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: 10609795
• 负责人: Patrick D Worhunsky
• 金额: $ 40.6万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609795
• 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; Equilibrium; Functional Magnetic Resonance Imaging; Glutamates; Health; Hippocampus; 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; 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; 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; pharmacologic; 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.

项目概要/摘要 最近美国可卡因使用的重新抬头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（CUD）长期缺乏有效治疗方法的问题。 对尚未探索的成瘾大脑机制的高度创新研究可能会为替代方案提供见解 治疗解决方案。拟议的研究计划将研究这样一种大脑系统，即 1 型大脑系统。 毒蕈碱乙酰胆碱受体 (M1)，在 CUD 个体中采用分阶段研究方法 与 NIDA 阶段性创新奖 (PAR-19-282) 的范围一致。 M1 受体是大脑中最丰富的乙酰胆碱受体，乙酰胆碱是一种主要的调节剂 神经递质系统，与神经可塑性有关。 M1 受体在整个组织中高度表达 大脑，特别集中在纹状体和海马体，这是成瘾相关的关键枢纽 发挥作用。临床前证据一致证明 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， 在常规使用可卡因的临床前模型中，M1 受体的数量较低。鉴于 M1 的这些影响 CUD 中的受体功能，以及与调节多巴胺的密切神经生物学联系，多巴胺是另一个关键因素 成瘾中的神经递质，M1 靶向药物疗法有可能使患有成瘾的个体受益 CUD 激发了对成瘾神经生物学这一新领域的探索。 最近开发的 M1 选择性激动剂放射性示踪剂 [11C]-LSN3172176 首次允许 时间，体内评估人类 M1 受体的可用性。不寻求治疗的个体 当前 CUD 和匹配的健康比较参与者将完成 [11C]-LSN3172176 PET 成像和 使用分阶段研究设计进行探索性 MRI 和神经认知测试。这种方法提供了一种 对初步数据进行临时评估以确定进一步收集数据的优点的机会 以及可能的程序细化，以优化这项高度探索性研究的效益。更大 M1 受体的知识有可能为 CUD 有效干预措施的开发提供信息， 特别是在认知增强和药物增强行为的发展领域 治疗。