Imaging Molecular Mechanisms of Tobacco Smoking Withdrawal

 描述(申请人提供)：治疗烟草吸烟依赖的最大问题之一是早期戒烟期间的高复发率，这主要是由于强烈的戒断综合征，包括认知障碍，强烈的渴望，和糟糕的情绪。众所周知，神经递质乙酰胆碱(ACh)和多巴胺(DA)介导了吸烟的强化效应，它们也驱动了最初的行为戒断症状；然而，导致烟草吸烟者戒烟和复发的最基本的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，它与含有烟碱乙酰胆碱受体(β2*-nAChRs)的神经元β2亚基结合，导致包括DA在内的神经递质水平的广泛变化，并导致整个大脑中β2*-nAChRs数量的增加。我们以前已经证明，在戒断过程中，β2*-nAChRs的数量存在动态变化；但我们不知道其功能意义，即在戒断过程中ACh神经传递是否发生改变，以及ACh水平是否改变与认知功能障碍和复发易感性有关。大量临床前文献表明，nAChRs和胆碱能系统通过促进、抑制和过滤纹状体DA的释放来动态地控制中脑边缘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调节刺激的突显，是线索反应的基础。很少有研究系统地研究了线索诱导的长时间戒断期间的反应性，也没有研究过DA信号与线索诱导的反应性之间的联系，以及与吸烟者复发的关系。这项建议的总体目标是揭示烟草戒烟的分子机制，以及与戒烟相关行为(即认知功能、情绪、线索反应性)和复发的关系。我们现在有了用正电子发射计算机断层扫描(PET)探测人脑ACh和DA神经传递的工具。我们将在非吸烟者和吸烟者中用[18F]氟巴汀测量毒扁豆碱诱导的突触ACh的升高，用[11C]PHNO测量苯丙胺诱导的DA释放，以及在早期和长期戒断期间测量吸烟者的DA释放。此外，我们将调查ACh和DA水平的变化是否会对吸烟者和非吸烟者的认知功能(注意力、注意力、线索反应性)和情绪产生不同的影响，以及突触ACh和DA的变化是否预示着成功维持戒烟长达6-8周。如果ACh和DA功能、认知域和复发之间存在预测关系，认知测量最终可能作为成像测量的生物标志物，指导基于已识别的损害的胆碱能或多巴胺能系统恢复的个体化治疗策略。阐明烟草戒烟的机制可能最终导致新的和更有针对性的治疗，从而对公众健康产生重大影响。

 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.