神經精神藥理英文資料：2-animal model

AnimalModelinpsychiatry

MethodsofResearchinNeurobehavioralPharmacology

TechniquesinNeuropharmacologyMultipleNeurobiologicalTechniquesforAssessingtheCNSStereotaxicsurgeryisneededforaccurateinvivomeasuresofbrainfunctionNeurotransmitters,receptors,andotherproteinscanbebothquantifiedandvisuallylocatedintheCNSNewtoolsareusedforimagingthestructureandfunctionofthebrainGeneticengineeringhelpsneuroscientiststoaskandanswernewquestionsTechniquesinBehavioralPharmacologyEvaluatingAnimalBehaviorAnimaltestingneedstobevalidandreliabletoproduceusefulinformationAwidevarietyofbehaviorsareevaluatedbypsychopharmacologistsOperantconditioningtechniquesprovideasensitivemeasureofdrugeffectsAnimalmodelsforthepathophysiologicalstudiesofmentaldiseasesPharmacoloigicalisomorphism（同構）ForcedSwimmingTestTailsuspensiontestPlomin,NatRevNeurosci

(2001)ParentalPopulationSelectionGenerationMaze-BrightMaze-DullPrepulseinhibition,PPI;Latentinhibition,LIDrawingfromDr.KarenStevens

ACOUSTICSTARTLE

Acousticstartlemeasuredat100-120dBDose-responseanalysesforeffectsofnicotineandethanolRotarodtestJ.Olds&P.Milner(1954)

BrainstimulationrewardBSRisaphenomenoninwhichdirectstimulationofregionsofthebrainthrougheitherelectricalorchemicalmeansisrewardingandcanserveasanoperantreinforcer.ThestimulationactivatestherewardsystemandestablishesresponsehabitssimilartothoseestablishedbynaturalrewardssuchasfoodandwaterBSRhasbeenfoundinallvertebratestested,includinghumans,andithasprovidedausefultoolforunderstandinghownaturalrewardsareprocessedbythebrainaswellastheanatomicalstructuresandtheneurochemistryassociatedwiththebrain'srewardsystem.Sitesalongthelengthofthemedialforebrainbundle(MFB)throughthelateralandposteriorhypothalamus,theventraltegmentalarea(VTA),andintotheponsareassociatedwiththestrongestrewardeffectsofstimulation.Animalgeneticmodelsforthepathophysiologicalstudiesofmentaldiseases

Animalmodelscanprovideonestrategytostudy

traitsthatpredatethedisorderorare associatedwiththediseaseincluding

BroadCategoriesofEndophenotypes:

behavioral,cognitive,neurophysiological,or neurochemicalprocessesthatare associatedwithriskformentaldiseasesProvidemultipledifferentstrategiestoidentify candidategenesregulatingthesephenotypes.

GoalofUsingEndophenotypesforDissectionofComplexDisorders

AdaptedfromFigure1:Gottesman,I.I.andGould,T.D.:Amer.J.Psychiatry2003;160:636-645DecreasedcomplexityofbothphenotypeandgeneticanalysisExample:workingmemoryimpairmentsinschizophreniaLessMore#ofGenesIncreasedcomplexityofbothphenotypeandgeneticanalyses

AllBehavioralTraitsareRegulated

byMultigenicorPolygenicSystems

GeneticStrategiestoStudyComplexBehaviorsPolygenic

Genesregulatingvariationinhumansandanimals

StrainDifferencesRecombinantInbreds&QTLSinglegene

EssentialgenesforBehaviors,Physiologyetc.TransgenicsandNullMutantsSelectedlinesAlcoholism&GenesModelingofPhenotypesrelatedtothepredispositiontoalcoholismandassessingtheactionsofalcoholExample:Theroleofg-ProteinKinaseC

Initialsensitivity---LowRespondingAnxietyandrisktakingBehavioralDisinhibitionEthanolconsumptionSensitivityAnxiety,Risktaking

BehavioralDisinhibitionIncreasedalcoholconsumptionModelingPossiblePredisposingFactorsWhatgenesregulatingthesepharmacologicalandbehavioraltraits??Example:ProteinKinaseCProteinKinaseCisaCentralRegulatorofDiversePathwaysintheBrainPKCACCa/CAMBINDINGPROTEINSLIGAND-GATEDCHANNELSGABA5HTMUSCARINIC5HTDANEUROGRANINRECGRPIPIPDAGGERCa++3PKCSuperGeneFamilyPRK1PRK2PKC-iPKC-zPKC-dPKC-qPKC-hPKC-ePKC-gPKC-aPKC-bNeuronalExpressionPostnatalExpressionPostsynapticlocalizationg-PKCKnock-outMice:CreatedusingEScell technologyDeletioninsertedin g-PKCgeneLackexpressionof

g-PKCprotein throughoutbrainBUTespecially importantin cerebellum, hippocampus,striatum, andamygdalaMildhindlimbataxia(共濟失調）in mutantsSensitivityg-PKCSensitivity

Lowresponseassociatedwithincreasedriskforalcoholism:ataxiaandothersubjectivemeasures(Schuckitetal.) Increasedsensitivityassociatedwithlowerrisk(Heathetal.)

ConfoundsinHumanStudies: 1.Historyofalcoholexposureandsmoking (Madden,Heath,Martin) 2.RoleofAcuteFunctionalTolerance

Inouranimalstudies:

Cancontrol#1but#2ismoredifficultSensitivitytoHighDosesofEthanol

Mutantsarelesssensitivetofirst exposuretoethanolEthanolClearancewasnotdifferent

3.5g/kgI.PWhatneurotransmittersystemcouldbealtered duetolossofg-PKC?

Reducedethanol-potentiationofMuscimol-stimulated

chloridefluxinmicrosacsfromcerebellum, midbrain,andcortexAdditionalQuestions???Isthereanelectrophysiologicalcorrelatetothis?Isg-PKCtheonlyPKCisotypeinvolved?AlterationsinGABAergicsystemHarris/WehnerCollaboration(PNAS92:3658-3662,1995)PKCSuperGeneFamilyPRK1PRK2PKC-iPKC-zPKC-dPKC-qPKC-hPKC-ePKC-gPKC-aPKC-bNeuronalExpressionPostnatalExpressionPostsynapticlocalizationExpressedinmanytissuesShowntochangewith chronictreatmentinPC12cellsProctoretal.JPET305:264-270,2003e-PKCnullmutantmice:

moresensitivetoethanolcomparedtowildtypeswillself-administerlessethanol(Hodge etal.)

HippocampalRecordingsWeconclude:gPKCandePKCisotypesmaybeimportantregulatorsofinitialsensitivityforsystemsthatmayinvolveGABAergicfunctionBUTinitialsensitivityisnotoneprecisephenotypeArelowdosebehavioraleffectsdifferentbetweenmutantsandwildtypes?

g-PKCmutantsarealsolesssensitivetolow-doseeffectsSensitivityAnxiety,RisktakinggPKC?MutationleadstoreducedsensitivityNote:Novelty-seekinghasbeenhardtomodelHa!I’veoutwittedthematlast!PKCgnullmutantsmayberisktakers...SlidefromJasonKeller,WehnerlabElevatedPlusMazeMirroredChamberTestOpenFieldArenaMutantsdemonstratelessanxietyorgreaterexplorationofnovelplacesMUTHETWTgPKCmutantsappearlessanxiousandagainarewillingtoexplorenovelplacesOpen-fieldStudiesSecurityisanicewalltohug!Thateaglewillnevergetme.Iaminvincible!!!Open-fieldbehaviorunderwhitelighting-PKCmiceMutantsaremorewillingtoexplorecenterandspendmoretimethereconsistentwithincreasedrisktakingorlessanxietySensitivityAnxietyRisktaking

BehavioralDisinhibitiong-PKC?MutationleadstoreducedsensitivityMutationleadstoreducedanxiety

orincreasedRisktakingHumanGeneticModelingofBehavioralDisinhibitionBehavioral

DisinhibitionConductDisorderSubstanceAbuseAttentionDeficitDisorderNoveltySeekingExperimentationisdrivenbyenvironmentalfactorsSevereSubstanceAbusewithearlyonsethasalargegeneticcomponentColoradoAdolescentDrugDependenceResearchCenter***FromYoungetal:Amer.J.Med.Genetics96:684-695***

Measuringimpulsivityin themouseAppetitivelearningusing anoperantparadigmSlidefromDr.BarbaraBowersSIGNALEDAPPETITIVETASK

DRLtask:differentialreinforcementoflowrateofrespondingMicedeprivedto85%ofnormalweightMicelearntonosepokeforafoodreward.(FR1,FR3)3.Micelearntoassociaterewardwiththepresentationofaclickersound.Micemustlearntowithholdtheirnose-pokingresponseuntiltonetogainarewardonavariableschedule.Clockisresetwhennosepokeisnotappropriateresponse.EfficiencyRatioforWithholdingResponsesfor ImpulsivityTaskInbredStrainsurveyprovidesfirstevidenceforgeneticregulationofthewithholdingresponseImpulsivityisnegativelycorrelatedwithEthanolconsumptionr=-.63;P<.05BowersandWehner(2001)J.Neuroscience: 21:RC180(1-5)g-PKCNullmutantsareimpairedonwithholdingresponsestoreceivethesucroserewardWhatneurotransmittersystemmediatesthisresponse?

5HT2a/creceptors???-BowersSensitivityAnxietyRisktakingBehavioraldisinhibitionIncreasedalcoholconsumption???g-PKCg-PKCmutantsconsumemoreethanolinafree- choice2bottlechoicetestThereisnodifferenceinsaccharinandnicotinepreferenceorconsumptionbas