Psychostimulants and Plasticity

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的可塑性。我们最近的工作是基于这样的证据，即药物寻找的最终共同途径涉及皮质和边缘谷氨酸输入，终止于伏核(NAC)神经元，该神经元反过来投射到负责执行药物寻找的运动区。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转运对控制突触强度的重要性，我们正在检验一种假设，即AMPAR转运到NAC突触的增加是戒断可卡因暴露后增强可卡因寻求的基础。自2000年以来，我一直受到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创新的方法，导致我们目前专注于AMPAR贩运。因此，我们第一个研究了AMPAR在NAc神经元中的转运，并确定了它在可卡因成瘾大鼠模型中的重要性(行为敏感化和戒断后线索诱导的可卡因渴求的孵化)。在K02奖的推动下取得的进步导致了NIDA优秀奖和My R01的持续资助。这些赠款的重点是确定AMPAR在NAC中传播的基本特性，并了解接触可卡因影响AMPAR贩运的机制。最近由这些赠款资助的研究表明，一个非典型的AMPAR亚型，在长期戒断后添加到NAC突触中，介导了增强的可卡因渴望，因此是抗渴望药物开发的目标。我正在申请K05奖，以保持从教学和服务职责中解脱出来，以便我能够最有效地实现我的NIDA赠款的目标，并通过不断的创新，使我的实验室能够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，以便验证AMPAR突触插入触发可卡因戒断后NAC树突状重塑的假设。其次，我想开发使用病毒介导的基因传递的能力，以更有效地探索构成可卡因诱导的AMPAR、结构和行为可塑性的信号通路。我已经确定了两名专家顾问，协助制定这些新方向。此外，K05奖所带来的受保护时间将使我能够扩大我作为导师的贡献。这份申请书包含了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全面的职业发展以及NIDA资助的项目的发展。

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.