NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization 英文参考文献.docVIP
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NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization 英文参考文献
NMDAReceptorsonNon-DopaminergicNeuronsinthe
VTASupportCocaineSensitization
YuLuo1.,CameronH.Good1.,OscarDiaz-Ruiz1,YaJunZhang1,AlexanderF.Hoffman1,LufeiShan1,
SerenaY.Kuang1,NasirMalik1,VladimirI.Chefer2,AndreasC.Tomac1¤,CarlR.Lupica1,CristinaM.
Ba¨ckman1*
1Cellular Neurobiology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America, 2Behavioral
NeuroscienceBranch,NationalInstituteonDrugAbuse,NationalInstitutesofHealth,Baltimore,Maryland,UnitedStatesofAmerica
Abstract
Background:TheinitiationofbehavioralsensitizationtococaineandotherpsychomotorstimulantsisthoughttoreflectN-
methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The
importanceofdruginducedNMDARmediatedadaptationsinventraltegmentalarea(VTA)DAneurons,anditsassociation
with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons
expressingCrerecombinaseunderthecontroloftheendogenousdopaminetransportergene(NR1DATCre
mice).
MethodologyandPrincipalFindings:UsinganadditionalNR1DATCre mousetransgenicmodel,wedemonstratethatwhile
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
remainintactinNR1DATCremice.SinceVTADAneuronsprojectingtotheprefrontalcortexandamygdalaexpresslittleorno
detectablelevelsofthedopaminetransporter,ithasbeenspeculatedthatNMDAreceptorsinDAneuronsprojectingto
thesebrainareasmayhavebeensparedinNR1DATCremice.HerewedemonstratethattheNMDAreceptorgeneisablatedin
themajorityofVTADAneurons,includingthoseexhibitingundetectableDATexpressionlevelsinourNR1DATCre
transgenic
model, and that application of an NMDAR antagonist within the VTA of NR1DATCre animals still blocks sensitization to
cocaine.
Conclusions/Significance: Theseresults elim
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