Psychostimulants and Plasticity

描述（由申请人提供）：在过去的20年里，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的可塑性方面发挥了重要作用。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包括皮层和边缘谷氨酸输入，最终终止于伏隔核（NAc）神经元，而伏隔核又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贩运对控制突触强度的重要性，我们正在测试一种假设，即AMPAR贩运到NAc突触的增加是可卡因暴露戒断后发生的可卡因寻求增强的基础。自2000年以来，我一直得到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，从而导致我们目前关注AMPAR贩运。因此，我们首次研究了AMPAR在NAc神经元中的转运，并确定了其在可卡因成瘾大鼠模型中的重要性（行为致敏和自我戒断可卡因后线索诱导的可卡因渴望的潜伏期）。在K02奖的推动下，我获得了NIDA优秀奖，并继续资助我的R01。这些赠款的重点是确定麻醉品抗麻醉品在非洲国家传播的基本特性，并了解可卡因接触影响麻醉品抗麻醉品贩运的机制。最近由这些基金资助的研究表明，在长时间戒断后，一种非典型的AMPAR亚型被添加到NAc突触中，介导了对可卡因的增强渴望，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中解脱出来，这样我就可以最有效地追求我的NIDA资助的目标，并定位我的实验室，通过持续的创新为该领域做出更大的贡献。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和加速我们的进展，以了解有助于可卡因成瘾的可塑性机制。首先，我想开发分析树突脊柱形态和数量的方法，这样我就可以验证AMPAR突触插入触发可卡因戒断后NAc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、结构和行为可塑性的信号通路。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，获得K05奖所带来的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. 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.