title: DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.
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.
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: A L
authors: AL
authors: Northcutt
authors: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
authors: M R
authors: MR
authors: Hutchinson
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.|Biofrontiers Institute, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: X
authors: X
authors: Wang
authors: Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: M V
authors: MV
authors: Baratta
authors: Department 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.
authors: T
authors: T
authors: Hiranita
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: T A
authors: TA
authors: Cochran
authors: Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: M B
authors: MB
authors: Pomrenze
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: E L
authors: EL
authors: Galer
authors: Department 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.
authors: T A
authors: TA
authors: Kopajtic
authors: Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors: C M
authors: CM
authors: Li
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: J
authors: J
authors: Amat
authors: Department of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
authors: G
authors: G
authors: Larson
authors: Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: D C
authors: DC
authors: Cooper
authors: Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors: Y
authors: Y
authors: Huang
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: C E
authors: CE
authors: O'Neill
authors: Biofrontiers Institute, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.|Department of Chemistry and Biochemistry, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.|Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing, China.
authors: H
authors: http://orcid.org/0000-0002-9762-4818
authors: H
authors: Yin
authors: Department of Pharmacology and Program in Neuroscience, University of Colorado, Denver, Denver, CO, USA.
authors: N R
authors: NR
authors: Zahniser
authors: Department 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.
authors: J L
authors: JL
authors: Katz
authors: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
authors: K C
authors: KC
authors: Rice
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: S F
authors: SF
authors: Maier
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.|Institute for Behavioral Genetics, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: R K
authors: RK
authors: Bachtell
authors: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Boulder, CO, USA.
authors: L R
authors: LR
authors: Watkins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D053583:Interleukin-1beta; D009292:Narcotic Antagonists; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D009270:Naloxone; D003042:Cocaine
references: J Neurosci. 2008 May 28;28(22):5756-61
references: 18509037
references: J Neurosci. 2013 Jul 17;33(29):12105-21
references: 23864696
references: Microbes Infect. 2004 Dec;6(15):1361-7
references: 15596121
references: J Pharmacol Exp Ther. 2011 Nov;339(2):662-77
references: 21859929
references: Brain Behav Immun. 2010 Jan;24(1):83-95
references: 19679181
references: Science. 1998 Dec 11;282(5396):2085-8
references: 9851930
references: Neuropsychopharmacology. 2006 Nov;31(11):2476-88
references: 16407899
references: Glia. 2003 Sep;43(3):281-91
references: 12898707
references: Psychiatry Res. 2009 Aug 15;168(3):173-80
references: 19233481
references: Trends Neurosci. 2006 Nov;29(11):610-6
references: 16956674
references: J Neurosci. 1993 Aug;13(8):3574-81
references: 8393485
references: J Pharmacol Exp Ther. 2009 May;329(2):677-86
references: 19228996
references: Glia. 2001 Nov;36(2):180-90
references: 11596126
references: Pharmacogenet Genomics. 2009 Nov;19(11):869-76
references: 19801958
references: Neurochem Int. 2004 Jul-Aug;45(2-3):397-407
references: 15145554
references: Semin Immunol. 2004 Feb;16(1):11-6
references: 14751758
references: Neuropsychologia. 2001;39(4):376-89
references: 11164876
references: Biol Psychiatry. 2013 Apr 15;73(8):729-37
references: 23384483
references: J Exp Med. 1999 Jun 7;189(11):1777-82
references: 10359581
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Nature. 1997 Apr 24;386(6627):827-30
references: 9126740
references: Biol Psychiatry. 2011 Feb 1;69(3):208-17
references: 20950794
references: Science. 1987 Sep 4;237(4819):1219-23
references: 2820058
references: Neurochem Res. 2011 Apr;36(4):686-92
references: 21399909
references: J Neurosci. 1998 Aug 1;18(15):5614-29
references: 9671653
references: Brain Behav Immun. 2008 Nov;22(8):1248-56
references: 18706994
references: Brain Res Rev. 2007 Nov;56(1):148-69
references: 17706291
references: J Leukoc Biol. 2008 Oct;84(4):932-9
references: 18495785
references: J Med Chem. 1978 Apr;21(4):398-400
references: 206698
references: J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
references: 12430718
references: Neurosci Lett. 1993 Apr 2;152(1-2):177-80
references: 8515873
references: Trends Immunol. 2001 Feb;22(2):78-83
references: 11286707
references: J Pain. 2012 May;13(5):498-506
references: 22520687
references: J Neurosci. 1987 Feb;7(2):357-68
references: 2880937
references: Parasite Immunol. 2007 Mar;29(3):127-37
references: 17266740
references: Naunyn Schmiedebergs Arch Pharmacol. 2012 Mar;385(3):225-41
references: 22282331
references: J Neurosci. 2001 May 1;21(9):RC141: 1-4
references: 11312315
references: Neuropharmacology. 2014 Jan;76 Pt B:218-27
references: 23764149
references: Annu Rev Psychol. 2000;51:29-57
references: 10751964
references: F1000Res. 2013 Feb 15;2:53
references: 24358869
references: J Neurosci. 2003 Sep 24;23(25):8692-700
references: 14507968
references: J Neurosci. 2012 Aug 15;32(33):11187-200
references: 22895704
references: J Neurosci. 2005 Mar 23;25(12):3219-28
references: 15788779
references: Nature. 2009 Apr 30;458(7242):1191-5
references: 19252480
references: Nature. 2010 Nov 11;468(7321):223-31
references: 21068831
references: Ann N Y Acad Sci. 2008 Oct;1139:103-11
references: 18991854
references: Neurochem Res. 2008 Oct;33(10):2044-53
references: 18368483
references: Brain Res. 1990 Jul 23;523(2):342-6
references: 1698106
references: Pharmacol Ther. 2012 May;134(2):219-45
references: 22316499
references: J Neurosci. 2001 Sep 1;21(17):6480-91
references: 11517237
references: Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6325-30
references: 22474354
references: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12304-8
references: 8618890
references: Nat Rev Neurosci. 2007 Jan;8(1):57-69
references: 17180163
references: Eur J Neurosci. 2008 Jul;28(1):20-9
references: 18662331
references: Neuroscience. 2010 May 19;167(3):880-93
references: 20178837
references: Curr Protein Pept Sci. 2013 Feb;14(1):33-42
references: 23441900
references: Science. 1988 Nov 4;242(4879):715-23
references: 2903550
references: J Neuroimmunol. 2010 Sep 14;226(1-2):20-6
references: 20605229
references: Brain Res. 1994 Mar 28;641(1):83-91
references: 7912635