title: NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.
abstract: BACKGROUND
  The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre) mice).
  
  
  RESULTS
  Using an additional NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine.
  
  
  CONCLUSIONS
  These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.
authors.affiliation: Cellular Neurobiology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.forename: Cameron H
authors.initials: CH
authors.lastname: Good
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Ruiz
authors.forename: YaJun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Lufei
authors.initials: L
authors.lastname: Shan
authors.forename: Serena Y
authors.initials: SY
authors.lastname: Kuang
authors.forename: Nasir
authors.initials: N
authors.lastname: Malik
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Chefer
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Tomac
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D018698:Glutamic Acid / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000502:physiology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C045073:Cre recombinase; D019426:Integrases; D003042:Cocaine; D004298:Dopamine
references.citation: Genesis. 2006 Oct;44(10):454-64
references.pmid: 16981198
references.citation: Behav Pharmacol. 2004 Sep;15(5-6):327-39
references.pmid: 15343056
references.citation: Neuropsychopharmacology. 2003 Jan;28(1):73-6
references.pmid: 12496942
references.citation: J Pharmacol Exp Ther. 1993 Oct;267(1):486-95
references.pmid: 8229779
references.citation: Behav Pharmacol. 2004 Sep;15(5-6):373-6
references.pmid: 15343062
references.citation: J Neurosci. 2009 Feb 11;29(6):1735-42
references.pmid: 19211880
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7281-8
references.pmid: 19342487
references.citation: Brain Res Dev Brain Res. 1996 Apr 30;92(2):172-81
references.pmid: 8738124
references.citation: Science. 2005 Mar 11;307(5715):1642-5
references.pmid: 15761155
references.citation: FASEB J. 2008 Jan;22(1):261-75
references.pmid: 17690153
references.citation: J Neurosci. 2004 Aug 25;24(34):7482-90
references.pmid: 15329395
references.citation: Methods Mol Biol. 2009;530:423-33
references.pmid: 19266333
references.citation: Cell. 1996 Dec 27;87(7):1327-38
references.pmid: 8980238
references.citation: Trends Neurosci. 2007 May;30(5):203-10
references.pmid: 17400301
references.citation: Science. 2009 May 22;324(5930):1080-4
references.pmid: 19389999
references.citation: Neuron. 2008 Aug 14;59(3):353-5
references.pmid: 18701061
references.citation: Psychopharmacology (Berl). 2000 Aug;151(2-3):184-91
references.pmid: 10972464
references.citation: J Neurosci. 2006 Aug 23;26(34):8810-8
references.pmid: 16928870
references.citation: Eur J Neurosci. 2007 Jan;25(1):106-18
references.pmid: 17241272
references.citation: Neuroscience. 2004;129(3):841-7
references.pmid: 15541905
references.citation: Nature. 2005 Oct 13;437(7061):1027-31
references.pmid: 16222299
references.citation: Psychopharmacology (Berl). 2009 May;204(1):1-11
references.pmid: 19099297
references.citation: Neuron. 2008 Aug 14;59(3):486-96
references.pmid: 18701073
references.citation: Genesis. 2006 Aug;44(8):383-90
references.pmid: 16865686
references.citation: Nat Rev Neurosci. 2001 Dec;2(12):861-70
references.pmid: 11733793
references.citation: Neuron. 2008 Aug 14;59(3):497-508
references.pmid: 18701074
references.citation: Science. 2003 Mar 21;299(5614):1898-902
references.pmid: 12649484
references.citation: J Neurosci. 2002 Jun 1;22(11):4709-19
references.pmid: 12040078
references.citation: J Physiol. 1992 May;450:455-68
references.pmid: 1331427
references.citation: Nat Rev Neurosci. 2007 Nov;8(11):844-58
references.pmid: 17948030
references.citation: Brain Res. 1996 Nov 11;739(1-2):169-81
references.pmid: 8955937
references.citation: Nature. 2001 May 31;411(6837):583-7
references.pmid: 11385572
references.citation: Psychopharmacology (Berl). 2005 Apr;179(1):172-80
references.pmid: 15580483
references.citation: Nat Neurosci. 2003 Sep;6(9):968-73
references.pmid: 12897785
references.citation: Neuron. 2008 Mar 13;57(5):760-73
references.pmid: 18341995