Evidence map›Paper›PMID 25644383›Full record

ArticleMolecular psychiatry2015

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 and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular psychiatry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.

0numbers the graph read from it
0cells of the map it votes in
140citing papers in PubMed
10.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

140 citing papers in PubMed, 219 citations in OpenAlex.

  1. Trial
  2. The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026
    Review
  3. Article
  4. Review
  5. Review
  6. Review
  7. Article
  8. Review
  9. Article
  10. Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
    Review
  11. Article
  12. Article
  13. Review
  14. Changes in nucleus accumbens core translatome accompanying incubation of cocaine craving.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025
    Article
  15. Article
  16. Article
  17. Review
  18. Review
  19. Article
  20. Review

80 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 6 institutions in 3 countries.

A L NorthcuttDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
M R HutchinsonDiscipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
X WangDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
M V BarattaInstitute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
T HiranitaDepartment of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
T A CochranDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
M B PomrenzeInstitute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
E L GalerDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
T A KopajticDepartment of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
C M LiDrug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
J AmatDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
G LarsonDepartment of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
D C CooperInstitute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
Y HuangDrug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
C E O'NeillDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
H YinBiofrontiers Institute, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.ORCID http://orcid.org/0000-0002-9762-4818
N R ZahniserDepartment of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
J L KatzDepartment of Health and Human Services, Medications Discovery Research Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Biomedical Research Center MDRB, Baltimore, MD, USA.
K C RiceChemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
S F MaierDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
R K BachtellDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
L R WatkinsDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
University of Colorado Boulder · USNational Institutes of Health · USUniversity of California, San Francisco · USUniversity of Colorado Denver · USNational Institute on Drug Abuse · USThe University of Adelaide · AU

Funding

Research Training-Genetics of Substance AbuseT32DA017637 · NIDA · UNIVERSITY OF COLORADO AT BOULDER · PI STITZEL, JERRY A · 2004 to 2023
$5.3M
Basic Dopamine Transporter Mechanisms Of CocaineZIADA000103 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI KATZ, JONATHAN L · 2009 to 2016
$4.6M
Medicinal Chemistry of Drugs Acting on Toll-like ReceptorsZIADA000530 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI RICE, KENNER · 2009 to 2020
$4.0M
Preventing Transition of Acute-to-Chronic Neuropathic Pain: Models, Mechanisms &R01DE021966 · NIDCR · UNIVERSITY OF COLORADO · PI BARTH, DANIEL S., FLESHNER, MONIKA · 2011 to 2015
$2.0M
Exploring the Potential of Glia for Regulating Clinically Relevant Opiod ActionsR01DA023132 · NIDA · UNIVERSITY OF COLORADO · PI WATKINS, LINDA · 2008 to 2012
$1.9M
Adenosine Receptor Involvement in Methamphetamine Reward and RelapseR01DA033358 · NIDA · UNIVERSITY OF COLORADO · PI BACHTELL, RYAN K · 2013 to 2017
$1.9M
Medicinal Chemistry of Drugs Acting on CRH ReceptorsZIADA000528 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI RICE, KENNER · 2009 to 2018
$1.8M
Exogenous Chemical Probes of TLR-Mediated NeuroinflammationR01GM101279 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2017
$1.4M
Dissecting Cell Signaling Mediated by Protein-Protein Interactions in MembranesR01GM103843 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2016
$1.3M
Optimizing the Clinical Efficacy of Opioids by TLR4 BlockadeR21DA026950 · NIDA · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2009 to 2010
$273k
Effects of Adenosine Signaling on Cocaine Reward and RelapseR03DA029240 · NIDA · UNIVERSITY OF COLORADO · PI BACHTELL, RYAN K · 2011 to 2012
$152k
Intramural NIH HHSNIDA NIH HHS DA029420NIDA NIH HHS DA033358NIDA NIH HHS N01DA-9-8883NIDA NIH HHS R01 DA023132NIDA NIH HHS R01 DA033358NIDA NIH HHS R03 DA029240NIDA NIH HHS R21 DA026950NIDA NIH HHS T32 DA017637NIDCR NIH HHS R01 DE021966NIGMS NIH HHS GM101279NIGMS NIH HHS GM103843NIGMS NIH HHS R01 GM101279NIGMS NIH HHS R01 GM103843
6 · The paper itself

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.

Indexed as

AnimalsCells, CulturedCocaineDopamine Plasma Membrane Transport ProteinsInterleukin-1betaMaleMiceMice, Inbred C3HMutationNaloxoneNarcotic AntagonistsNeurogliaRatsRats, Sprague-DawleyReinforcement, PsychologyRewardCocaineDopamine Plasma Membrane Transport ProteinsInterleukin-1betaNaloxoneNarcotic AntagonistsRNA, MessengerTLR4 protein, humanToll-Like Receptor 4

Identifiers

PMID25644383
PMCPMC4523496
OpenAlexW2017453007

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.