Neural Substrates of Cognitive Deficits in Nicotine Withdrawal

描述（由申请人提供）：在慢性吸烟者中，尼古丁戒断会产生认知缺陷，从而促使复发。了解这些戒断症状的机制对于开发更好的尼古丁成瘾治疗方法至关重要。拟议的项目旨在确定大脑机制的基础上戒烟引起的认知症状的吸烟者使用综合方法，结合神经影像学，药理学和遗传学。我们专注于功能性儿茶酚-O-甲基转移酶COMT（val 158 met）多态性，这与尼古丁依赖和认知功能有关。我们已经完成了一项BOLD功能磁共振成像试验研究，该研究表明，高活性瓦尔等位基因的吸烟者对戒烟挑战对认知和脑功能的影响更为敏感。这项为期3年的R 01申请旨在：（a）在更大的样本中复制和扩展这些结果，以及（B）进行一项关键的机制验证实验，该实验测试了COMT抑制剂托卡朋对按COMT val 158 met基因型分层的戒烟吸烟者的认知能力和脑功能的影响。具体而言，我们提出了一个受试者内的双盲交叉神经影像学研究短期（13天）托卡朋（与安慰剂）管理。40名长期吸烟者（20例具有瓦尔/瓦尔基因型和20例具有met/met基因型）将在2个给药期期间进行BOLD fMRI，同时进行工作记忆任务（N-back任务）和持续注意力任务（连续性能任务）：1）在使用托卡朋期间监测禁欲3天后，和2）在服用安慰剂期间监测禁欲3天后（药物顺序与2周洗脱相平衡）。包括治疗前（基线）扫描，以比较正常吸烟与戒烟（安慰剂）的结局。主要结局是禁欲3天后药物对任务相关BOLD激活的影响（受试者内）。将检查行为表现和主观症状的变化与大脑活动变化的关系。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，从而促进新型药物的开发。本研究产生的数据可能进一步确立认知表现指标作为尼古丁依赖的重要内表型。公共卫生相关性：这项研究将提高我们对大脑机制的理解，这些机制是戒烟引起的认知缺陷的基础，这些认知缺陷促进了吸烟复吸。

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.