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

项目摘要 虽然有几种药物已被批准用于酒精使用障碍（AUD），但许多患者没有反应。 或者配合治疗酒精使用的提醒引发的复发是一个特殊的挑战， 防止，因为潜在的记忆对行为产生了强大的动机影响，并代表了一个 终身复发风险因素。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。记忆稳定性随后通过抑制 肌动蛋白动力学，稳定细胞骨架。因此，记忆不受肌动蛋白解聚的影响， 分钟的学习。然而，实验室先前的工作发现， 甲基安非他明和安非他明的记忆在训练后很长时间内在杏仁核中保持独特的动态。 这使得这些记忆的选择性、不依赖于提取的破坏以及与药物寻求相关的记忆能够被恢复。 单次给予肌动蛋白解聚剂。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，重点转移到非肌肉肌球蛋白II（NMII），学习刺激肌动蛋白聚合的直接驱动力 在刺。NMII的遗传和药理学靶向确定了它是一个可行的治疗靶点， 一个临床上安全的NMII抑制剂的资助药物开发项目正在进行中，目前处于 IND使能研究（UH 3 NS 096833）。当前提案的核心假设是， NMII抑制剂的给药将产生对酒精寻求的持久破坏。目标1将 确定NMII抑制破坏触发酒精寻求的关联的独立于检索的能力， 比如冰毒和安非他命有趣的是，NMII抑制的非恢复依赖性效应确实 不延伸到恐惧，食物，空间记忆或其他几种滥用药物的记忆。但这并 破坏与滥用药物（包括可卡因）有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再巩固的影响。但 相对独特的方法重新激活记忆的无条件刺激（美国;少量的 酒精），而不是条件刺激（CS;相关的上下文和线索）。这个美国的 这种方法规避了基于CS的再激活策略固有的局限性，这种策略需要潜在地 在临床环境中可以回想起数百种关联，以实现中断。作为原则性证明，初步 数据表明，基于US的再激活使可卡因（COC）相关记忆对NMII敏感 抑制作用拟议的工作预计将确定一种新的治疗方法，以防止复发， 酒精寻求与潜在的快速翻译通过使用一流的化合物，其NIH- 资助的开发项目正在等待FDA的批准。重要的是，拟议的研究还将奠定 为后续R 01中的深入机制研究奠定基础。

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.