Psychostimulants and Plasticity

精神兴奋剂和可塑性

• 批准号: 8225385
• 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/8225385
• 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. PUBLIC HEALTH RELEVANCE: Learning plays an important role in addiction. For example, environmental cues that addicts have learned to associate with drug availability are powerful triggers for relapse, even long after abstinence is achieved. Our goal is to understand the role of glutamate neurotransmission in addiction-related learning and plasticity, with the goal of identifying targets for the development of anti-craving medications.

描述（由申请人提供）：过去 20 年，我的实验室在证明导致药物成瘾的神经元适应涉及谷氨酸依赖性可塑性方面发挥了重要作用。我们最近的工作基于以下证据：药物寻找的最终共同途径涉及终止于伏隔核（NAc）神经元的皮质和边缘谷氨酸输入，这些神经元反过来投射到负责执行药物寻找的运动区域。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 运输对于控制突触强度的重要性，我们正在测试以下假设：AMPAR 向 NAc 突触的运输增加是戒断可卡因暴露后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 提供的受保护的时间和工资节省使我的实验室能够开发出创新方法，从而使我们目前重点关注 AMPAR 贩运。因此，我们第一个研究了 NAc 神经元中的 AMPAR 贩运，并确定了其在可卡因成瘾大鼠模型中的重要性（行为敏化和在戒断可卡因自我给药后提示诱发的可卡因渴望的孵化）。 K02 奖推动的进步让我获得了 NIDA 优异奖，并为我的 R01 提供了持续的资助。这些资助的重点是定义 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。最近由这些拨款资助的工作表明，长期戒断后添加到 NAc 突触的非典型 AMPAR 亚型可介导可卡因渴望增强，因此是开发抗渴望药物的目标。我正在申请 K05 奖，以减轻教学和服务职责，以便我能够最有效地实现 NIDA 资助的目标，并使我的实验室通过持续创新为该领域做出更大的贡献。特别是，我建议追求两个新的研究方向，以促进我的职业发展并加快我们在理解导致可卡因成瘾的可塑性机制方面的进展。首先，我想开发分析树突棘形态和数量的方法，以便我可以检验 AMPAR 突触插入在可卡因戒断后触发 NAc 中树突重塑的假设。其次，我想开发利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、结构和行为可塑性背后的信号传导途径。我已经确定了两位专家顾问来协助这些新方向的发展。此外，K05 奖带来的受保护时间将使我能够扩大我作为导师的贡献。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名助理教授，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。 公共卫生相关性：学习在成瘾中起着重要作用。例如，成瘾者学会将环境因素与药物可用性联系起来，即使在戒毒很久之后，也会成为复发的强大触发因素。我们的目标是了解谷氨酸神经传递在成瘾相关的学习和可塑性中的作用，目的是确定开发抗渴望药物的目标。