PET Imaging of alpha-7-nAChR in Tobacco Use Disorder

总结 虽然大多数吸烟者都想戒烟，但很少有人能成功戒烟。α7烟碱乙酰胆碱 受体（nAChR）是开发新的戒烟方法的重要药理学靶点 药物治疗α7 nAChRs调节注意力、学习和记忆的认知过程，以及情绪 影响和奖励，同样的过程被急性尼古丁增强，并在吸烟期间被破坏。 戒断临床前研究提供的证据表明，α7 nAChR在增强 尼古丁和尼古丁戒断的表达，这些受体在关键的大脑区域上调， 慢性尼古丁暴露后。拟议的概念验证试点研究将首先量化α7 nAChR， 最近戒烟的吸烟者使用人体正电子发射断层扫描（PET）与α7 nAChR 选择性放射性示踪剂（18F-ASEM），以确定吸烟者的α7 nAChR可用性是否高于 健康对照非吸烟者，以及α7 nAChR可用性是否与烟草使用量相关（Aim 1）。 Ain 2还将探索α7 nAChR可用性与临床相关指标的潜在关系， 急性戒断期间的烟草戒断将入组患有TUD的非寻求治疗的重度吸烟者 纳入门诊方案，其中包括24小时后α7 nAChR可用性的18F-ASEM PET成像 戒烟烟草渴望、戒断不适和负面影响以及心脏的自我报告 当吸烟时，将在基线评估测量注意力处理的任务的速度和表现。 与往常一样，在戒烟的第一天，然后在戒烟尝试期间的每次研究访视。我们将使用一个标准， 经验证的行为干预（应急管理），以激励戒烟8天 退出尝试;在每次研究访视时，参与者将根据以下标准水平获得奖励 呼出的一氧化碳（CO）和尿可替宁水平指示戒断依从性， 将确定成功禁欲的天数。FDA批准18F-ASEM用于人体 这些数据为了解TUD中α7 nAChR特征迈出了关键的第一步 并作为促进戒烟的潜在药理学靶点。

SUMMARY Although most smokers want to stop smoking, few successfully quit long-term. α7 nicotinic acetylcholine receptors (nAChR) are an important pharmacological target for development of new smoking cessation medications. α7 nAChRs regulate cognitive processes of attention, learning and memory, as well emotional affect and reward, the same processes that are enhanced by acute nicotine, and disrupted during tobacco withdrawal. Preclinical research provides evidence that α7 nAChR play a role in the reinforcing effects of nicotine and expression of nicotine withdrawal, and that these receptors are upregulated in key brain regions after chronic nicotine exposure. The proposed proof-of-concept pilot study will first quantify α7 nAChR in recently abstinent tobacco smokers using human Positron Emission Tomography (PET) with an α7 nAChR selective radiotracer (18F-ASEM) to determine if α7 nAChR availability is higher in smokers when compared to healthy control nonsmokers, and if α7 nAChR availability is correlated with magnitude of tobacco use (Aim1). Ain 2 will also explore the potential relationship of α7 nAChR availability to clinically relevant measures of tobacco withdrawal during acute abstinence. Non-treatment seeking heavy smokers with TUD will be enrolled into an outpatient protocol that includes 18F-ASEM PET imaging of α7 nAChR availability after 24-hrs of smoking abstinence. Self-report of tobacco craving, withdrawal discomfort, and negative affect as well as heart rate and performance on a task that measures attention processing will be assessed at baseline when smoking as usual, on the first day of abstinence, then each study visit during the quit attempt. We will use a standard, validated behavioral intervention (contingency management) to motivate smoking abstinence during the 8-day quit attempt; at each study visit participants will receive incentive payments contingent upon criterion levels of exhaled carbon oxide (CO) and urinary cotinine levels indicative of abstinence compliance, and number of days of successful abstinence will be determined. Use of 18F-ASEM is approved by the FDA for human use under an IND. These data provide a critical first step towards understanding α7 nAChR characteristics in TUD and as a potential pharmacotherapeutic target to promote smoking cessation.