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DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.
Northcutt, A L; Hutchinson, M R; Wang, X; Baratta, M V; Hiranita, T; Cochran, T A; Pomrenze, M B; Galer, E L; Kopajtic, T A; Li, C M; Amat, J; Larson, G; Cooper, D C; Huang, Y; O'Neill, C E; Yin, H; Zahniser, N R; Katz, J L; Rice, K C; Maier, S F; Bachtell, R K; Watkins, L R.
Affiliation
  • Northcutt AL; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Hutchinson MR; Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
  • Wang X; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Baratta MV; Biofrontiers Institute, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
  • Hiranita T; Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
  • Cochran TA; Department of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
  • Pomrenze MB; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Galer EL; Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
  • Kopajtic TA; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Li CM; Department of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
  • Amat J; Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
  • Larson G; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Cooper DC; Department of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
  • Huang Y; Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
  • O'Neill CE; Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
  • Yin H; Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Zahniser NR; Biofrontiers Institute, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
  • Katz JL; Department of Chemistry and Biochemistry, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
  • Rice KC; Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing, China.
  • Maier SF; Department of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
  • Bachtell RK; Department of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
  • Watkins LR; Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
Mol Psychiatry ; 20(12): 1525-37, 2015 Dec.
Article in En | MEDLINE | ID: mdl-25644383
ABSTRACT
The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Cocaine / Toll-Like Receptor 4 Limits: Animals Language: En Journal: Mol Psychiatry Journal subject: BIOLOGIA MOLECULAR / PSIQUIATRIA Year: 2015 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Cocaine / Toll-Like Receptor 4 Limits: Animals Language: En Journal: Mol Psychiatry Journal subject: BIOLOGIA MOLECULAR / PSIQUIATRIA Year: 2015 Document type: Article Affiliation country: United States