Cholinergic transmission abnormalities associated with smoking behavior in humans

与人类吸烟行为相关的胆碱能传递异常

• 批准号: 10153749
• 负责人: Scott J Moeller
• 金额: $ 19.94万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153749
• 关键词: Abstinence; Acetylcholine; Acute; Affinity; Agonist; Attention; Award; Basic Science; Behavior; Biological; Brain; Brain region; Choline; Cholinergic Receptors; Chronic; Cigarette; Clinical; Corpus striatum structure; Data; Dependence; Development; Drug Addiction; Drug usage; Enrollment; Foundations; Functional disorder; General Population; Goals; Grant; Human; Image; Imaging Device; Individual; Investigation; Label; Laboratories; Lead; Measures; Mediating; Mental Health; Molecular Target; Morbidity - disease rate; Neuropsychology; Nicotine; Nicotine Dependence; Nicotinic Receptors; Patients; Pharmaceutical Preparations; Phenotype; Population; Positron-Emission Tomography; Prevalence; Protocols documentation; Public Health; Receptor Signaling; Reproducibility; Research; Resistance; Rodent; Self Administration; Severities; Signal Transduction; Smoke; Smoker; Smoking; Smoking Behavior; Smoking History; Speed; Substance Use Disorder; System; Testing; Therapeutic; Time; Tobacco; Tracer; United States; Universities; Vesicle; acetylcholine transporter; addiction; attentional bias; cholinergic; cigarette smoke; cigarette smoking; comorbidity; data integrity; drug seeking behavior; high reward; high risk; human data; imaging study; in vivo; indexing; innovation; mortality; nerve supply; nicotine exposure; non-smoker; non-smoking; novel; postsynaptic; presynaptic; psychosocial; radiotracer; receptor; receptor function; single photon emission computed tomography; smoking addiction; smoking cessation; smoking prevalence; transmission process

PROJECT SUMMARY/ABSTRACT In recent decades, the prevalence of cigarette smoking has plummeted in the general population of the United States, but a subset of smokers has been unable to quit. As nicotine acts at receptors that form part of the brain cholinergic system, medications that modulate cholinergic receptor signaling have been developed, implemented, and shown to be efficacious for smoking cessation. Yet, little is known in human smokers about the integrity of the cholinergic system in vivo beyond postsynaptic receptor functioning, due to a lack of tools for imaging cholinergic transmission specifically. A better understanding of presynaptic cholinergic integrity could provide novel medication targets that can be used adjunctively with currently approved medications acting at postsynaptic receptors. This strategy could be especially fruitful among chronic smokers for whom available therapeutics have been insufficient to accomplish complete cessation. Here, we will use the newly-developed radiotracer [18F]VAT in conjunction with positron emission tomography (PET) to image a different molecular target, the vesicular acetylcholine transporter (VAChT); VAChT is presynaptic and specific to cholinergic vesicles, and therefore can provide a measure of cholinergic storage in terminals that directly relates to transmission. Our preliminary data demonstrate that [18F]VAT: is currently in routine use at Stony Brook University, shows initial evidence for test-retest reproducibility, and has sufficient sensitivity to detect group differences between healthy and clinical populations, including drug addiction. In this application, we satisfy the Cutting-Edge Basic Research Awards (CEBRA) criteria by testing the innovative and significant hypothesis, for which there is little available human data due to the previous unavailability of presynaptic cholinergic tracers, that smokers have lower cholinergic transmission compared with non-smokers. We will study 14 smokers and 14 matched non-smokers with [18F]VAT, and we will correlate the resulting presynaptic cholinergic integrity data, indexed as [18F]VAT total distribution volume (VT) in striatal and select prefrontal cortical regions, with the amount and speed of cigarette smoking in a laboratory self-administration paradigm, and with measures of chronic smoking severity. Results of this study will also provide the foundational data needed to take on larger smoking investigations as well as potentially apply this new tracer for use in other addictions, consistent with the goals of the CEBRA mechanism. Finally, results can potentially inform new avenues for medication development to help addicted smokers achieve lasting cigarette abstinence.

项目总结/摘要 近几十年来，吸烟的流行率在美国的普通人群中急剧下降。 但仍有一部分吸烟者无法戒烟。当尼古丁作用于构成大脑一部分的受体时 胆碱能系统，已经开发出调节胆碱能受体信号传导的药物， 实施，并显示对戒烟有效。然而，对人类吸烟者知之甚少， 体内胆碱能系统的完整性超出突触后受体功能，由于缺乏工具， 特别是对胆碱能传递的成像更好地理解突触前胆碱能完整性可以 提供了新的药物靶点，其可以与目前批准的作用于 突触后受体这一策略可能是特别富有成效的慢性吸烟者， 治疗方法不足以实现完全停止。在这里，我们将使用新开发的 放射性示踪剂[18F]VAT与正电子发射断层扫描（PET）结合，以成像不同的分子 囊泡乙酰胆碱转运蛋白（VAChT）是突触前的胆碱能特异性靶蛋白。 囊泡，因此可以提供一个衡量胆碱能储存在终端，直接涉及到 传输我们的初步数据表明，[18 F]VAT：目前在斯托尼布鲁克常规使用 大学，显示了测试-重测重现性的初步证据，并具有足够的灵敏度来检测组 健康人群和临床人群之间的差异，包括药物成瘾。在本申请中，我们满足 尖端基础研究奖（CEBRA）的标准，通过测试创新和重大的假设， 由于以前无法获得突触前胆碱能示踪剂，因此几乎没有可用的人类数据， 吸烟者的胆碱能传递比不吸烟者低。我们将研究14名吸烟者， 14个匹配的非吸烟者与[18F]VAT，我们将相关的突触前胆碱能完整性数据， 指数为纹状体和选择的前额叶皮质区域中的[18F]VAT总分布体积（VT）， 在实验室自我管理模式中吸烟的速度，以及慢性 吸烟严重性这项研究的结果还将提供更大规模吸烟所需的基础数据 调查以及潜在地应用这种新的示踪剂用于其他成瘾，符合的目标， CEBRA机制。最后，研究结果可能为药物开发提供新的途径， 吸烟成瘾者实现持久的戒烟。