Nicotine Abstinence-Induced Cognitive Alterations by COMT Genotype

描述（由申请人提供）：在慢性吸烟者中，尼古丁戒断会产生预测复发的厌恶性认知症状。因此，了解这些戒烟引起的认知缺陷的遗传和神经机制对于开发更有效的尼古丁成瘾治疗方法至关重要。本R 03申请的总体目标是检查儿茶酚-O-甲基转移酶（COMT val 158 met多态性）的遗传变异是否与慢性吸烟者尼古丁戒断的不良认知影响相关。COMT是一种甲基化酶，可以降解多巴胺并调节额叶皮质中的多巴胺水平。COMT基因具有常见的功能多态性（val 158 met）;瓦尔等位基因与COMT酶活性的增加和大脑多巴胺水平的降低相关。重要的是，我们小组和其他人的研究已经将COMT瓦尔等位基因与尼古丁依赖和吸烟复发联系起来。我们实验室的新数据表明，COMT瓦尔等位基因携带者吸烟复发风险增加可能归因于该吸烟者亚组尼古丁戒断期间认知缺陷的加重。然而，这项最初的研究规模很小，仅限于评估工作记忆。考虑到这种多态性与吸烟复发的有效关系，显然需要对COMT val 158 met在戒烟诱导的认知功能中的作用进行更大范围和更广泛的检查。为此，我们建议使用在我们先前的工作中验证的尼古丁戒断挑战实验室范例来检查COMT val 158 met与认知和脑功能的关联。40名合格的吸烟者（20名met/met和20名瓦尔/瓦尔）将参加两次血氧水平依赖性（BOLD）功能性磁共振成像（fMRI）检查，间隔1-2周，按平衡顺序进行：照常吸烟vs.整夜（= 14小时）戒烟。BOLD fMRI将在他们执行验证任务时获得，这些任务探测执行认知功能的关键组成部分，包括持续注意力（连续执行任务; CPT），工作记忆（N-back）和行为抑制（Go-No-Go）。这些任务是根据其对禁欲效应和/或COMT基因型关联的敏感性选择的。主要结果是任务相关的BOLD激活和表现在禁欲与饱腹感。本研究产生的数据可能进一步确立认知测量作为尼古丁依赖遗传研究的重要内表型。提出的新的遗传学和神经影像学方法也可以在未来应用于研究遗传变异在其他药物成瘾表型中的作用。 公共卫生相关性：这项研究将提高我们对戒烟期间出现的认知缺陷的个体差异的理解，并预测复发。

DESCRIPTION (provided by applicant): In chronic smokers, abstinence from nicotine produces aversive cognitive symptoms which predict relapse. Understanding the genetic and neural mechanisms that underlie these abstinence-induced cognitive deficits is therefore critical to develop more efficacious treatments for nicotine addiction. The overall goal of this R03 application is to examine whether genetic variation in catechol-O-methyltransferase (COMT val158met polymorphism) is associated with adverse cognitive effects of nicotine abstinence in chronic smokers. COMT is a methylation enzyme that degrades dopamine and regulates dopamine levels in the frontal cortex. The COMT gene has a common functional polymorphism (val158met); the val allele is associated with an increase in COMT enzyme activity and a decrease in brain dopamine levels. Importantly, research by our group and others has linked the COMT val allele with nicotine dependence and smoking relapse. New data from our laboratory suggest that the increased smoking relapse risk in COMT val allele carriers may be attributable to an exacerbation of cognitive deficits during nicotine abstinence in this subgroup of smokers. However, this initial study was small and was limited to assessment of working memory. Given the validated relationship of this polymorphism with smoking relapse, a larger and broader examination of the role of COMT val158met in abstinence-induced cognitive function is clearly needed. Toward this end, we propose to examine the association of COMT val158met with cognition and brain function using a nicotine abstinence challenge laboratory paradigm validated in our prior work. Forty eligible smokers (20 met/met and 20 val/val) will participate in two blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) sessions occurring 1-2 weeks apart in counterbalanced order: smoking as usual vs. overnight (= 14 hours) abstinent. BOLD fMRI will be acquired while they perform validated tasks probing key components of executive cognitive function, including sustained attention (continuous performance task; CPT), working memory (N-back), and behavioral inhibition (Go-No-Go). These tasks have been selected based upon their sensitivity to abstinence effects and/or COMT genotype associations. The primary outcomes are task-related BOLD activation and performance during abstinence vs. satiety. Data generated from this study may further establish cognitive measures as important endophenotypes for genetic studies of nicotine dependence. The novel genetics and neuroimaging approach proposed can also be applied in the future to study the role of genetic variation in other drug addiction phenotypes. PUBLIC HEALTH RELEVANCE: This study will improve our understanding of individual differences in cognitive deficits that arise during abstinence from smoking and predict relapse.