2. 2010, J Neurosci, IP3 receptor sensitization during in vivo amphetamine experience enhances NMDA receptor plasticity in dopamine neurons of the ventral tegmental area

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1、TheJournalofNeuroscience,May12,2010•30(19):6689–6699•6689Cellular/MolecularIP3ReceptorSensitizationduringInVivoAmphetamineExperienceEnhancesNMDAReceptorPlasticityinDopamineNeuronsoftheVentralTegmentalAreaKee-ChanAhn,BrianE.Bernier,MarkT.Harnett,andHitoshiMorikaw

2、aWaggonerCenterforAlcoholandAddictionResearch,SectionofNeurobiologyandInstituteforNeuroscience,UniversityofTexasatAustin,Austin,Texas78712Synapticplasticityinthemesolimbicdopamine(DA)systemiscriticallyinvolvedinreward-basedconditioningandthedevelopmentof2
drugad

3、diction.Casignalstriggeredbypostsynapticactionpotentials(APs)drivetheinductionofsynapticplasticityintheCNS.2
However,itisnotclearhowAP-evokedCasignalsandtheresultingsynapticplasticityarealteredduringinvivoexposuretodrugsofabuse.Wehaverecentlydescribedlong-termpo

4、tentiation(LTP)ofNMDAreceptor(NMDAR)-mediatedtransmissionontoDAneurons2
thatisinducedinamannerdependentonburstsofAPs.LTPinductionrequiresamplificationofburst-evokedCasignalsbyprecedingactivationofmetabotropicglutamatereceptors(mGluRs)generatinginositol1,4,5-tris

5、phosphate(IP3).Inthisstudy,usingbrainslicespreparedfrommalerats,weshowthatrepeatedinvivoexposuretothepsychostimulantamphetamine(5mg/kg,i.p.,3–7d)upregulates2
mGluR-dependentfacilitationofburst-evokedCasignalsinDAneuronsoftheventraltegmentalarea(VTA).Proteinkinas

6、eA(PKA)-inducedsensitizationofIP3receptorsmediatesthisupregulationofmGluRaction.Asaconsequence,NMDAR-mediatedtrans-missionbecomesmoresusceptibletoLTPinductionafterrepeatedamphetamineexposure.Wehavealsofoundthatthemagnitudeof2
amphetamine-conditionedplacepreferen

7、ce(CPP)inbehavingratscorrelateswiththemagnitudeofmGluR-dependentCasignalfacilitationmeasuredinVTAslicespreparedfromtheserats.Furthermore,thedevelopmentofamphetamineCPPissignificantlyattenuatedbyintra-VTAinfusionofthePKAinhibitorH89.WeproposethatenhancementofmGlu

8、R-dependentNMDARplasticityintheVTAmaypromotethelearningofenvironmentalstimulirepeatedlyassociatedwithamphetamineexperience.Introduction2004;Hymanetal.,2006;Stuberetal