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

项目概要/摘要 最近在美国可卡因使用的复苏是一个重大的公共卫生问题， 迫切需要解决可卡因使用障碍长期缺乏有效治疗的问题。 对未探索的成瘾大脑机制的高度创新研究可能会为替代药物提供见解。 治疗解决方案。拟议中的研究计划将调查这样一个大脑系统，1型 毒蕈碱型乙酰胆碱受体（M1），在CUD患者中采用分阶段研究方法 符合NIDA阶段性创新奖（PAR-19-282）的范围。 M1受体是脑中最丰富的乙酰胆碱受体，乙酰胆碱是脑中主要的调节剂。 神经递质系统，并与神经可塑性有关。M1受体在整个组织中高度表达， 大脑中，特别是集中在纹状体和海马，成瘾相关的关键枢纽 功能临床前证据一致表明M1受体的激活减少，并且M1 抑制增强了可卡因的奖励作用。同样，研究一致表明， 在常规可卡因使用的临床前模型中，M1受体的数量较低。考虑到M1的这些含义 受体功能，并密切神经生物学联系，以调节多巴胺，另一个关键 神经递质成瘾，M1靶向药物治疗的潜力，使个人受益， 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[11 C]-LSN 3172176的最新开发允许，对于第一个 时间，人体M1受体可用性的体内评估。不寻求治疗的个人 当前CUD和匹配的健康对照受试者将完成[11 C]-LSN 3172176 PET成像， 探索性MRI和神经认知测试，采用分阶段研究设计。这种方法提供了一个 有机会对初步数据进行临时评估，以确定进一步收集数据的价值 以及可能的程序改进，以优化这项高度探索性研究的益处。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行为增强的发展中领域， 疗法

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.