AMPA Receptor Trafficking and Cocaine Reinstatement

AMPA 受体贩运和可卡因恢复

• 批准号: 8442554
• 负责人: LISA A BRIAND
• 金额: $ 15.83万
• 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/8442554
• 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

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一个主要公共卫生问题。在最新的全国研究中，目前吸食可卡因的 12 岁以上人数估计为 160 万人，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。长期接触可卡因会导致谷氨酸能突触发生变化，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背后的机制以及它们如何导致复发是本次拨款申请的目标。更具体地说，利用体外切片生理学和体内现场记录的工作表明，重复接触可卡因会导致伏隔核（NAc）内的长期抑制减少。 尽管这种效应的确切机制尚不清楚，但学习和记忆领域的现有证据表明，PKC 介导的 AMPA 受体内吞作用对于长期抑郁症是必要的。我们的初步结果表明，利用 AMPA 受体 GluA2 亚基上缺乏 PKC 磷酸化位点的转基因小鼠来阻断这种内吞作用，会导致药物寻求行为的恢复增加。 拟议拨款的指导部分的具体目标是利用这种基因小鼠来探索可卡因恢复的分子机制。目标 1 侧重于利用膜片钳电生理学描述可卡因相关线索促进恢复的机制。目标 2 扩展了这项工作，包括压力诱导的可卡因寻求恢复。拨款独立（R00）阶段的拟议目标将进一步调查 AMPA 受体贩运的各个组成部分，检查新型 PKC 异构体​​ PKM？在线索和压力诱导恢复的能力中的作用。因此，拟议实验的总体目标是确定 AMPA 受体贩运在可卡因诱导的突触可塑性变化中的作用，以及可卡因恢复的两种不同形式（复发的动物模型）是否需要这些可卡因的变化。 迄今为止，我在可卡因成瘾领域的研究为我在行为和分子方法方面奠定了坚实的基础。然而，该奖项 K99 阶段提出的电生理学专业培训将拓宽我的知识基础，并为我未来的职业生涯提供真正的多学科方法。 此外，这个培训和个性化研究项目将为我为未来的学术终身职位做好准备。