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

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dc.contributor.authorNorthcutt, A.
dc.contributor.authorHutchinson, M.
dc.contributor.authorWang, X.
dc.contributor.authorBaratta, M.
dc.contributor.authorHiranita, T.
dc.contributor.authorCochran, T.
dc.contributor.authorPomrenze, M.
dc.contributor.authorGaler, E.
dc.contributor.authorKopajtic, T.
dc.contributor.authorLi, C.
dc.contributor.authorAmat, J.
dc.contributor.authorLarson, G.
dc.contributor.authorCooper, D.
dc.contributor.authorHuang, Y.
dc.contributor.authorO'Neill, C.
dc.contributor.authorYin, H.
dc.contributor.authorZahniser, N.
dc.contributor.authorKatz, J.
dc.contributor.authorRice, K.
dc.contributor.authorMaier, S.
dc.contributor.authoret al.
dc.date.issued2015
dc.descriptionAdvance online publication 3 February 2015
dc.description.abstractThe 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.
dc.description.statementofresponsibilityA 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
dc.identifier.citationMolecular Psychiatry, 2015; 20(12):1525-1537
dc.identifier.doi10.1038/mp.2014.177
dc.identifier.issn1359-4184
dc.identifier.issn1476-5578
dc.identifier.orcidHutchinson, M. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/92388
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/arc/DP110100297
dc.rights© 2015 Macmillan Publishers Limited
dc.source.urihttps://doi.org/10.1038/mp.2014.177
dc.subjectVentral Tegmental Area
dc.subjectNeuroglia
dc.subjectCells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred C3H
dc.subjectMice
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectNaloxone
dc.subjectCocaine
dc.subjectRNA, Messenger
dc.subjectNarcotic Antagonists
dc.subjectSelf Administration
dc.subjectReward
dc.subjectSignal Transduction
dc.subjectMutation
dc.subjectMale
dc.subjectDopamine Plasma Membrane Transport Proteins
dc.subjectToll-Like Receptor 4
dc.subjectInterleukin-1beta
dc.subjectReinforcement, Psychology
dc.titleDAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling
dc.typeJournal article
pubs.publication-statusPublished

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