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Imaging Molecular Mechanisms of Tobacco Smoking Withdrawal

戒烟的分子机制成像

基本信息

批准号：
9841911
负责人：
Kelly P Cosgrove
金额：
$ 69.25万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9841911
关键词：
Abstinence Acetylcholine Acetylcholinesterase Inhibitors Acute Affect Age Alcohols Amphetamines Arousal Attention Concentration Behavior Behavioral Binding Brain Cause of Death Chemicals Chronic Cocaine Cognition Cognitive Corpus striatum structure Cues Data Disease Dopamine Emission-Computed Tomography Goals Gold Human Image Impaired cognition Impairment Individual Lead Learning Literature Measures Mediating Molecular Moods Neurons Neurotransmitters Nicotine Nicotinic Receptors Phase Physostigmine Play Positron Positron-Emission Tomography Prediction of Response to Therapy Public Health Relapse Role Signal Transduction Smoker Smoking Stimulus Substance Withdrawal Syndrome Synapses System Time Tobacco smoke Tobacco smoking behavior Up-Regulation Withdrawal Withdrawal Symptom base cholinergic cognitive function craving cue reactivity dynamic system imaging biomarker in vivo individualized medicine mesolimbic system molecular imaging neurotransmission non-smoker novel pre-clinical public health relevance radioligand radiotracer relapse prediction response restoration sex smoking addiction smoking cessation success targeted treatment tobacco smokers tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): One of the biggest issues in treating tobacco smoking dependence is the high rate of relapse during early abstinence, which is primarily due to the powerful withdrawal syndrome including cognitive impairment, intense craving, and a poor mood. The neurotransmitters acetylcholine (ACh) and dopamine (DA) are known to mediate the reinforcing effects of smoking and they also drive the primary behavioral withdrawal symptoms; however, the very basic cholinergic and dopaminergic brain mechanisms that underlie withdrawal and relapse in tobacco smokers are unknown. Nicotine, the primary addictive chemical in tobacco smoke, binds to neuronal beta2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs) leading to widespread changes in neurotransmitter levels including DA, and an increase in the number of β2*-nAChRs throughout the brain. We have previously shown that there are dynamic changes in numbers of β2*-nAChRs over abstinence; but we do not know the functional significance, i.e., if ACh neurotransmission is altered over the course of abstinence, and if altered ACh levels are associated with cognitive dysfunction and relapse vulnerability. A substantial preclinical literature demonstrates that nAChRs and the cholinergic system dynamically control the mesolimbic DA system by enhancing, inhibiting and filtering striatal DA release. A primary issue in tobacco smoking withdrawal is the intense craving in response to cues and we know that DA regulates the salience of stimuli and underlies cue-reactivity. Few studies have systematically examined cue-induced reactivity over prolonged abstinence periods and none have examined the association between DA signaling and cue-induced reactivity and the relationship to relapse in human smokers. The overall goal of this proposal is to uncover the molecular mechanisms underlying tobacco smoking withdrawal, and the relationship to withdrawal-related behaviors (i.e., cognitive function, mood, cue-reactivity) and relapse. We now have the tools to probe both ACh and DA neurotransmission in the human brain with positron emission computed tomography (PET). We will measure physostigmine-induced elevations in synaptic ACh with [18F]Flubatine and amphetamine-induced DA release with [11C]PHNO, within-subject, in nonsmokers and in tobacco smokers during early and prolonged withdrawal. Further, we will investigate whether alterations in ACh and DA levels differentially affect cognitive function (attention, concentration, cue reactivity) and mood in smokers vs. nonsmokers and whether changes in synaptic ACh or DA are predictive of success in maintaining abstinence for up to 6-8 weeks. If there are predictive relationships between ACh and DA function, cognitive domains and relapse, the cognitive measures may ultimately serve as biomarkers of the imaging measures to direct individualized treatment strategies toward restoration of the cholinergic or dopaminergic systems based on the identified impairments. An elucidation of the mechanisms underlying tobacco smoking withdrawal may ultimately lead to novel and more targeted treatment, and thus have a major impact on public health.

描述（申请人提供）：治疗吸烟依赖的最大问题之一是早期戒烟期间的高复发率，这主要是由于严重的戒断综合症，包括认知障碍、强烈的渴望和情绪不佳。众所周知，神经递质乙酰胆碱 (ACh) 和多巴胺 (DA) 可以介导吸烟的强化作用，并且还会导致主要的行为戒断症状；然而，吸烟者戒断和复吸的基本胆碱能和多巴胺能大脑机制尚不清楚。尼古丁是烟草烟雾中的主要成瘾化学物质，它与含有神经元 β2 亚基的烟碱乙酰胆碱受体 (β2*-nAChR) 结合，导致包括 DA 在内的神经递质水平发生广泛变化，并增加整个大脑中 β2*-nAChR 的数量。我们之前已经表明，随着戒断，β2*-nAChR 的数量会发生动态变化；但我们不知道其功能意义，即乙酰胆碱神经传递在禁欲过程中是否发生改变，以及乙酰胆碱水平的改变是否与认知功能障碍和复发易感性相关。大量临床前文献表明，nAChR 和胆碱能系统通过增强、抑制和过滤纹状体 DA 释放来动态控制中脑边缘 DA 系统。戒烟的一个主要问题是对暗示的强烈渴望，我们知道 DA 调节刺激的显着性并构成暗示反应性的基础。很少有研究系统地研究长期戒烟期间线索诱导的反应性，也没有研究研究 DA 信号传导和线索诱导的反应性之间的关联以及与人类吸烟者复吸的关系。该提案的总体目标是揭示吸烟戒断背后的分子机制，以及与戒断相关行为（即认知功能、情绪、提示反应性）和复吸的关系。我们现在拥有利用正电子发射计算机断层扫描 (PET) 探测人脑中 ACh 和 DA 神经传递的工具。我们将测量受试者体内、非吸烟者和吸烟者在早期和长期戒断期间用[18F]氟巴汀诱导的毒扁豆碱诱导的突触ACh升高和用[11C]PHNO诱导的安非他明DA释放。此外，我们将研究 ACh 和 DA 水平的变化是否对吸烟者与非吸烟者的认知功能（注意力、专注力、提示反应性）和情绪产生不同的影响，以及突触 ACh 或 DA 的变化是否可以预测成功维持戒烟长达 6-8 周。如果 ACh 和 DA 功能、认知领域和复发之间存在预测关系，那么认知测量最终可能作为影像学测量的生物标志物，根据已识别的损伤指导个体化治疗策略恢复胆碱能或多巴胺能系统。阐明戒烟背后的机制可能最终会导致新颖且更有针对性的治疗，从而对公众健康产生重大影响。