Psychostimulants and Plasticity

精神兴奋剂和可塑性

• 批准号: 8433409
• 负责人: Marina Elizabeth Wolf
• 金额: $ 12.44万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433409
• 关键词: Abstinence; Acute; Animal Model; Award; Behavioral; Brain; Brain region; Cocaine; Cocaine Dependence; Cues; Culture Media; Cyclic AMP-Dependent Protein Kinases; Dendritic Spines; Development; Drug Addiction; Educational process of instructing; Funding; Gene Delivery; Glutamate Receptor; Glutamates; Goals; Grant; Hippocampus (Brain); In Vitro; Independent Scientist Award; Institution; Ion Channel; Learning; Light; Literature; Mediating; Mentors; Methods; Mitogen-Activated Protein Kinases; Modeling; Morphology; Motor; National Institute of Drug Abuse; Neuronal Plasticity; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Play; Positioning Attribute; Property; Rattus; Relapse; Research; Research Personnel; Role; Savings; Self Administration; Senior Scientist Award; Services; Signal Pathway; Surface; Synapses; Testing; Time; Viral; Wages; Withdrawal; Wolves; Work; addiction; base; behavioral sensitization; calmodulin-dependent protein kinase II; career development; cocaine exposure; craving; genetic regulatory protein; in vivo; innovation; neurotransmission; professor; protein expression; psychostimulant; public health relevance; receptor; response; trafficking; transmission process

DESCRIPTION (provided by applicant): My lab has played an important role over the past 20 years in showing that neuronal adaptations leading to drug addiction involve glutamate-dependent plasticity. Our recent work is based on evidence that the final common pathway for drug seeking involves cortical and limbic glutamate inputs terminating on nucleus accumbens (NAc) neurons, which in turn project to motor regions responsible for execution of drug seeking. These glutamate inputs activate NAc neurons via AMPA-type glutamate receptors (AMPAR). In light of the importance of AMPAR trafficking for controlling synaptic strength, we are testing the hypothesis that increased trafficking of AMPAR into NAc synapses underlies the enhancement of cocaine seeking that occurs after withdrawal from cocaine exposure. Since 2000, I have been supported by a NIDA K02 Award. Protected time and salary savings afforded by the K02 enabled my lab to develop the innovative methods that led to our current focus on AMPAR trafficking. As a result, we were the first to study AMPAR trafficking in NAc neurons and to establish its importance in rat models of cocaine addiction (behavioral sensitization and incubation of cue-induced cocaine craving after withdrawal from cocaine self-administration). Advances facilitated by the K02 Award led to a NIDA Merit Award and to the continued funding of my R01. These grants focus on defining fundamental properties of AMPAR transmission in the NAc and understanding the mechanisms by which cocaine exposure influences AMPAR trafficking. Recent work funded by these grants has shown that an atypical AMPAR subtype, added to NAc synapses after prolonged withdrawal, mediates enhanced cocaine craving and is therefore a target for the development of anti-craving medications. I am applying for a K05 Award to maintain relief from teaching and service duties so that I can most effectively pursue the Aims of my NIDA grants and position my lab for even stronger contributions to the field through continued innovation. In particular, there are two New Research Directions that I propose to pursue in order to enhance my career development and accelerate our progress towards understanding plasticity mechanisms that contribute to cocaine addiction. First, I want to develop methods to analyze dendritic spine morphology and number, so that I can test the hypothesis that AMPAR synaptic insertion triggers dendritic remodeling in the NAc after cocaine withdrawal. Second, I want to develop the capability to use viral- mediated gene delivery to more effectively explore signaling pathways that underlie cocaine-induced AMPAR, structural and behavioral plasticity. I have identified two expert consultants to assist with the development of these new directions. In addition, protected time resulting from this K05 Award will enable me to expand my contributions as a mentor. This application contains a detailed plan for mentoring young investigators, particularly three Assistant Professors at my institution who I am helping with overall career development as well as the development of NIDA-funded projects.

描述（由申请人提供）：我的实验室在过去20年中发挥了重要作用，表明导致药物成瘾的神经元适应涉及谷氨酸依赖性可塑性。我们最近的工作是基于这样的证据，即药物寻求的最终共同途径涉及皮质和边缘系统谷氨酸输入终止于神经核（NAc）神经元，这反过来又投射到负责执行药物寻求的运动区域。这些谷氨酸输入通过AMPA型谷氨酸受体（AMPAR）激活NAc神经元。鉴于AMPAR运输对控制突触强度的重要性，我们正在检验以下假设：增加AMPAR进入NAc突触的运输是可卡因暴露后戒断的可卡因寻求增强的基础。自2000年以来，我一直获得NIDA K02奖的支持。K02提供的保护时间和工资节省使我的实验室能够开发创新方法，导致我们目前专注于AMPAR贩运。因此，我们是第一个研究AMPAR在NAc神经元中的运输，并建立其在可卡因成瘾大鼠模型中的重要性（行为敏化和可卡因自我给药戒断后线索诱导的可卡因渴望的孵化）。由K02奖促进的进步导致了NIDA优异奖和我的R01的持续资助。这些赠款的重点是确定NAc中AMPAR传播的基本特性，并了解可卡因暴露影响AMPAR贩运的机制。最近由这些赠款的工作表明，一种非典型的AMPAR亚型，在长时间戒断后添加到NAc突触中，介导了增强的可卡因渴望，因此是开发抗渴望药物的目标。我正在申请K05奖，以保持从教学和服务职责的救济，使我可以最有效地追求我的NIDA赠款的目标，并定位我的实验室，通过不断创新，为该领域作出更大的贡献。特别是，有两个新的研究方向，我建议追求，以提高我的职业发展，并加快我们的进展，了解可塑性机制，有助于可卡因成瘾。首先，我想开发方法来分析树突棘的形态和数量，这样我就可以测试的假设，AMPAR突触插入触发树突重塑后，可卡因戒断NAc。第二，我想开发使用病毒介导的基因传递的能力，以更有效地探索可卡因诱导的AMPAR、结构和行为可塑性的信号通路。我已物色了两名专家顾问，协助制订这些新方向。此外，从这个K05奖产生的保护时间将使我能够扩大我作为一个导师的贡献。该申请包含指导年轻研究人员的详细计划，特别是我所在机构的三位助理教授，我正在帮助他们进行整体职业发展以及NIDA资助项目的开发。