD 20892.
    Affiliations
    Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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  • David M. Lovinger
    Affiliations
    Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
    Search for articles by this author
      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 (
      • Kalivas P.W.
      The glutamate homeostasis hypothesis of addiction.
      ). Presynaptic metabotropic glutamate receptors (mGluRs) can limit glutamate release by acting as autoreceptors on glutamatergic terminals (
      • Moussawi K.
      • Kalivas P.W.
      Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction.
      ). 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. Group II mGluRs have received considerable attention in recent years as contributing factors and therapeutic targets for drug abuse disorders (
      • Moussawi K.
      • Kalivas P.W.
      Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction.
      ). For example, several studies demonstrated that agonists of group II mGluRs decrease operant self-administration of drugs, including cocaine, alcohol, nicotine, and methamphetamine. In addition, activation of group II mGluRs attenuates cue-induced reinstatement of cocaine, heroin, alcohol, and methamphetamine self-administration as well as drug priming–induced reinstatement of nicotine, methamphetamine, and cocaine seeking. Conversely, an antagonist of group II mGluRs increases alcohol drinking (
      • Zhou Z.
      • Karlsson C.
      • Liang T.
      • Xiong W.
      • Kimura M.
      • Tapocik J.D.
      • et al.
      Loss of metabotropic glutamate receptor 2 escalates alcohol consumption.
      ). There is an evolving idea that presynaptic group II mGluRs may provide a “gatekeeper” function, limiting glutamate release at key synapses in addiction circuitry.
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