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

. zeta抑制肽对药物相关记忆消除机制的研究。 项目摘要： 可卡因滥用在美国是一个主要的公共卫生问题，复发率高，缺乏有效的预防措施。 药物治疗选择。我们最近证明，zeta抑制肽（ZIP）注入 在可卡因复发的动物模型中，此外，ZIP的影响 在肽从大脑中清除后持续长达1周，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，本提案的目的 研究ZIP影响可卡因诱导的行为、突触和结构可塑性的机制。 我们和其他人已经表明，可卡因自我管理导致受损的NMDA依赖性长期 抑郁症（LTD）的发生。未来的学习，如药物相关线索的消失， 没有能力重新调整这些突触。由于LTD依赖于GluA 2的去除， 含有AMPAR，我们假设ZIP可以通过防止可卡因后LTD的能力恢复， PKC介导的含GluA 2的AMPAR的去除。AMPAR贩运的变化是动态的， 结构可塑性的改变，如棘密度的变化，提供了一种持久的机制， 受体水平的变化。事实上，慢性可卡因已被证明会导致大脑中的结构可塑性。 破坏这种结构可塑性的核团和操作会降低可卡因的奖赏 行为，包括恢复行为。由于结构可塑性依赖于肌动蛋白聚合， 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 通过破坏肌动蛋白动力学的可塑性。由于ZIP消除可卡因的能力， 一种设计潜在疗法的途径，了解这些效应发生的机制， 很危险目的1着重于确定在延髓核中给予ZIP如何影响突触的形成。 可塑性和AMPAR运输。此外，这一目标将确定ZIP对可卡因的影响是否 恢复取决于钝化有限责任公司的能力，ZIP的能力，以扭转这一必要性 行为效应的可塑性。目标2将重点关注ZIP对可卡因诱导的结构性 可塑性目的3的重点是确定ZIP的作用是否依赖于另一种非典型PKC， PKC 1/λ。因此，拟议实验的总体目标是阐明ZIP可能 在受体和树突水平上破坏可卡因诱导的可塑性。

. 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.