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Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell

  • Xiaohui Wang*
    Xiaohui Wang
    Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
    Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
    Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
    *Phone: 86-431-85626 2249. Fax: 86-431-8526 2240. E-mail: [email protected]
    More by Xiaohui Wang
  • Alexis L. Northcutt
    Alexis L. Northcutt
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Thomas A. Cochran
    Thomas A. Cochran
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Xiaozheng Zhang
    Xiaozheng Zhang
    Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
  • Timothy J. Fabisiak
    Timothy J. Fabisiak
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Mackenzie E. Haas
    Mackenzie E. Haas
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Jose Amat
    Jose Amat
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
    More by Jose Amat
  • Hongyuan Li
    Hongyuan Li
    Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
    More by Hongyuan Li
  • Kenner C. Rice
    Kenner C. Rice
    Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, United States
  • Steven F. Maier
    Steven F. Maier
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Ryan K. Bachtell
    Ryan K. Bachtell
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
  • Mark R. Hutchinson
    Mark R. Hutchinson
    Discipline of Physiology, Adelaide Medical School  and  ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, Adelaide, South Australia 5000, Australia
  • , and 
  • Linda R. Watkins
    Linda R. Watkins
    Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
Cite this: ACS Chem. Neurosci. 2019, 10, 8, 3622–3634
Publication Date (Web):July 8, 2019
Copyright © 2019 American Chemical Society

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    Abstract Image

    Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and therefore amplifying the reward changes in the neuronal activity induced by METH. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) is unknown. Herein, we provide direct evidence that METH creates neuroinflammation, at least in part, via the activation of the innate immune Toll-like receptor 4 (TLR4). Biophysical studies revealed that METH bound to MD-2, the key coreceptor of TLR4. Molecular dynamics simulations showed METH binding stabilized the active heterotetramer (TLR4/MD-2)2 conformation. Classic TLR4 antagonists LPS-RS and TAK-242 attenuated METH induced NF-κB activation of microglia, whereas added MD-2 protein boosted METH-induced NF-κB activation. Systemically administered METH (1 mg/kg) was found to specifically up-regulate expression of both CD11b (microglial activation marker) and the proinflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), but not in either the nucleus accumbens shell (NAc) or prefrontal cortex (PFC). Systemic administration of a nonopioid, blood–brain barrier permeable TLR4 antagonist (+)-naloxone inhibited METH-induced activation of microglia and IL-6 mRNA overexpression in VTA. METH was found to increase conditioned place preference (CPP) as well as extracellular dopamine concentrations in the NAc, with both effects suppressed by the nonopioid TLR4 antagonist (+)-naloxone. Furthermore, intra-VTA injection of LPS-RS or IL-6 neutralizing antibody suppressed METH-induced elevation of extracellular NAc dopamine. Taken together, this series of studies demonstrate that METH-induced neuroinflammation is, at least in part, mediated by TLR4-IL6 signaling within the VTA, which has the downstream effect of elevating dopamine in the NAc shell. These results provide a novel understanding of the neurobiological mechanisms underlying acute METH reward that includes a critical role for central immune signaling and offers a new target for medication development for treating drug abuse.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.9b00225.

    • Graphic illustration of CPP testing; graphic illustration of microdialysis testing; overlap of the best binding pose of METH with classic TLR4 agonist Lipid A; time evolution of the Cα RMSD for TLR4/MD-2 interacting with METH (PDF)

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