Assessing central muscarinic acetylcholine type-1 receptors in cocaine use disorder with 11C-LSN3172176.

项目摘要/摘要 最近可卡因在美国的使用重新抬头是一个重大的公共卫生问题，而且有一个 迫切需要解决长期以来缺乏有效治疗可卡因使用障碍的问题。 对未被探索的成瘾大脑机制的高度创新研究可能为替代方案提供洞察力 治疗方案。拟议的研究计划将研究一个这样的大脑系统，类型1 遵循阶段性研究方法的CUD患者的M受体(M1) 与NIDA阶段性创新奖(PAR-19-282)的范围一致。 M1受体是大脑中对乙酰胆碱最丰富的受体，乙酰胆碱是一种主要的调节物质 神经递质系统，与神经可塑性有关。M1受体在整个脑组织中高度表达。 大脑，尤其集中在纹状体和海马体，这两个与成瘾有关的关键中枢 功能正常。临床前证据一致地表明，M1受体的激活减少，M1 抑制作用增强了可卡因的奖励效应。同样，研究也一致地证明， 在常规使用可卡因的临床前模型中，M1受体的数量较少。鉴于M1的这些含义 受体在CUD中的功能，以及与调节多巴胺密切的神经生物学联系，这是另一个关键 成瘾中的神经递质，M1靶向药物治疗对患有以下疾病的个人的潜在益处 CUD激发了对成瘾神经生物学这一新领域的探索。 M1选择性激动剂放射性示踪剂[11C]-LSN3172176的最新开发首次允许 时间，在人体内评估M1受体的可用性。未寻求治疗的个人，患有 目前的CUD和匹配的健康对照参与者将完成[11C]-LSN3172176 PET成像和 使用阶段性研究设计的探索性核磁共振和神经认知测试。这种方法提供了一种 有机会对初步数据进行中期评估，以确定进一步收集数据的好处 以及可能的程序改进，以优化这项高度探索性研究的好处。更大 对M1受体的了解有可能为开发有效的CUD干预措施提供信息， 特别是在认知增强和药物增强行为的发展领域 心理治疗。

PROJECT SUMMARY/ABSTRACT The recent resurgence in cocaine use in the U.S. is a significant public health concern and there is an urgent need to address the long-standing absence of effective treatments for cocaine-use disorder (CUD). Highly innovative research into unexplored brain mechanisms of addiction may provide insights into alternative therapeutic solutions. The proposed research program will investigate one such brain system, the type-1 muscarinic acetylcholine receptor (M1), in individuals with CUD following a phased research approach consistent with the scope of the NIDA Phased Innovation Award (PAR-19-282). The M1 receptor is the most abundant receptor in the brain for acetylcholine, a principal modulatory neurotransmitter system, and is linked to neural plasticity. M1 receptors are highly expressed throughout the brain and are particularly concentrated in the striatum and hippocampus, key hubs of addiction-related functioning. Preclinical evidence is consistent in demonstrating that activation of M1 receptors reduces, and M1 inhibition enhances, the rewarding effects of cocaine. Similarly, research is consistent in demonstrating that the number of M1 receptors is lower in preclinical models of regular cocaine use. Given these implications of M1 receptor functioning in CUD, and close neurobiological links to regulating dopamine, another critical neurotransmitter in addictions, the potential for M1-targeting pharmacotherapies to benefit individuals with CUD motivates exploration into this novel area of addiction neurobiology. The recent development of the M1-selective agonist radiotracer [11C]-LSN3172176 allows, for the first time, in vivo assessment of M1 receptor availability in humans. Non-treatment-seeking individuals with a current CUD, and matched healthy comparison participants will complete [11C]-LSN3172176 PET imaging and exploratory MRI and neurocognitive testing using a phased research design. This approach provides an opportunity for an interim assessment of the preliminary data to determine the merits of further data collection and possible refinement of procedures to optimize the benefit of this highly exploratory research. Greater knowledge of the M1 receptor holds potential to inform the development of effective interventions for CUD, particularly in the developing area of cognitive enhancement and pharmacologically augmented behavioral therapy.