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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（由申请人提供）：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，这主要是由于强大的戒断综合征，包括认知障碍，强烈的渴望和不良情绪。已知神经递质乙酰胆碱（ACh）和多巴胺（DA）介导吸烟的强化作用，并且它们还驱动主要的行为戒断症状;然而，烟草吸烟者中作为戒断和复发基础的非常基本的胆碱能和多巴胺能脑机制尚不清楚。尼古丁是烟草烟雾中的主要成瘾化学物质，与含有神经元β 2亚基的烟碱乙酰胆碱受体（β2*-nAChR）结合，导致神经递质水平（包括DA）的广泛变化，以及整个大脑中β2*-nAChR数量的增加。我们先前已经表明，在禁欲期间，β2*-nAChR的数量存在动态变化;但我们不知道其功能意义，即，乙酰胆碱神经传递是否在禁欲过程中发生改变，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有关。大量的临床前文献表明，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线索的强烈渴望，我们知道DA调节刺激的显着性和线索反应性的基础。很少有研究系统地研究了长期戒烟期间的线索诱导反应，没有研究DA信号传导和线索诱导反应之间的关联以及与人类吸烟者复发的关系。这项提案的总体目标是揭示烟草戒断背后的分子机制，以及与戒断相关行为的关系（即，认知功能、情绪、线索反应性）和复发。我们现在有工具来探测乙酰胆碱和DA的神经传递在人类大脑与正电子发射计算机断层扫描（PET）。我们将在受试者内、非吸烟者和吸烟者中，在早期和长期戒断期间，测量毒扁豆碱诱导的[18 F]氟巴汀引起的突触ACh升高和安非他明诱导的[11 C]PHNO引起的DA释放。此外，我们将研究ACh和DA水平的改变是否对吸烟者与非吸烟者的认知功能（注意力、注意力、线索反应性）和情绪产生差异性影响，以及突触ACh或DA的变化是否可预测戒烟成功达6-8周。如果在ACh和DA功能、认知域和复发之间存在预测关系，则认知测量可最终用作成像测量的生物标志物，以基于所识别的损伤指导个体化治疗策略朝向胆碱能或多巴胺能系统的恢复。阐明戒烟的机制可能最终导致新的和更有针对性的治疗，从而对公共卫生产生重大影响。