Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/92388
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Type: Journal article
Title: DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling
Author: Northcutt, A.
Hutchinson, M.
Wang, X.
Baratta, M.
Hiranita, T.
Cochran, T.
Pomrenze, M.
Galer, E.
Kopajtic, T.
Li, C.
Amat, J.
Larson, G.
Cooper, D.
Huang, Y.
O'Neill, C.
Yin, H.
Zahniser, N.
Katz, J.
Rice, K.
Maier, S.
et al.
Citation: Molecular Psychiatry, 2015; 20(12):1525-1537
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 1359-4184
1476-5578
Statement of
Responsibility: 
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 Maier, R K Bachtell, and L R Watkins
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.
Keywords: Ventral Tegmental Area; Neuroglia; Cells, Cultured; Animals; Mice, Inbred C3H; Mice; Rats; Rats, Sprague-Dawley; Naloxone; Cocaine; RNA, Messenger; Narcotic Antagonists; Self Administration; Reinforcement (Psychology); Reward; Signal Transduction; Mutation; Male; Dopamine Plasma Membrane Transport Proteins; Toll-Like Receptor 4; Interleukin-1beta
Description: Advance online publication 3 February 2015
Rights: © 2015 Macmillan Publishers Limited
RMID: 0030022500
DOI: 10.1038/mp.2014.177
Grant ID: http://purl.org/au-research/grants/arc/DP110100297
Appears in Collections:Physiology publications

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