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

• 批准号: 9905503
• 负责人: LISA A BRIAND
• 金额: $ 48.91万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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/9905503
• 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

. 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抑制性胡椒粉与药物相关记忆的基础机制。 项目摘要： 可卡因滥用是美国的主要公共卫生问题，退休率很高，缺乏 药理治疗选择。我们最近证明了Zeta抑制性肽（ZIP）注入 伏隔核进入可卡因恢复原状，这是一种救济动物模型。此外，拉链的效果 在从大脑中清除胡椒后长达1周，拉链不会改变食物的恢复原状。 最近的证据称ZIP的作用机理受到质疑。因此，该提议的目标 是为了检查拉链影响可卡因诱导的行为，突触和结构可塑性的机制。 我们和其他人已经表明，可卡因自我给药会导致NMDA依赖性长期受损 伏伏氏抑郁症（Ltd）。未来的学习，例如扩展与药物相关的提示，可以 被遮挡，没有能力缩放这些突触的能力。因为ltd取决于去除glua2- 包含AMPAR，我们假设拉链可以通过防止可卡因后恢复LTD的能力 PKC介导的含GLUA2的AMPAR的去除。 AMPAR贩运的变化是动态的， 结构可塑性的改变，例如脊柱密度的变化，为持久性提供了一种机制 在接收器级别的更改。实际上，慢性可卡因已被证明会导致结构可塑性 伏隔核和破坏这种结构可可卡因奖励的操纵 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此过程，我们建议拉链可以逆转可卡因诱导的结构 通过破坏肌动蛋白动力学的可塑性。由于拉链消除可卡因恢复原状的能力可以提供 设计潜在疗法的途径，了解这些影响的机制是 批判的。 AIM 1专注于确定伏隔核中的拉链给药如何影响突触 可塑性和AMPAR贩运。此外，此目标将决定拉链对可卡因的影响 恢复原状取决于blunt ltd的能力，这是拉链扭转这一能力的必要能力 其行为影响的可塑性。 AIM 2将重点关注拉链对可卡因诱导的结构的潜在影响 可塑性。 AIM 3专注于确定拉链的影响是否取决于另一个非典型PKC， PKCι/λ。这是，提出的实验的总体目标是阐明邮政编码的机制 在接收器和树突水平上破坏可卡因诱导的可塑性。