Role of Serine Racemase in Behavioral Sensitization in Mice after Repeated Administration of Methamphetamine 英文参考文献.docVIP

RoleofSerineRacemaseinBehavioralSensitizationin MiceafterRepeatedAdministrationof Methamphetamine MaoHorio1,MamiKohno1,YukoFujita1,TamakiIshima1,RanInoue2,HisashiMori2,KenjiHashimoto1* 1Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan, 2Department of Molecular Neuroscience, Toyama University GraduateSchoolofMedicine,Toyama,Japan Abstract Background: The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administrationofthepsychostimulant,methamphetamine(METH).Serineracemase(SRR)isanenzymewhichsynthesizes D-serine,anendogenousco-agonistofNMDAreceptors.UsingSrrknock-out(KO)mice,weinvestigatedtheroleofSRRon METH-inducedbehavioralabnormalitiesinmice. Methodology/Principal Findings: Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbensafteradministrationofMETHwasexaminedusinginvivomicrodialysistechnique.Additionally,phosphorylation levelsofERK1/2proteinsinthestriatum,frontalcortexandhippocampuswereexaminedusingWesternblotanalysis.Acute hyperlocomotionafterasingleadministrationofMETH(3mg/kg)wascomparablebetweenwild-type(WT)andSrr-KOmice. However,repeatedadministrationofMETH(3mg/kg/day,oncedailyfor5days)resultedinbehavioralsensitizationinWT, but not Srr-KO mice. Pretreatment with D-serine (900mg/kg, 30min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewardingeffectsweredemonstrableinbothWTandSrr-KOmice.InvivomicrodialysisstudyshowedthatMETH(1mg/kg)- inducedDAreleaseinthenucleusaccumbensofSrr-KOmicepreviouslytreatedwithMETHwassignificantlylowerthanthat of the WT mice previously treated with METH. Interestingly, a single administration of METH (3mg/kg) significantly increasedthephosphorylationstatusofERK1/2inthestriatumo