DAT isn't all that: Cocaine reward and reinforcement require Toll-like receptor 4 signaling

A. L. Northcutt, M. R. Hutchinson, X. Wang, M. V. Baratta, T. Hiranita, T. A. Cochran, M. B. Pomrenze, E. L. Galer, T. A. Kopajtic, C. M. Li, J. Amat, G. Larson, D. C. Cooper, Y. Huang, C. E. O'Neill, H. Yin, N. R. Zahniser, J. L. Katz, K. C. Rice, S. F. MaierR. K. Bachtell, L. R. Watkins

Research output: Contribution to journalArticlepeer-review

169 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1525-1537
Number of pages13
JournalMolecular psychiatry
Issue number12
StatePublished - Dec 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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