Nicotine Abstinence-Induced Cognitive Alterations by COMT Genotype

COMT 基因型尼古丁戒断引起的认知改变

• 批准号: 7932225
• 负责人: CARYN LERMAN
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932225
• 关键词: Abstinence; Alleles; Anterior; Attention; Back; Behavioral Genetics; Behavioral inhibition; Bilateral; Brain; COMT gene; Catechol O-Methyltransferase; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Dopamine; Dorsal; Drug Addiction; Enzymes; Exhibits; Fractals; Functional Magnetic Resonance Imaging; Future; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Hour; Impaired cognition; Individual; Individual Differences; Inferior frontal gyrus; Knowledge; Laboratories; Link; Measures; Medial; Memory impairment; Methylation; Modeling; Neurobehavioral Manifestations; Neurocognitive; Nicotine; Nicotine Dependence; Performance; Phenotype; Prefrontal Cortex; Reaction Time; Relapse; Research; Risk; Role; Satiation; Sex Characteristics; Short-Term Memory; Signal Transduction; Smoker; Smoking; Subgroup; Symptoms; Task Performances; Testing; Work; base; blood oxygen level dependent; cingulate cortex; cognitive function; cost; endophenotype; enzyme activity; frontal lobe; high risk; improved; methionylmethionine; neural circuit; neuroimaging; neuromechanism; novel; primary outcome; public health relevance; response; smoking relapse; valylvaline

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.

描述（由申请人提供）：在慢性吸烟者中，尼古丁的禁欲会产生厌恶的认知症状，以预测复发。因此，了解这些戒酒引起的认知缺陷的基础的遗传和神经机制对于开发更有效的尼古丁成瘾治疗至关重要。该R03应用的总体目标是检查儿茶酚-O-甲基转移酶（COMT Val158MET多态性）的遗传变异是否与尼古丁戒烟对慢性吸烟者的不良认知作用有关。 COMT是一种甲基化酶，可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（Val158met）； Val等位基因与COMT酶活性的增加和脑多巴胺水平降低有关。重要的是，我们小组和其他人的研究将COMT VAL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 VAL等位基因载体中的吸烟复发风险增加可能归因于这种吸烟者亚组中尼古丁戒酒期间认知缺陷的加剧。但是，这项最初的研究很小，仅限于评估工作记忆。鉴于这种多态性与吸烟复发的验证关系，显然需要对COMT Val158met在禁欲引起的认知功能中的作用进行更大和更广泛的研究。为此，我们建议使用尼古丁的禁欲挑战实验室范式来检查COMT Val158met与认知和大脑功能的关联，并在我们先前的工作中验证。 40名合格的吸烟者（20 MET/MET和20 Val/val）将参加两个血氧水平依赖性（BOLD）功能磁共振成像（fMRI）会话，以平衡的顺序相隔1-2周：像往常一样吸烟与过夜（= 14小时）戒烟。大胆的fMRI将在执行验证的任务探索执行认知功能的关键组成部分时获取，包括持续关注（连续绩效任务； CPT），工作记忆（N-BACK）和行为抑制（GO-NO-NO-GO）。这些任务是基于它们对禁欲效应和/或COMT基因型关联的敏感性选择的。主要结果是与任务相关的大胆激活和戒酒与饱腹感期间的性能。这项研究产生的数据可能会进一步建立认知度量作为尼古丁依赖性遗传研究的重要内表型。将来还可以应用新的遗传学和神经影像学方法来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在戒烟和预测复发期间出现的认知缺陷中个体差异的理解。