Young E J, Blouin A M, Briggs S B, Daws S E, Lin L, Cameron M D, Rumbaugh G, Miller C A
Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
Mol Psychiatry. 2016 May;21(5):615-23. doi: 10.1038/mp.2015.103. Epub 2015 Aug 4.
Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations.
与药物使用相关的记忆会增加物质使用障碍（SUD）复发的易感性，并且目前尚无预防复发的药物疗法。此前，我们报道了一项有前景的发现：与甲基苯丙胺（METH）相关的记忆存储，而非恐惧或食物奖励的记忆，易受基底外侧杏仁核复合体（BLC）中肌动蛋白解聚的干扰。然而，由于肌动蛋白在全身具有众多功能，它并非一个可行的治疗靶点。在此，我们报告了一个可行的治疗靶点的发现，即非肌肉肌球蛋白IIB（NMIIB），一种通过直接驱动突触肌动蛋白聚合来支持记忆的分子马达。用Blebbistatin（Blebb）进行单次BLC内治疗，Blebb是一种包括NMIIB在内的II类肌球蛋白亚型的小分子抑制剂，可对情境诱导的药物寻求行为产生持久干扰（至少30天）。此外，对BLC中表达最高的NMII重链Myh10进行巩固后基因敲低，足以导致与METH相关的记忆丧失。研究发现Blebb具有高度的脑渗透性。单次全身注射该化合物可选择性地干扰与METH相关的记忆存储，并逆转伴随的BLC棘突密度增加。这种效应是METH相关记忆所特有的，因为它对听觉恐惧记忆没有影响。该效应也与记忆提取无关，因为在单次全身注射Blebb并在家笼中给药24小时后，与METH相关的记忆受到了干扰。总之，这些结果支持进一步开发NMII小分子抑制剂，作为预防由药物关联引发的SUD复发的潜在疗法。
