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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We thank the NIDA Addiction Treatment Discovery Program (NIDA ATDP) for data generated through a contract with Caliper Life Sciences. A portion of this work was supported by the intramural research programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. This work was supported by NIH Grants DA029420, DA033358, GM103843 and GM101279, NIDA Grant N01DA-9-8883 and DoD Grant PR110146. MRH is funded by an Australian Research Council Research Fellowship (DP110100297).
AL Northcutt: design, completion and statistical analyses of the conditioned place preference and follow-up control studies; oversight, design, completion and statistical analyses of in vivo microdialysis and follow-up control studies; design, oversight and analysis of neonatal microglial cell culture studies; oversight and completion of HPLC procedures, quantification and analysis; design and completion of brain mRNA studies, oversight of RT-PCR procedures, statistical analysis of RT-PCR data, design and completion of pharmacodynamic study; data graphics and figure preparation; manuscript preparation and review. MR Hutchinson: all aspects of in silico analyses and data presentation; data graphics; general project oversight; figure and manuscript preparation and review. X Wang: design, completion and analysis of biophysical ELISA binding assays, Bis-ANS displacement assay; figure design; manuscript review. MV Barrata: oversight of design, completion and statistical analysis of mouse self-administration studies; manuscript preparation and review. T Hiranita: design, completion and analysis of rat self-administration studies; figure preparation; manuscript preparation and review. TA Cochran: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection, HPLC sample preparation, collection and processing of micropunches for RT-PCR procedures, completion of neonatal microglial cell studies. MB Pomrenze: design, completion and statistical analysis of mouse self-administration studies, figure preparation, manuscript preparation and review. EL Galer: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection and HPLC sample preparation; assistance with tissue collection for HPLC analysis of brain cocaine concentration. TA Kopajtic: design and completion of the σ1 binding study and striatal membrane transporter binding study; table preparation; manuscript preparation and review. CM Li: design, completion and analysis of pharmacokinetic profiling (+)- naltrexone. J Amat: training and oversight of HPLC analyses; manuscript review. G Larson: assistance and oversight of tissue collection; completion of HPLC analysis for brain cocaine concentration study; data analysis; manuscript review. DC Cooper: training and oversight of mouse-self administration procedures. Y Huang: oversight of design and completion of pharmacokinetic profiling (+)- naltrexone. CE O’neill: assistance with statistical analysis; figure and manuscript preparation and review. H Yin: oversight of design and analysis of biophysical ELISA binding assays; Bis-ANS displacement assay; and BV-2 cell culture studies; manuscript review. NR Zahniser: oversight of design and analysis of studies assessing brain cocaine concentrations via HPLC; manuscript preparation and review. J. Katz: design and oversight of σ1, σ2 and striatal membrane assays; design and oversight of rat self-administration studies and analysis; figure and table preparation; manuscript drafting and review. KC Rice: design, synthesis, purification and verification of (+)-naloxone and (+)-naltrexone; manuscript preparation and review. SF Maier: oversight of experimental designs, control studies and statistics; manuscript drafting and review. RK Bachtell: oversight of experimental designs and control studies; oversight of statistical analysis; manuscript drafting, organization, preparation, drafting and review. LR Watkins: general project management, organization and oversight; figure and manuscript drafting, preparation and review.
The authors declare no conflict of interest.
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Northcutt, A., Hutchinson, M., Wang, X. et al. DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry 20, 1525–1537 (2015). https://doi.org/10.1038/mp.2014.177
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