Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide

检查 Zeta 抑制肽导致药物相关记忆擦除的机制

基本信息

批准号：
9752721
负责人：
LISA A BRIAND
金额：
$ 48.07万
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：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752721
关键词：
A kinase anchoring protein AMPA Receptors Abstinence Actins Affect Animal Model Behavior Behavioral Biological Brain Cell Culture Techniques Chronic Cocaine Cocaine Abuse Cocaine Dependence Country Cues Data Dendrites Dendritic Spines Disease Down-Regulation Effectiveness Electrophysiology (science)Excision Extinction (Psychology)Food Future Goals Grant Health Health Care Costs Hippocampus (Brain)Impairment Infusion procedures Knock-out Learning Long-Term Depression Long-Term Effects Measures Medial Mediating Mediator of activation protein Memory Molecular Morphogenesis N-Methylaspartate Nature Neurons Nucleus Accumbens Peptides Pharmaceutical Preparations Pharmacological Treatment Physiological Physiology Prefrontal Cortex Process Protein Isoforms Public Health Relapse Research Rewards Role Self Administration Shapes Stimulus Structure Substrate Specificity Synapses Synaptic plasticity Techniques Therapeutic Therapeutic Intervention Translations United States Vertebral column Work cocaine relapse density design experience experimental study inhibitor/antagonist insight novel polymerization prevent protein kinase C zeta receptor trafficking

项目摘要

. Examining mechanisms underlying drug-associated memory erasure by zeta-inhibitory peptide. Project Summary: Cocaine abuse is a major public health problem in the United States with high rates of relapse and a lack to pharmacological treatment options. We have recently demonstrated that zeta-inhibitory peptide (ZIP) infused into the nucleus accumbens blocks cocaine reinstatement, an animal model of relapse. Further, ZIP's effects persist up to 1 week after the peptide is cleared from the brain and ZIP does not alter food reinstatement. Recent evidence has called the mechanism of action of ZIP into question. Therefore, the goal of this proposal is to examine mechanisms by which ZIP affects cocaine-induced behavioral, synaptic and structural plasticity. We, and others, have shown that cocaine self-administration leads to impaired NMDA-dependent long-term depression (LTD) within the accumbens. Future learning, such as the extinction of drug-associated cues, could be occluded without the ability to rescale these synapses. As LTD is dependent upon the removal of GluA2- containing AMPARs, we hypothesize that ZIP may restore the capacity for LTD following cocaine by preventing PKC-mediated removal of GluA2-containing AMPARs. Changes in AMPAR trafficking are dynamic and alterations in structural plasticity, such as changes in spine density, provide a mechanism for persistent changes at the receptor level. In fact, chronic cocaine has been shown to lead to structural plasticity within the nucleus accumbens and manipulations that disrupt this structural plasticity decrease cocaine reward behaviors, including reinstatement behavior. As structural plasticity is dependent upon actin polymerization and cocaine has been shown to alter this process, we propose that ZIP may reverse cocaine-induced structural plasticity via disruption of actin dynamics. As the ability of ZIP to eliminate cocaine reinstatement could provide an avenue to designing potential therapeutics, understanding the mechanism by which these effects occur is critical. Aim 1 focuses on determining how ZIP administration in the nucleus accumbens affects synaptic plasticity and AMPAR trafficking. Additionally, this aim will determine whether the effects of ZIP on cocaine reinstatement are dependent upon the ability to blunt LTD the necessity of the ability of ZIP to reverse this plasticity in its behavioral effects. Aim 2 will focus on the potential affects of ZIP on cocaine-induced structural plasticity. Aim 3 focuses on determining whether the effects of ZIP are dependent upon another atypical PKC, PKCι/λ. Thus, the overall goal of the proposed experiments is to elucidate the mechanisms by which ZIP may disrupt cocaine-induced plasticity at the level of the receptor and the dendrite.

。检查 zeta 抑制肽消除药物相关记忆的潜在机制。项目概要：可卡因滥用是美国的一个主要公共卫生问题，复发率很高，而且缺乏预防措施我们最近证明了注射 zeta 抑制肽 (ZIP)。进入伏隔核可阻止可卡因恢复，这是一种复发的动物模型。在肽从大脑中清除后，ZIP 可以持续长达 1 周，并且 ZIP 不会改变食物恢复。最近的证据对 ZIP 的作用机制提出了质疑，因此该提案的目标。目的是研究 ZIP 影响可卡因诱导的行为、突触和结构可塑性的机制。我们和其他人已经证明，可卡因自我给药会导致长期 NMDA 依赖性受损伏隔核内的抑郁症（LTD）可能会导致未来的学习，例如与药物相关的线索的消失。被闭塞而无法重新缩放这些突触，因为 LTD 依赖于 GluA2- 的去除。含有 AMPAR，我们认为 ZIP 可以通过阻止可卡因恢复 LTD 的容量 PKC 介导的含 GluA2 AMPAR 的去除 AMPAR 运输的变化是动态的且变化的。结构可塑性的改变，例如脊柱密度的变化，提供了一种持久的机制事实上，慢性可卡因已被证明会导致受体水平的结构可塑性。伏隔核和破坏这种结构可塑性的操作会降低可卡因奖励行为，包括恢复行为，因为结构可塑性取决于肌动蛋白聚合和可卡因已被证明可以改变这一过程，我们建议 ZIP 可以逆转可卡因诱导的结构 ZIP 消除可卡因恢复的能力可以通过破坏肌动蛋白动力学来提供可塑性。设计潜在疗法、了解这些效应发生机制的一种途径是目标 1 的重点是确定伏隔核中的 ZIP 给药如何影响突触。此外，这一目标将确定 ZIP 是否对可卡因产生影响。恢复取决于削弱 LTD 的能力 ZIP 扭转这种情况的能力的必要性目标 2 将关注 ZIP 对可卡因诱导的结构的潜在影响。目标 3 侧重于确定 ZIP 的影响是否依赖于另一种非典型 PKC，因此，所提出的实验的总体目标是阐明 ZIP 可能的机制。在受体和树突水平上破坏可卡因诱导的可塑性。