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

。 研究Zeta抑制肽消除药物相关记忆的机制。 项目总结： 在美国，可卡因滥用是一个主要的公共卫生问题，复发率很高，缺乏 药物治疗方案。我们最近证明了Zeta抑制肽(ZIP) 进入伏核阻断可卡因的恢复，这是一种复发的动物模型。此外，ZIP的影响 在多肽从大脑中清除后持续1周，ZIP不会改变食物的恢复。 最近的证据使ZIP的作用机制受到质疑。因此，这项提议的目标是 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，可卡因自我管理会导致NMDA依赖的长期受损 伏隔内的凹陷(LTD)。未来的学习，例如与毒品有关的线索的消失，可能会 被闭塞而不能重新调整这些突触。AS LTD依赖于移除GluA2- 包含AMPAR，我们假设ZIP可以通过防止 PKC介导的含有GluA2的AMPAR的去除。AMPAR贩运的变化是动态的和 结构可塑性的变化，如脊柱密度的变化，提供了一种持久的机制 在受体水平上的变化。事实上，慢性可卡因已被证明导致脑内结构可塑性 伏隔核和破坏这种结构可塑性的操作会降低可卡因的奖赏 行为，包括恢复行为。因为结构的可塑性依赖于肌动蛋白聚合和 可卡因已被证明可以改变这一过程，我们认为ZIP可能逆转可卡因诱导的结构 通过肌动蛋白动力学的破坏而产生的可塑性。因为ZIP消除可卡因的能力恢复可以提供 要设计潜在的治疗方法，了解这些效应发生的机制，一个途径是 危急时刻。目标1着重于确定伏隔核内注射ZIP对突触的影响 可塑性和AMPAR贩运。此外，这一目标将决定ZIP对可卡因的影响 复职取决于能否钝化有限公司ZIP扭转这一局面的能力的必要性 其行为效果的可塑性。目标2将重点放在ZIP对可卡因诱导的结构性结构的潜在影响 可塑性。目的3集中于确定ZIP的作用是否依赖于另一个非典型PKC， Pkcι/λ.因此，拟议的实验的总体目标是阐明ZIP可能通过的机制 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.