Identifying the Distinct Intracellular Pathways That Mediate Dopamine-Driven Behaviors
确定介导多巴胺驱动行为的独特细胞内途径
基本信息
- 批准号:10477942
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAntipsychotic AgentsArrestinsAutomobile DrivingAutopsyBehaviorBehavioralBindingBiological AssayBrainBrain regionCategoriesCellsChronicClustered Regularly Interspaced Short Palindromic RepeatsCocaineCollaborationsComplexCorpus striatum structureDRD2 geneDataDevelopmentDiseaseDopamineDopamine ReceptorDopaminergic AgentsDrug abuseEngineeringExhibitsFoodFutureG-Protein-Coupled ReceptorsGTP-Binding ProteinsGene ExpressionGenesHumanInvestigationKnock-outKnockout MiceLearningLocationLocomotionMediatingMediator of activation proteinMolecularMotivationMusNR2B NMDA receptorNeuronsNeurotransmittersNuclearNucleus AccumbensPathologyPathway interactionsPharmaceutical PreparationsPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesProcessProtein Phosphatase 2A Regulatory Subunit PR53ProteinsRNA InterferenceReceptor ActivationRecording of previous eventsResearchRewardsRoleSignal PathwaySignal TransductionSignaling ProteinSurfaceTissuesTreatment EfficacyUp-RegulationWorkarrestin 2beta-arrestinbrain cellcell typecocaine exposurecocaine self-administrationconditioned place preferencedesigndifferential expressiondimerexperimental studyglycogen synthase kinase 3 betahuman subjectinsightnetwork modelsnovelpreferencepreventpsychostimulantputamenreceptorrecruitreward processingscaffoldside effectstimulant dependencestimulant exposuretranscriptometranscriptome sequencingtranscriptomicswillingness
项目摘要
PROJECT SUMMARY/ABSTRACT
Dopamine (DA), a neurotransmitter implicated in learning and motivation, is also a critical player in the
mechanisms of psychostimulant action and the pathology of drug abuse. Dopamine binds five receptors (D1-
D5R), of which D2R carries particular relevance, as it takes on various functional roles in different brain regions
and cells types and is a target of all antipsychotic medications. Dopamine receptors are G protein-coupled
receptors (GPCRs) that activate intracellular G proteins and their downstream signaling cascades. This signal
is terminated upon arrestin binding to the intracellular domain of the receptor. More recently, arrestins have
been found to initiate their own G protein-independent signaling cascades by scaffolding various proteins upon
receptor activation. The functional roles of these distinct intracellular pathways are unclear.
D2R is expressed on striato-pallidal medium spiny neurons (spMSNs) of the nucleus accumbens,
where it functions to mediate many psychostimulant-induced behaviors. Previous research in mice has shown
that in these cells the arrestin pathway is able to mediate locomotion but not motivation, thus indicating that
certain behaviors may be driven by arrestin independently of G protein signaling. GSK-3β, a kinase, is
activated downstream of arrestin and is essential for the expression of certain cocaine-induced behaviors.
Additionally, upon activation, striatal D2Rs dimerize with the NMDA receptor NR2B subunit, a mechanism that
may be GSK-3β-dependent and seems to mediate conditioned place preference (CPP) for cocaine but not
food. In post-mortem striatal sections from psychostimulant dependent humans, the proportion of D2R/NMDAR
heteromers was ~3-fold higher compared to controls despite a substantial decrease of D2R expression. It is
not clear what mediates the formation of these heteromers downstream of D2R.
I hypothesize that, in spMSNs, D2R-driven arrestin and downstream GSK-3β signaling mediate cocaine
but not food reward processing by facilitating D2R-NR2B heteromerization and transcriptomic changes. I will
address this hypothesis through the following Specific Aims: Aim 1 will determine the roles of D2R-driven
arrestin and GSK-3β signaling in cocaine versus food reward processing. I will use CRISPR to knockout β-
arrestin 2 or GSK-3β in spMSNs of adult mice and assay preference for locations associated with, and
willingness to work for, a food reward and cocaine. Aim 2 will use the same knockout strategy to investigate
the molecular and transcriptomic changes mediated by βarr2 and GSK-3β upon chronic psychostimulant
exposure. I will analyze ex vivo NAc tissue for NR2B-D2R heteromerization, as well as GSK-3β and NR2B
phosphorylation, and perform transcriptomic analysis on spMSNs after chronic cocaine exposure using nuclear
RNAseq. Together, the proposed experiments will provide insight into the molecular basis for D2R-driven
behaviors and identify novel avenues for developing drugs for dopamine-related diseases.
项目总结/文摘
项目成果
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