Preventing alcohol seeking with a nonmuscle myosin II inhibitor under clinical development

项目概要 虽然多种药物已被批准用于治疗酒精使用障碍 (AUD)，但许多患者未能做出反应 或配合治疗。提醒人们饮酒而引发的旧病复发对于患者来说是一个特殊的挑战。 预防，因为潜在的记忆对行为产生强大的动机影响并代表 终生复发的危险因素。这些关联的学习得到了树突结构可塑性的支持 棘，由训练诱导的肌动蛋白聚合驱动。随后通过阻止来实现记忆稳定性 肌动蛋白动力学，稳定细胞骨架。因此，记忆不受内部肌动蛋白解聚的影响。 分钟的学习时间。然而，实验室之前的工作发现，肌动蛋白细胞骨架支持 训练后很长一段时间，甲基苯丙胺和苯丙胺记忆在杏仁核中仍然保持着独特的活力。 这使得能够选择性地、独立于检索地破坏这些记忆以及相关的药物寻找 肌动蛋白解聚剂的单次施用。因为肌动蛋白在体内的关键作用限制了它的治疗作用 潜力，焦点转向非肌肉肌球蛋白 II (NMII)，它是学习刺激肌动蛋白聚合的直接驱动因素 在刺中。 NMII 的遗传和药理学靶向确定了它是一个可行的治疗靶点和 NIH- 临床安全 NMII 抑制剂的资助药物开发项目正在进行中，目前处于阶段 支持 IND 的研究 (UH3 NS096833)。当前提案的中心假设是单个 服用 NMII 抑制剂将会对饮酒产生持久的干扰。目标1将 确定 NMII 抑制的独立于检索的能力，以破坏引发酒精寻求的关联， 例如甲基苯丙胺和安非他明。有趣的是，NMII 抑制的独立于检索的作用确实 不涉及恐惧、食物、空间记忆或其他几种滥用药物的记忆。然而，它确实 破坏与滥用药物（包括可卡因）相关的记忆的重新巩固。目标 2 将测试 NMII 抑制对酒精相关记忆和寻求的重新巩固的影响。然而， 用无条件刺激重新激活记忆的相对独特的方法（美国；少量 酒精），而不是条件刺激（CS；相关的背景和线索）将被利用。这家总部位于美国的 该方法规避了基于 CS 的重新激活策略固有的限制，该策略需要潜在的 在临床环境中调用数百个关联以实现破坏。作为原理证明，初步 数据表明，基于美国的重新激活使可卡因 (COC) 相关记忆容易受到 NMII 的影响 抑制。拟议的工作预计将确定一种新的治疗方法来预防复发 通过使用一流的化合物，酒精寻求具有快速转化的潜力，该化合物的 NIH- 资助的开发工作有望获得 FDA 批准。重要的是，拟议的研究还将奠定 为后续 R01 中深入的机械研究奠定基础。

PROJECT SUMMARY While several medications have been approved for alcohol use disorder (AUD), many patients fail to respond or comply with the treatments. Relapse triggered by reminders of alcohol use is a particular challenge to prevent, as the underlying memories exert a powerful motivational influence over behavior and represent a lifelong relapse risk factor. Learning of these associations is supported by structural plasticity in dendritic spines, driven by training-induced actin polymerization. Memory stability is subsequently achieved by arresting actin dynamics, stabilizing the cytoskeleton. As a result, memory is impervious to actin depolymerization within minutes of learning. However, prior work in the lab discovered that the actin cytoskeleton supporting methamphetamine and amphetamine memories remains uniquely dynamic in the amygdala long after training. This enables selective, retrieval-independent disruption of these memories and associated drug seeking with a single administration of an actin depolymerizer. Because actin’s critical roles in the body limit its therapeutic potential, focus shifted to nonmuscle myosin II (NMII), a direct driver of learning-stimulated actin polymerization in spines. Genetic and pharmacologic targeting of NMII established it is a viable therapeutic target and an NIH- funded medication development project for a clinically safe NMII inhibitor is underway, currently at the stage of IND-enabling studies (UH3 NS096833). The central hypothesis in the current proposal is that a single administration of an NMII inhibitor will produce a long-lasting disruption of alcohol seeking. Aim 1 will determine the retrieval-independent ability of NMII inhibition to disrupt associations that trigger alcohol seeking, like methamphetamine and amphetamine. Interestingly, the retrieval-independent effect of NMII inhibition does not extend to memories for fear, food, spatial memory or several other drugs of abuse. However, it does disrupt the reconsolidation of memories associated with drugs of abuse, including cocaine. Aim 2 will test the effect of NMII inhibition on reconsolidation of alcohol-associated memories and seeking. However, the relatively unique approach of reactivating memory with the unconditioned stimulus (US; a small amount of alcohol), rather than the conditioned stimuli (CS; associated context and cues) will be utilized. This US-based approach circumvents the limitation inherent to CS-based reactivation strategies, which require that potentially hundreds of associations be recalled in a clinical setting to enable disruption. As proof-of-principle, preliminary data indicate that US-based reactivation renders cocaine (COC)-associated memory susceptible to NMII inhibition. The proposed work is expected to identify a new therapeutic approach to the prevention of relapse to alcohol seeking with the potential for rapid translation through the use of a first in class compound whose NIH- funded development is on track for FDA approval. Importantly, the proposed studies will also lay the groundwork for an in depth mechanistic investigation in a subsequent R01.