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

项目总结 虽然有几种药物已被批准用于治疗酒精使用障碍(AUD)，但许多患者没有反应 或遵守治疗方案。由饮酒提醒引发的复发是对 防止，因为潜在的记忆对行为施加了强大的动机影响，并代表了 终生复发的危险因素。树突的结构可塑性支持了这些联系的学习 脊椎，由训练诱导的肌动蛋白聚合驱动。记忆稳定性随后通过以下方式实现 肌动蛋白动力学，稳定细胞骨架。因此，记忆不受体内肌动蛋白解聚的影响 学习纪要。然而，实验室先前的工作发现，支持肌动蛋白的细胞骨架 甲基苯丙胺和苯丙胺的记忆在经过很长时间的训练后仍在杏仁核中保持着独特的活力。 这使得选择性的、不依赖于提取的记忆中断以及与药物寻找相关的 单次给药肌动蛋白解聚器。因为肌动蛋白在体内的关键作用限制了它的治疗作用 潜在的，焦点转移到非肌肉肌球蛋白II(NMII)，一个直接驱动学习刺激的肌动蛋白聚合 在脊椎上。NMII的遗传和药理学靶向研究证实，它是一个可行的治疗靶点和NIH- 一种临床安全的NMII抑制剂的资助药物开发项目正在进行中，目前处于 支持IND的研究(UH3 NS096833)。目前提案中的中心假设是，单一的 使用NMII抑制剂将对酒精寻求产生长期的干扰。目标1将 确定NMII抑制对引发酒精寻求的联想的干扰作用的提取非依赖性能力， 比如冰毒和安非他明。有趣的是，NMII抑制的提取非依赖性效应 不会延伸到恐惧、食物、空间记忆或其他几种滥用药物的记忆。然而，它确实做到了 破坏与包括可卡因在内的滥用药物有关的记忆的重新巩固。目标2将测试 抑制NMII对酒精相关记忆和寻求再巩固的影响。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)，而不是条件性刺激(CS；相关的上下文和线索)。这家总部位于美国的公司 该方法绕过了基于CS的重新激活策略固有的限制，该策略可能需要 在临床环境中可以召回数百个关联，以实现中断。作为原则证明，初步 数据表明，美国的重新激活使可卡因(COC)相关的记忆容易受到NMII的影响 抑制力。这项拟议的工作有望确定一种新的治疗方法，以防止癌症复发 有可能通过使用一流的化合物进行快速翻译的酒精搜索，其NIH- 资助的开发正在等待FDA的批准。重要的是，拟议的研究还将奠定 为随后的R01进行深入的机械调查奠定基础。

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.