DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling
Date
2015
Authors
Northcutt, A.
Hutchinson, M.
Wang, X.
Baratta, M.
Hiranita, T.
Cochran, T.
Pomrenze, M.
Galer, E.
Kopajtic, T.
Li, C.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Molecular Psychiatry, 2015; 20(12):1525-1537
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
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Advance online publication 3 February 2015
Access Status
Rights
© 2015 Macmillan Publishers Limited