Cdk5ModulatesCocaineReward,Motivation,andStriatal NeuronExcitability

Cyclin-dependent kinase 5 (Cdk5) regulates dopamine neurotransmission and has been suggested to serve as a homeostatic target of chronic psychostimulant exposure. To study the role of Cdk5 in the modulation of the cellular and behavioral effects of psychoactive drugsofabuse,wedevelopedCre/loxPconditionalknock-outsystemsthatallowtemporalandspatialcontrolofCdk5expressioninthe adult brain. Here, we report the generation of Cdk5 conditional knock-out (cKO) mice using the CaMKII promoter-driven Cre transgenicline(CaMKII-Cre).Inthismodelsystem,lossofCdk5intheadultforebrainincreasedthepsychomotor-activatingeffectsofcocaine. Additionally,theseCaMKII-CreCdk5cKOmiceshowenhancedincentivemotivationforfoodasassessedbyinstrumentalrespondingon aprogressiveratioscheduleofreinforcement.Behavioralchangeswereaccompaniedbyincreasedexcitabilityofmediumspinyneurons in the nucleus accumbens (NAc) in Cdk5 cKO mice. To study NAc-specific effects of Cdk5, another model system was used in which recombinantadeno-associatedvirusesexpressingCrerecombinasecausedrestrictedlossofCdk5inNAcneurons.Targetedknock-outof Cdk5intheNAcfacilitatedcocaine-inducedlocomotorsensitizationandconditionedplacepreferenceforcocaine.Theseresultssuggest thatCdk5actsasanegativeregulatorofneuronalexcitabilityintheNAcandthatCdk5maygovernthebehavioraleffectsofcocaineand motivationforreinforcement.

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