Trk:ANeuromodulatorofAge-SpecificBehavioraland NeurochemicalResponsestoCocaineinMice

Responses to psychostimulants vary with age, but the molecular etiologies of these differences are largely unknown. The goal of the presentresearchwastoidentifyage-specificbehavioralandmolecularadaptationstococaineandtoelucidatethemechanismsinvolved therein. Postweanling, periadolescent, and adult male CD-1 mice were exposed to cocaine (20 mg/kg) for 7 d. The rewarding effects of cocainewereassessed,asweretheresponsetoaTrkantagonistandtheregulationofdopamineandcAMP-regulatedphosphoprotein,32 kDa (DARPP-32). Cocaine was rewarding in both periadolescent and adult mice using a conditioned place preference procedure. In contrast, postweanling mice failed to demonstrate significant cocaine-induced place preference. Because components of the neurotro- phinsystemincludingbrain-derivedneurotrophicfactorandTrkBaredevelopmentallyregulated,theirroleintheage-specificeffectsof cocainewasdeterminedusingtheTrkreceptorantagonistK252a.PostweanlingmicethatreceivedK252abeforedailycocaineshoweda significantplacepreferencetothecocaine-pairedenvironmentthatwasnotseenintheabsenceofK252a.DARPP-32proteinlevelswere significantly upregulated in the lateral region of the caudate-putamen exclusively in postweanling mice after chronic cocaine. Daily pretreatmentwithK252aattenuatedtheinductionofDARPP-32inthepostweanlingstriatum.ThesedataindicatethatTrkneurotrans- missionplaysaroleinage-specificbehavioralandmolecularresponsestococaineandconcurrentlymodulatesDARPP-32levels.