Diacylglycerol Kinase β Knockout Mice Exhibit Attention-Deficit Behavior and an Abnormal Response on Methylphenidate-Induced Hyperactivity 英文参考文献.docVIP

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Diacylglycerol Kinase β Knockout Mice Exhibit Attention-Deficit Behavior and an Abnormal Response on Methylphenidate-Induced Hyperactivity 英文参考文献.doc

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Diacylglycerol Kinase β Knockout Mice Exhibit Attention-Deficit Behavior and an Abnormal Response on Methylphenidate-Induced Hyperactivity 英文参考文献

DiacylglycerolKinasebKnockoutMiceExhibitAttention- DeficitBehaviorandanAbnormalResponseon Methylphenidate-InducedHyperactivity MitsueIshisaka1,KenichiKakefuda1,AtsushiOyagi1,YokoOno1,KazuhiroTsuruma1, MasamitsuShimazawa1,KiyoyukiKitaichi2,HideakiHara1* 1MolecularPharmacology,DepartmentofBiofunctionalEvaluation,GifuPharmaceuticalUniversity,Gifu,Japan,2DepartmentofPharmacy,GifuUniversityHospital,Gifu, Japan Abstract Background: Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKbisoneofthesubtypesoftheDGKfamilyandregulatesmanyintracellularsignalingpathwaysinthecentralnervous system.Previously,wedemonstratedthatDGKbknockout(KO)miceshowedvariousdysfunctionsofhigherbrainfunction, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. In the presentstudy,weconductedfurthertestsonDGKbKOmiceinordertoinvestigatethefunctionofDGKbinthecentral nervoussystem,especiallyinthepathophysiologyofattentiondeficithyperactivitydisorder(ADHD). Methodology/PrincipalFindings:DGKbKOmiceshowedattention-deficitbehaviorintheobject-basedattentiontestand itwasamelioratedbymethylphenidate(MPH,30mg/kg,i.p.).Intheopenfieldtest,DGKbKOmicedisplayedadecreased response tothelocomotor stimulating effectsof MPH (30mg/kg, i.p.),but showed asimilar response toan N-methyl-D- aspartate (NMDA) receptor antagonist, MK-801 (0.3mg/kg, i.p.), when compared to WT mice. Examination of the phosphorylation of extracellular signal-regulated kinase (ERK), which is involved in regulation of locomotor activity, indicatedthatERK1/2activationinducedbyMPHtreatmentwasdefectiveinthestriatumofDGKbKOmice. Conclusions/Significance:ThesefindingssuggestthatDGKbKOmiceshowedattention-deficitandhyperactivephenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGKb KO mice to MPH was due to dysregulation of ERK phosphorylation,andthatDGKbhasapivotalinvolvementinERKregulationinthestriatum. Citation: Ishisaka M