AMPA Receptor Trafficking and Cocaine Reinstatement

AMPA 受体贩运和可卡因恢复

• 批准号: 8606840
• 负责人: LISA A BRIAND
• 金额: $ 15.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606840
• 关键词: AMPA Receptors; Age; Amygdaloid structure; Animal Model; Applications Grants; Award; Behavior; Behavioral; Chemosensitization; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Country; Cues; Electrophysiology (science); Endocytosis; Extinction (Psychology); Foundations; Future; Gene Expression; Genetic; Glutamates; Goals; Grant; Health; Health Care Costs; Hippocampus (Brain); In Vitro; Individual; Lead; Learning; Long-Term Depression; Mediating; Memory; Mentors; Molecular; Molecular Probes; Mus; Mutation; Nucleus Accumbens; PKC Phosphorylation Site; Pathology; Pharmaceutical Preparations; Phase; Physiological; Physiology; Population; Positioning Attribute; Protein Isoforms; Public Health; Relapse; Research; Research Project Grants; Rewards; Role; Self Administration; Slice; Solid; Stress; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Training; Transgenic Mice; United States; Ventral Tegmental Area; Work; career; cocaine exposure; design; drug seeking behavior; in vivo; knowledge base; neuroadaptation; novel; patch clamp; programs; protein expression; research study; response; trafficking; AMPA Receptors; Age; Amygdaloid structure; Animal Model; Applications Grants; Award; Behavior; Behavioral; Chemosensitization; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Country; Cues; Electrophysiology (science); Endocytosis; Extinction (Psychology); Foundations; Future; Gene Expression; Genetic; Glutamates; Goals; Grant; Health; Health Care Costs; Hippocampus (Brain); In Vitro; Individual; Lead; Learning; Long-Term Depression; Mediating; Memory; Mentors; Molecular; Molecular Probes; Mus; Mutation; Nucleus Accumbens; PKC Phosphorylation Site; Pathology; Pharmaceutical Preparations; Phase; Physiological; Physiology; Population; Positioning Attribute; Protein Isoforms; Public Health; Relapse; Research; Research Project Grants; Rewards; Role; Self Administration; Slice; Solid; Stress; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Training; Transgenic Mice; United States; Ventral Tegmental Area; Work; career; cocaine exposure; design; drug seeking behavior; in vivo; knowledge base; neuroadaptation; novel; patch clamp; programs; protein expression; research study; response; trafficking

DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem in the United States. In the latest national study, the number of people over the age of 12 who are current cocaine users is estimated at 1.6 million, or 0.7% of the total population. In recent years extensive research has demonstrated that cocaine addiction is associated with neuroadaptations and consequent pathology of reward learning. Chronic cocaine exposure leads to alterations in glutamatergic synapses, including changes in glutamate release, gene and protein expression, and synaptic plasticity. Further elucidating the mechanisms underlying these changes and how they lead to relapse is the goal of this grant application. More specifically, work utilizing both in vitro slice physiology and in vivo field recordings indicate tat repeated exposure to cocaine leads to a decrease in long-term depression within the nucleus accumbens (NAc). Although the exact mechanisms underlying this effect are unclear, existing evidence from the learning and memory field indicates that PKC-mediated AMPA receptor endocytosis is necessary for long-term depression. Our preliminary results show that blocking this endocytosis, utilizing a transgenic mouse lacking the PKC phosphorylation site on the AMPA receptor GluA2 subunit, leads to increased reinstatement of drug seeking behavior. The specific aims for the mentored component of the proposed grant are designed to use this genetic mouse to probe the molecular mechanisms underlying cocaine reinstatement. Aim 1 focuses on delineating the mechanisms responsible for reinstatement promoted by cocaine-associated cues using patch clamp electrophysiology. Aim 2 expands this work to include stress- induced reinstatement of cocaine seeking. Aims proposed for the independent (R00) phase of the grant will investigate further the individual components of AMPA receptor trafficking, examining the role of the novel PKC isoform, PKM?, in the ability of cues and stress to elicit reinstatement. Thus, the overall goal of the proposed experiments is to determine the role of AMPA receptor trafficking in cocaine-induced changes in synaptic plasticity and whether these changes in plasticity are required for two distinct forms of cocaine reinstatement, an animal model of relapse. My research so far in the field of cocaine addiction has given me a solid foundation in behavioral and molecular approaches. However, the specialized training proposed in electrophysiology during the K99 phase of this award will broaden my knowledge base and allow for a truly multi-disciplinary approach in my future career. Furthermore, this training and individualized research project will serve me well as I prepare for a future academic tenure-track position.

描述（由申请人提供）：可卡因滥用是美国的主要公共卫生问题。在最新的全国研究中，现任可卡因使用者的12岁以上人数估计为160万，占总人口的0.7％。近年来，广泛的研究表明，可卡因成瘾与神经适应和随之而来的奖励学习病理有关。慢性可卡因暴露会导致谷氨酸能突触的改变，包括谷氨酸释放，基因和蛋白质表达以及突触可塑性的变化。 进一步阐明这些变化的机制以及它们如何导致复发是该赠款应用的目标。更具体地说，利用体外切片生理和体内现场记录的工作表明，反复暴露于可卡因会导致伏隔核（NAC）内长期抑郁症的减少。 尽管此效果的确切机制尚不清楚，但学习和记忆场的现有证据表明，PKC介导的AMPA受体内吞作用对于长期抑郁症是必需的。我们的初步结果表明，通过使用AMPA受体GLUA2亚基上缺乏PKC磷酸化位点的转基因小鼠阻止这种内吞作用，从而导致恢复对药物寻求行为的恢复。 拟议赠款的指导成分的具体目的旨在使用这种遗传小鼠来探测可卡因恢复的分子机制。 AIM 1的重点是描述使用贴片夹电生理学通过可卡因相关的线索促进的负责恢复的机制。 AIM 2扩大了这项工作，包括应力引起的可卡因寻求恢复。赠款的独立阶段提出的目的将进一步研究AMPA受体运输的各个组成部分，研究新型PKC同工型，PKM？，在提示和压力引起恢复的能力方面的作用。因此，提出的实验的总体目标是确定AMPA受体运输在可卡因诱导的突触可塑性变化中的作用，以及两种可卡因恢复的两种不同形式的可塑性所需的这些变化，这是一种复发的动物模型。 到目前为止，我在可卡因成瘾领域的研究为我的行为和分子方法提供了坚实的基础。但是，在该奖项的K99阶段提出的电生理学专业培训将扩大我的知识基础，并在我未来的职业生涯中采用真正的多学科方法。 此外，当我为未来的学术终身制职位做准备时，这个培训和个性化的研究项目将为我提供很好的服务。