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.

项目概要/摘要 近几十年来，美国总人口中吸烟率大幅下降 但仍有一部分吸烟者无法戒烟。由于尼古丁作用于构成大脑一部分的受体 胆碱能系统，调节胆碱能受体信号传导的药物已经开发出来， 已实施，并显示对戒烟有效。然而，人们对人类吸烟者知之甚少 由于缺乏工具，体内胆碱能系统的完整性超出了突触后受体的功能 专门对胆碱能传输进行成像。更好地了解突触前胆碱能完整性可以 提供新的药物靶点，可与目前批准的药物一起使用 突触后受体。对于长期吸烟者来说，这一策略可能特别有效，因为他们可以 治疗方法不足以实现完全戒烟。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) 相结合，对不同的分子进行成像 目标，囊泡乙酰胆碱转运蛋白（VAChT）； VAChT 是突触前的且特异性针对胆碱能 囊泡，因此可以提供与直接相关的终端中胆碱能储存的测量 传播。我们的初步数据表明 [18F]VAT：目前在石溪常规使用 大学，显示了重测重现性的初步证据，并且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，包括毒瘾。在这个应用中，我们满足 尖端基础研究奖（CEBRA）标准通过测试创新和重要的假设， 由于之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， 与不吸烟者相比，吸烟者的胆碱能传递较低。我们将研究 14 名吸烟者 14 名非吸烟者与 [18F]VAT 相匹配，我们将关联所得的突触前胆碱能完整性数据， 索引为纹状体和选定前额皮质区域的 [18F]VAT 总分布体积 (VT)，其数量 实验室自我管理范式中的吸烟速度和吸烟速度，以及慢性吸烟的测量 吸烟的严重程度。这项研究的结果还将提供应对大规模吸烟所需的基础数据 调查以及可能将这种新的示踪剂应用于其他成瘾，这与 CEBRA 机制。最后，结果可能会为药物开发的新途径提供信息，以帮助 吸烟成瘾者实现持久戒烟。