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

使用 11C-LSN3172176 评估可卡因使用障碍中的中枢毒蕈碱乙酰胆碱 1 型受体。

• 批准号: 10367251
• 负责人: Patrick D Worhunsky
• 金额: $ 43.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10367251
• 关键词: Abstinence; Acetylcholine; Achievement; Address; Admission activity; Affect; Agonist; Animal Model; Area; Behavior Therapy; Brain; Brain Chemistry; CHRM1 gene; Chronic; Clinical Trials; Cocaine; Cocaine use disorder; Communities; Complex; Confidence Intervals; Corpus striatum structure; Data; Data Collection; Desire for food; Development; Dopamine; Functional Magnetic Resonance Imaging; Glutamates; Health; Hippocampus (Brain); Human; Individual; Intervention; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Measures; Midbrain structure; Muscarinic M1 Receptor; Muscarinics; National Institute of Drug Abuse; Neurobiology; Neurocognitive; Neuronal Plasticity; Neurotransmitters; Parietal Lobe; Participant; Pathway interactions; Performance; Pharmacology; Pharmacotherapy; Phase; Phased Innovation Awards; Physiological; Positron-Emission Tomography; Pre-Clinical Model; Prevalence; Procedures; Process; Public Health; Quality of life; Recovery; Relapse; Research; Research Design; Research Domain Criteria; Resistance; Rest; Rewards; Role; Sampling; Sensory Receptors; Societies; System; Tail; Therapeutic; Time; addiction; addiction liability; antagonist; cocaine use; cognitive enhancement; cognitive function; effective intervention; effective therapy; expectation; experience; frontal lobe; improved; in vivo; innovation; insight; interest; maladaptive behavior; neurocognitive test; neuromelanin; novel; overdose death; pre-clinical; pre-clinical research; programs; radiotracer; receptor; receptor function; recruit; treatment strategy

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.

项目摘要/摘要 美国最近在美国使用可卡因的复兴是一个重大的公共卫生问题，并且有一个 迫切需要解决可卡因使用障碍（CUD）有效治疗的长期缺乏。 对未开发的成瘾的大脑机制的高度创新性研究可能会提供有关替代方案的见解 治疗解决方案。拟议的研究计划将研究一个这样的大脑系统，即1型 毒蕈碱乙酰胆碱受体（M1），在分阶段研究方法后具有CUD的个体 与NIDA分阶段创新奖的范围一致（Par-19-282）。 M1受体是乙酰胆碱大脑中最丰富的受体，一种主调节 神经递质系统，与神经可塑性有关。 M1受体在整个过程中高度表达 大脑，特别集中在纹状体和海马，与成瘾有关的关键枢纽 功能。临床前证据在证明M1受体的激活和M1的激活方面是一致的 抑制增强了可卡因的奖励作用。同样，研究在证明 在常规可卡因使用的临床前模型中，M1受体的数量较低。鉴于M1的这些含义 受体在CUD中的功能，并与调节多巴胺的神经生物学联系紧密，这是另一个关键 成瘾中的神经递质，M1靶向药物疗法的潜力使人受益于 CUD激发了对这个成瘾神经生物学新颖领域的探索。 M1选择性激动剂radiotracer [11C] -LSN3172176的最新发展允许第一个 时间，体内对人类M1受体供应的评估。非治疗的人 当前的CUD和匹配的健康比较参与者将完成[11C] -LSN3172176 PET成像和 探索性MRI和神经认知测试使用分阶段的研究设计。这种方法提供了 对初步数据进行临时评估的机会，以确定更多数据收集的优点 并可能改进程序，以优化这项高度探索性研究的好处。更大 对M1受体的了解有可能告知开发CUD的有效干预措施 特别是在认知增强和药理增强行为的发展领域 治疗。