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

烟草使用障碍中 α-7-nAChR 的 PET 成像

基本信息

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
项目类别：
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

项目摘要

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停止吸烟，但很少能成功退出长期戒烟。 α7烟碱乙酰胆碱受体（NACHR）是开发新戒烟的重要药物目标药物。 α7NACHRS调节注意力，学习和记忆的认知过程以及情感影响和奖励，急性尼古丁增强并在烟草中破坏的相同过程提取。临床前研究提供了证据，表明α7NACHR在增强作用中起作用尼古丁戒断的尼古丁和表达，并且这些受体在关键的大脑区域被上调慢性尼古丁暴露后。拟议的概念验证试验研究将首先量化α7NACHR 最近，使用人类正电子发射断层扫描（PET）戒酒的烟草吸烟者与α7NACHR 选择性radiotracer（18F-ASEM）确定吸烟者的α7NACHR可用性是否较高健康控制的非吸烟者，如果α7NACHR的可用性与烟草使用的幅度相关（AIM1）。 AIN 2还将探索α7NACHR可用性与临床相关度量的潜在关系急性戒酒期间烟草戒断。将招募非治疗寻求吸烟者的吸烟者进入门诊方案，包括24小时后α7NACHR可用性的18F-ASEM PET成像戒烟。自我报告烟草渴望，戒断不适和负面影响以及心脏的自我报告在吸烟时将评估测量注意力处理的任务的速率和绩效像往常一样，在禁欲的第一天，然后在戒烟期间进行每次研究。我们将使用标准经过验证的行为干预（应急管理），以激励8天的戒烟退出尝试；在每个研究中，参与者将获得激励付款，包括标准水平呼出的氧化碳（CO）和尿中可替氨酸水平，表明戒酒的依从性以及数量将确定成功节制的日子。 FDA批准使用18F-ASEM供人使用在印度。这些数据为理解TUD中的α7NACHR特征提供了关键的第一步作为促进戒烟的潜在药物治疗靶标。