AMPA Receptor Trafficking and Cocaine Reinstatement

AMPA 受体贩运和可卡因恢复

基本信息

批准号：
9000679
负责人：
LISA A BRIAND
金额：
$ 24.53万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9000679
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 Exhibits Extinction (Psychology)Funding Future Gene Expression Glutamates Goals Grant Health Health Care Costs Hippocampus (Brain)In Vitro Interview Knock-out Lead Learning Learning Skill Link Long-Term Depression Mediating Membrane Memory Mentors Mus Mutation Nucleus Accumbens PKC Phosphorylation Site Pathology Pharmaceutical Preparations Phase Physiological Physiology Population Positioning Attribute Protein Isoforms Proteins Public Health Publishing Relapse Research Rewards Role Self Administration Signal Transduction Slice Stress Synapses Synaptic plasticity Techniques Testing Time Training Transgenic Mice United States Ventral Tegmental Area Work cocaine exposure cocaine relapse drug seeking behavior glutamate receptor interacting protein in vivo knock-down neuroadaptation neuropsychopharmacology protein expression research study response skill acquisition tenure track trafficking

项目摘要

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 lo relapse is the goal of this grant application. More specifically, work utilizing both in vitro slice physiology and in vivo field recordings indicate that 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. Additional evidence obtained during the K99 phase of funding indicates that blocking long-term depression, either via potentiating endocytosis via deletion of the anchoring protein glutamate receptor interacting protein (GRIP), or disrupting endocytosis, utilizing a transgenic mouse lacking the PKC phosphorylation site on the AMPA receptor GluA2 subunit, leads to increased reinstatement of drug seeking behavior. Aims proposed for the ROO phase of the grant will expand upon these findings to examine the role AMPA receptor trafficking in stress-induced reinstatement. This will be acomplished using the two lines of mice described above and examining how manipulating AMPA endocytosis alters stress-induced behaviors as well as physiology. None of the aims of the grant have changed since the original K99 submission, however one aim from the K99 phase has been switched with an already-completed aim from the ROO phase, as discussed in the Research Strategy section.

可卡因滥用是美国的一个主要公共卫生问题。在最新的国家研究中，数字目前吸食可卡因的 12 岁以上人口估计为 160 万人，占总数的 0.7% 人口。近年来，大量研究表明可卡因成瘾与奖励学习的神经适应和随之而来的病理学。长期接触可卡因会导致谷氨酸突触的改变，包括谷氨酸释放、基因和蛋白质表达的变化，和突触可塑性。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表明，反复接触可卡因会导致长期伏隔核（NAc）内的抑制。尽管这种效应背后的确切机制是尚不清楚，来自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是必要的。在 K99 阶段获得的额外证据资金表明，通过删除增强内吞作用来阻止长期抑郁症锚定蛋白谷氨酸受体相互作用蛋白（GRIP），或破坏内吞作用，利用转基因小鼠在 AMPA 受体 GluA2 亚基上缺乏 PKC 磷酸化位点，导致寻求毒品行为的恢复增加。原产地规则阶段的赠款拟议目标将扩大根据这些发现来检查 AMPA 受体贩运在压力诱导的恢复中的作用。这将使用上述两系小鼠并检查如何操纵 AMPA 来完成内吞作用改变应激诱导的行为和生理。这笔赠款的目的均未实现自最初的 K99 提交以来发生了变化，但是 K99 阶段的一个目标已更改为正如研究战略部分所讨论的，原产地规则阶段已完成的目标。