FMRP in the striatum: mechanisms of early drug reward
纹状体中的 FMRP:早期药物奖励机制
基本信息
- 批准号:10379954
- 负责人:
- 金额:$ 5.22万
- 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:2021-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAffectBacterial Artificial ChromosomesBehaviorBiologicalBiological AssayBiological FactorsBrain regionCellsCocaineCorpus striatum structureCuesCytoskeletonDRD2 geneDataDevelopmentDiseaseDopamine D1 ReceptorDoseDrug ExposureFMR1FoodFutureGoalsImpairmentIndividualInfusion proceduresIntravenousKnockout MiceLearningLoxP-flanked alleleMediatingMemoryMissionModelingMusNational Institute of Drug AbuseNucleus AccumbensPharmaceutical PreparationsPhenotypePreventionProteinsPublishingRNA-Binding ProteinsReceptor SignalingRegulationRelapseRewardsRiskRisk FactorsRoleScienceScientistSelf AdministrationSpecificitySubstance Use DisorderSubstance abuse problemSynapsesSynaptic plasticityTestingTherapeutic InterventionTrainingTraining SupportTransgenic AnimalsTranslationsUnited StatesVentral StriatumVirusWorkaddictionbasebrain circuitrycareercell typecocaine self-administrationconditioned place preferencedrug developmentdrug rewarddrug seeking behaviorinsightintravenous administrationknock-downnext generationoverexpressionprotein expressionprotein functionreinforcersmall hairpin RNAtargeted treatment
项目摘要
Project Summary/Abstract
Substance use disorders, affecting approximately 20.1 million individuals in the U.S., are characterized by a
shift in voluntary drug-taking to compulsive drug-seeking and -taking behaviors, which persist despite negative
consequences and remain prone to relapse after periods of abstinence. Though environmental influences have
been identified as risk factors, there are major gaps in understanding of biological factors that contribute to the
development of substance use disorders, limiting our ability to provide effective and lasting treatments.
Previous work suggests that the fragile X mental retardation protein (FMRP), an RNA-binding protein that
regulates synaptic plasticity, is required for cocaine-induced synapse elimination in the striatum, a brain region
critical to reward function. Moreover, loss of FMRP, either broadly or in the ventral striatum (nucleus
accumbens; NAc), is capable of dampening cocaine-induced behaviors that are considered indicative of higher
addiction-related risk. The main objective of this R36 application is to determine the mechanism by which
FMRP facilitates operant self-administration of intravenous cocaine and reinstatement of drug-seeking
behavior. The central hypothesis, based on published and preliminary data, is that FMRP positively mediates
cocaine intravenous self-administration and reinstatement of drug-seeking via its regulation of the activity-
regulated cytoskeleton-associated protein (Arc) in D1-receptor (D1R) expressing cells of the NAc. This
hypothesis will be tested in two specific aims, each utilizing conditional knockdown approaches and an
extensive self-administration assay that includes cue- and drug-induced reinstatement paradigms. Aim 1 will
determine whether FMRP mediates these phenotypes via its function in specifically D1R or D2R cells of the
NAc, while Aim 2 will determine whether FMRP’s regulation of Arc contributes to these phenotypes. This work
will complete the applicant’s dissertation, as part of her training for a career in addiction-related science,
provide insight into the mechanism by which FMRP mediates drug-related behaviors, providing critical direction
for future studies aimed at identifying downstream targets for therapeutic intervention.
项目总结/文摘
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Working around the CLOCK: Cocaine-induced phase shift of NPAS2 and SIRT1 and their roles in directing drug-related behaviour (commentary on Becker-Krail et al., 2021).
围绕时钟工作:可卡因诱导的 NPAS2 和 SIRT1 相移及其在指导药物相关行为中的作用(Becker-Krail 等人的评论,2021)。
- DOI:10.1111/ejn.15464
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Huebschman,JessicaL;Smith,LauraN
- 通讯作者:Smith,LauraN
Jugular Vein Catheter Design and Cocaine Self-Administration Using Mice: A Comprehensive Method.
- DOI:10.3389/fnbeh.2022.880845
- 发表时间:2022
- 期刊:
- 影响因子:3
- 作者:
- 通讯作者:
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