Neuromolecular Drivers of Impulsivity in Addictive Disorders
成瘾性疾病冲动的神经分子驱动因素
基本信息
- 批准号:8937072
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-12-01 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAbstinenceAcuteAddictive BehaviorAddressAgonistAnimal ModelAttention Deficit DisorderAttenuatedAutistic DisorderBehaviorBehavior ControlBehavioralBinge eating disorderBiological AssayBiologyBrainCell LineChronicCocaineCocaine AbuseCocaine DependenceCognitiveComplexCuesCycloserineDataDecision MakingDevelopmentDevelopment PlansDimensionsDiseaseDoctor of PhilosophyDrug AddictionDrug abuseDrug usageEquilibriumEventExhibitsFacultyFutureGene SilencingGene TransferGenetic TechniquesGlutamatesGoalsHealthHumanImmunohistochemistryImpaired cognitionImpulsive BehaviorImpulsivityIn VitroInstitutionLaboratoriesLinkMAPK3 geneMaintenanceMedialMediatingMembraneMentorsMolecularMolecular GeneticsN-Methyl-D-Aspartate ReceptorsNatureNeurobiologyNeuronsNeurosciencesObesityOutputPharmaceutical PreparationsPharmacologyPhasePhenotypePhosphorylationPlayPositioning AttributePrefrontal CortexPreventionPrevention strategyProcessPsychopharmacologyRattusReaction TimeReceptor Mediated Signal TransductionRecoveryRegulationRelapseRelative (related person)Request for ProposalsResearchRoleRunningSelf AdministrationSerotoninSerotonin Receptor 5-HT2CSignal TransductionStagingStudentsSurfaceSynapsesSystemTechniquesTestingTrainingViralWithdrawaladdictioncareercareer developmentcue reactivitydesigndrug seeking behaviorin vitro Assayinnovationneurochemistryneurotransmissionnovelpreventprogramsprotein crosslinkprotein expressionreceptorreceptor expressionreceptor functionreceptor-mediated signalingskillstrait impulsivitytranslational studytreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
This proposal requests support for a comprehensive training plan that will enable Noelle C. Anastasio, Ph.D.,
to broaden, enhance, and refine technical skills that are necessary for a productive independent research
career. My long-term career goal is to obtain a tenure-track faculty position at a research-intensive academic
institution and build a research program focused upon the ultimate scientific goal to understand the
psychopharmacology of the impulsivity trait to advance prevention and treatment of addiction. Various aspects
of drug abuse, including the initiation of drug-taking, the transition from casual to compulsive drug use, the
maintenance of drug-seeking behaviors as well as the penchant to reinstate drug-seeking correlate with high
levels of inherent impulsivity. Dysregulation in serotonin (5-HT) 2C receptor (5-HT2CR) function within the
mesocorticolimbic circuit has been implicated in these stages of the addiction cycle as well as the
manifestation of the impulsive phenotype. There is evidence that both serotonin (5-HT) neurotransmission
through its cognate 5-HT2C receptor (5-HT2CR) and glutamate neurotransmission through the ionotropic
glutamate N-methyl-D-aspartate receptor (NMDAR) play key roles in the cognitive and/or behavioral
dimensions of impulsivity and addictive behaviors, especially in the mPFC, a region integral to decision-making
and goal-directed behavior. Thus, the interaction between 5-HT and glutamate systems in the mPFC may
contribute to the cognitive impairments seen in cocaine addiction. I will receive multifaceted training during the
K99 mentored phase (Years 1-2; Aims 1-2) from a team of collaborating mentors that includes training in
molecular techniques (e.g., protein crosslinking, creation of cell lines, bioresponsive assays) to analyze
receptor subcellular localization and signal transduction regulation, as well as sophisticated behavioral
neuroscience/pharmacology/molecular genetics techniques (e.g., immunohistochemistry, intracranial
microinfusion, viral-mediated gene transfer). I will also receive mentoring in career development,
grantsmanship, laboratory staff and student management and fiscal and planning responsibilities critical to
running an independent laboratory. The research plan that is proposed during the R00 independent phase
(Years 3-5; Aims 3-4) builds on this training to focus more specifically on the neurobiology of the mPFC
NMDAR and the 5-HT2CR:NMDAR heteromeric complex as functional rheostats in expression of inherent
impulsivity and cocaine-associated relapse events. The central hypothesis is that a balance of 5-HT2CR and
NMDAR function drives mPFC output and that the loss of this balance contributes to inherent impulsivity,
leading to vulnerability for the development of addictive disorders and associated relapse events. We will test
this hypothesis and uncover neuromolecular drivers responsible for inherent impulsivity as well as the cocaine-
evoked impulsivity in relation to cocaine-associated relapse events (e.g., cue reactivity). To address this
hypothesis, four specific aims have been formulated: Aim 1) establish the role for mPFC 5-HT2CR in inherent
impulsivity; Aim 2) establish the role for mPFC 5-HT2CR in aggregate impulsivity/cue reactivity; Aim 3) elucidate
the role for mPFC NMDAR in inherent impulsivity and aggregate impulsivity/cue reactivity; Aim 4) explore the
biology of the 5-HT2CR:NMDAR complex in vitro and ex vivo. We will determine that neuronal 5-HT2CR and
NMDAR systems govern impulsivity and that rebalancing these systems may ultimately support behavioral
recovery in disorders marked by impulsivity. Together, these innovative translational studies will be the first to
systemically explore the contribution and interaction of 5-HT2CR- and NMDAR-mediated function in addiction-
relevant phenotypes, ultimately allowing for the design of targeted pharmacotherapeutics to promote
abstinence and prevent relapse in addictive disorders.
项目概要/摘要
该提案要求支持一项全面的培训计划,该计划将使 Noelle C. Anastasio 博士能够
扩大、增强和完善富有成效的独立研究所需的技术技能
职业。我的长期职业目标是在研究密集型学术机构获得终身教职
机构并建立一个专注于最终科学目标的研究计划,以了解
冲动特征的精神药理学促进成瘾的预防和治疗。各方面
药物滥用的发生,包括开始吸毒、从随意吸毒到强迫吸毒的转变、
维持寻求毒品的行为以及恢复寻求毒品的倾向与高相关性
固有的冲动程度。血清素 (5-HT) 2C 受体 (5-HT2CR) 功能失调
中皮质边缘回路与成瘾周期的这些阶段以及
冲动表型的表现。有证据表明血清素 (5-HT) 神经传递
通过其同源 5-HT2C 受体 (5-HT2CR) 和谷氨酸神经传递
谷氨酸 N-甲基-D-天冬氨酸受体 (NMDAR) 在认知和/或行为中发挥关键作用
冲动和成瘾行为的维度,特别是在 mPFC 中,这是决策不可或缺的区域
和目标导向的行为。因此,mPFC 中 5-HT 和谷氨酸系统之间的相互作用可能
导致可卡因成瘾中出现的认知障碍。期间我将接受多方面的培训
K99 由合作导师团队指导的阶段(1-2 年;目标 1-2),包括以下方面的培训:
分子技术(例如蛋白质交联、细胞系创建、生物反应测定)进行分析
受体亚细胞定位和信号转导调节,以及复杂的行为
神经科学/药理学/分子遗传学技术(例如免疫组织化学、颅内
微输注、病毒介导的基因转移)。我还将获得职业发展方面的指导,
资助、实验室工作人员和学生管理以及财务和规划责任至关重要
经营一个独立的实验室。 R00独立阶段提出的研究计划
(3-5 年;目标 3-4)在此培训的基础上更具体地关注 mPFC 的神经生物学
NMDAR 和 5-HT2CR:NMDAR 异聚复合物作为功能变阻器表达固有的
冲动和可卡因相关的复发事件。中心假设是 5-HT2CR 和
NMDAR 功能驱动 mPFC 输出,这种平衡的丧失会导致固有的冲动,
导致容易发生成瘾性疾病和相关的复发事件。我们将测试
这一假设并揭示了导致固有冲动以及可卡因的神经分子驱动因素
诱发与可卡因相关的复发事件相关的冲动(例如提示反应性)。为了解决这个问题
假设,制定了四个具体目标: 目标 1) 确定 mPFC 5-HT2CR 在固有机制中的作用
冲动;目标 2) 确定 mPFC 5-HT2CR 在总冲动/提示反应性中的作用;目标 3) 阐明
mPFC NMDAR 在固有冲动性和总冲动性/提示反应性中的作用;目标 4) 探索
5-HT2CR:NMDAR 复合物的体外和离体生物学。我们将确定神经元 5-HT2CR 和
NMDAR 系统控制冲动,重新平衡这些系统可能最终支持行为
以冲动为特征的疾病的康复。总之,这些创新的转化研究将是第一个
系统地探讨 5-HT2CR 和 NMDAR 介导的功能在成瘾中的贡献和相互作用
相关的表型,最终允许设计靶向药物治疗以促进
戒瘾并防止成瘾性疾病复发。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Noelle C Anastasio其他文献
Noelle C Anastasio的其他文献
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{{ truncateString('Noelle C Anastasio', 18)}}的其他基金
Neuromolecular Drivers of Impulsivity in Addictive Disorders
成瘾性疾病冲动的神经分子驱动因素
- 批准号:
9069772 - 财政年份:2014
- 资助金额:
$ 24.9万 - 项目类别:
Neuromolecular Drivers of Impulsivity in Addictive Disorders
成瘾性疾病冲动的神经分子驱动因素
- 批准号:
8443304 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
Neuromolecular Drivers of Impulsivity in Addictive Disorders
成瘾性疾病冲动的神经分子驱动因素
- 批准号:
8601060 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
Role of NMDAR Regulation in Phencyclidine-Induced Neurotoxicity
NMDAR 调节在苯环己哌啶诱导的神经毒性中的作用
- 批准号:
7222076 - 财政年份:2006
- 资助金额:
$ 24.9万 - 项目类别:
Role of NMDAR Regulation in Phencyclidine-Induced Neurotoxicity
NMDAR 调节在苯环己哌啶诱导的神经毒性中的作用
- 批准号:
7496507 - 财政年份:2006
- 资助金额:
$ 24.9万 - 项目类别:
Role of NMDAR Regulation in Phencyclidine-Induced Neurotoxicity
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- 批准号:
7294890 - 财政年份:2006
- 资助金额:
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