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

烟草使用障碍中 α-7-nAChR 的 PET 成像

• 批准号: 9978034
• 负责人: Elise M Weerts
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978034
• 关键词: Abstinence; Acetylcholine; Acute; Affect; Affinity; Agonist; Amygdaloid structure; Anhedonia; Anterior; Anxiety; Attention; Behavior; Behavior Therapy; Binding; Biological; Brain; Brain region; Carbon; Cessation of life; Characteristics; Chronic; Cigarette; Cigarette Smoker; Clinical; Cognition; Cognitive deficits; Cotinine; Data; Databases; Development; Emotional; Enrollment; Exhalation; FDA approved; Future; Goals; Heart Rate; High Prevalence; Hippocampus (Brain); Hour; Human; Imaging Techniques; Imaging technology; Incentives; Intervention; Learning; Measures; Memory; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Outpatients; Oxides; Participant; Patient Self-Report; Performance; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Positron-Emission Tomography; Process; Protocols documentation; Psychological reinforcement; Public Health; Radiopharmaceuticals; Receptor Activation; Regulation; Relapse; Reproducibility; Rewards; Rodent Model; Role; Schizophrenia; Severities; Sleep Disorders; Smoke; Smoker; Smoking; Subgroup; Synaptic plasticity; Testing; Tobacco; Tobacco Use Disorder; Tobacco smoking behavior; Tobacco use; United States; Up-Regulation; Ventral Striatum; Visit; Weight Gain; Withdrawal; Withdrawal Symptom; alpha-bungarotoxin receptor; cigarette smoking; clinically relevant; cognitive process; contingency management; craving; desensitization; experience; feeding; first-in-human; frontal lobe; in vivo; increased appetite; innovation; interest; negative affect; neuropsychiatry; nicotine exposure; nicotine use; nicotinic receptor beta2; non-smoker; payment; pre-clinical research; preclinical study; radioligand; radiotracer; receptor; receptor density; receptor function; single photon emission computed tomography; smoking abstinence; smoking cessation; success; therapeutic target; tobacco control; tobacco smokers; treatment strategy; urinary; varenicline

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.

概括 尽管大多数吸烟者都想戒烟，但很少有人能长期成功戒烟。 α7烟碱乙酰胆碱 受体（nAChR）是开发新型戒烟的重要药理学靶点 药物。 α7 nAChR 调节注意力、学习和记忆以及情绪的认知过程 影响和奖励，与急性尼古丁增强的相同过程，但在吸烟期间被破坏 撤回。临床前研究提供证据表明 α7 nAChR 在增强作用中发挥作用 尼古丁和尼古丁戒断的表达，以及这些受体在关键大脑区域上调 长期接触尼古丁后。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带有 α7 nAChR 的人体正电子发射断层扫描 (PET) 选择性放射性示踪剂 (18F-ASEM) 以确定与吸烟者相比，吸烟者的 α7 nAChR 可用性是否更高 健康对照非吸烟者，以及 α7 nAChR 可用性是否与烟草使用程度相关（目标 1）。 Ain 2 还将探讨 α7 nAChR 可用性与临床相关指标的潜在关系 急性戒烟期间的戒烟。患有 TUD 且寻求不治疗的重度吸烟者将被纳入 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。自我报告烟草渴望、戒断不适、负面情绪以及心脏 吸烟时测量注意力处理任务的速率和表现将在基线上进行评估 像往常一样，在戒烟的第一天，然后在尝试戒烟期间的每次研究访问。我们将使用一个标准， 经过验证的行为干预（应急管理），以激励 8 天戒烟 放弃尝试；在每次研究访问时，参与者将根据标准水平获得奖励金 呼出的一氧化碳 (CO) 和尿可替宁水平表明戒酒依从性，以及戒断次数 将确定成功禁欲的天数。 18F-ASEM 经 FDA 批准用于人类 根据 IND 。这些数据为了解 TUD 中的 α7 nAChR 特性迈出了关键的第一步 并作为促进戒烟的潜在药物治疗靶点。