Neural Substrates of Cognitive Deficits in Nicotine Withdrawal

描述(申请人提供)：在慢性吸烟者中，戒除尼古丁会导致认知缺陷，导致复发。了解这些戒断症状背后的机制对于开发更好的尼古丁成瘾治疗方法至关重要。这项拟议的项目旨在使用一种结合神经成像、药理学和遗传学的综合方法来确定吸烟者禁欲诱导认知症状背后的大脑机制。我们关注功能性儿茶酚-O-甲基转移酶COMT(Val158met)基因多态性，该基因与尼古丁依赖和认知功能有关。我们已经完成了一项初步的BOLD功能磁共振研究，该研究表明，高活性Val等位基因纯合的吸烟者对戒烟挑战对认知和大脑功能的影响更敏感。这项为期3年的R01应用旨在：(A)在更大的样本中复制和扩展这些结果，以及(B)进行关键的机制实验，以测试COMT抑制剂Tolcapone对COMT val158met基因分层戒烟者的认知表现和脑功能的影响。具体地说，我们提出了一项短期(13天)托卡彭(与安慰剂)给药的受试者内双盲交叉神经成像研究。40名慢性吸烟者(20名Val/Val和20名MET/MET)将在两个服药期内接受BOLD fMRI检查，同时执行工作记忆任务(N-back任务)和持续注意力任务(持续表现任务)：1)在服用托卡彭期间进行3天监测戒烟，2)在安慰剂治疗期间监测戒烟3天(用药顺序与2周的洗脱相平衡)。包括治疗前(基线)扫描，以比较正常吸烟和戒烟(服用安慰剂)的结果。主要结果是禁食3天后，药物对任务相关的大胆激活的影响(在受试者内)。行为表现和主观症状的变化将与大脑活动的变化联系起来进行检查。这项拟议的研究将为COMT在尼古丁依赖中的作用提供关键的机制理解，从而促进新药的开发。这项研究产生的数据可能会进一步确立认知表现指标作为尼古丁依赖的重要内表型。与公共健康相关：这项研究将提高我们对戒烟导致的认知缺陷背后的大脑机制的理解，这些认知缺陷会促进吸烟复发。

DESCRIPTION (provided by applicant): In chronic smokers, abstinence from nicotine produces cognitive deficits that prompt relapse. Understanding the mechanisms that underlie these abstinence symptoms is critical to develop better treatments for nicotine addiction. The proposed project is designed to identify the brain mechanisms that underlie abstinence- induced cognitive symptoms in smokers using an integrated approach that combines neuroimaging, pharmacology, and genetics. We focus on the functional catechol-O-methyltransferase COMT (val158met) polymorphism, which has been implicated in both nicotine dependence and cognitive function. We have completed a pilot BOLD fMRI study which shows that smokers homozygous for the high activity val allele are more sensitive to the effects of an abstinence challenge on measures of cognition and brain function. This 3-year R01 application is designed to: (a) replicate and extend these results in a larger sample, and (b) perform a critical proof of mechanism experiment that tests the effects of the COMT inhibitor tolcapone on cognitive performance and brain function in abstinent smokers stratified by COMT val158met genotype. Specifically, we propose a within-subject double-blind cross-over neuroimaging study of short-term (13 days) tolcapone (vs. placebo) administration. Forty chronic smokers (20 with val/val genotypes and 20 with met/met genotypes) will undergo BOLD fMRI during 2 medication periods while performing a working memory task (N-back Task) and a sustained attention task (Continuous Performance Task): 1) after 3 days of monitored abstinence while on tolcapone, and 2) after 3 days of monitored abstinence while on placebo (medication order counterbalanced with a 2-week washout). A pre-treatment (baseline) scan is included to compare outcomes while smoking as usual to those while abstinent (on placebo). The primary outcome is medication effects (within subject) on task-related BOLD activation after 3 days of abstinence. Changes in behavioral performance and subjective symptoms will be examined in relation to brain activity changes. The proposed study will provide a critical mechanistic understanding of the role of COMT in nicotine dependence, thereby facilitating development of novel medications. Data generated from this study may further establish cognitive performance measures as important endophenotypes for nicotine dependence. PUBLIC HEALTH RELEVANCE: This study will improve our understanding of the brain mechanisms that underlie abstinence-induced cognitive deficits which promote smoking relapse.