Genetic Moderation of Attentional Deficits Resulting from Nicotine Withdrawal

描述（由申请人提供）：吸烟仍然是我们社会中最主要的可预防的疾病和死亡原因。尼古丁戒断是烟草持续使用的主要原因，也是戒烟后频繁复发的主要原因。注意力控制能力下降是尼古丁戒断的一个公认症状。恢复吸烟/尼古丁可减少这种注意力障碍，甚至可能使注意力控制提高到高于基线水平。尼古丁引起的注意力增强在有认知-注意力缺陷的亚群中可能更大，如精神分裂症和注意力缺陷障碍。重要的是，没有特定认知障碍的个体可能具有导致尼古丁戒断期间相对程度的注意力中断的表型，从而促进了使用烟草的动机。分子遗传水平上的个体差异可能部分解释了这些差异。烟碱乙酰胆碱活性与注意力处理有关，而特定烟碱乙酰胆碱受体基因的变异与吸烟行为有关。此外，尼古丁增加了大脑许多区域多巴胺的释放，包括那些与注意力控制有关的区域。事实上，许多与多巴胺相关的基因型都与吸烟行为和注意力有关，尽管方向相反。我们建议研究尼古丁相关基因型和多巴胺能基因型作为尼古丁剥夺对注意力控制行为和神经指标影响的调节因子。两个公认的任务（古怪和N-back）将被纳入评估注意力控制和工作记忆。使用事件相关脑电位（ERP）方法对这些任务进行了广泛的研究。相对于严格的行为测量，ERP可能提供更敏感的认知-注意差异指数。86名（43名男性）吸烟者将在一夜不吸烟后参加两次实验室测试。在双盲和平衡的方式下，参与者将在一个阶段抽四支含尼古丁的香烟，在另一个阶段抽四支不含尼古丁的香烟。在这两次会议中，参与者将完成与执行注意力相关的任务，包括并发ERP数据收集。我们假设尼古丁剥夺与注意力控制和工作记忆下降有关，并且表明多巴胺能和尼古丁胆碱能活性降低的基因型将缓和尼古丁剥夺引起的注意力控制和工作记忆的下降。我们期望利用从这项探索性/发展性研究中获得的信息来开发和评估戒烟和复发预防治疗方案。例如，有许多明显安全且不会上瘾的尼古丁相关化合物被认为可以改善认知；这些可能为基因型更容易出现戒断引起的注意缺陷的吸烟者戒烟提供额外的支持。公共卫生相关性：本研究的目的是更好地了解尼古丁戒断引起的注意力控制紊乱，包括这些影响的遗传调节。这项研究可能会导致实际应用，例如匹配个体遗传谱和认知特征与适当的行为和药物治疗戒烟治疗。

DESCRIPTION (provided by applicant): Smoking tobacco remains the top preventable cause of disease and death in our society. Nicotine withdrawal is a major contributor to the persistent nature of tobacco use, as well as the frequent occurrence of relapse following attempts at smoking cessation. Reduced attentional control is a well-established symptom of nicotine withdrawal. Resumption of smoking/nicotine reduces this attentional disturbance, and may even increase attentional control above baseline levels. Nicotine-induced enhancement of attention may be greater among subgroups that have cognitive-attentional deficits, such as schizophrenia and attention deficit disorder. Importantly, individuals without specific cognitive disorders may possess phenotypes that contribute to the relative degree of attentional disruption during nicotine withdrawal, thereby contributing to the motivation to use tobacco. Individual differences at the molecular genetic level may in part account for these differences. Nicotinic acetylcholine activity is associated with attentional processing, and variants on specific nicotinic acetylcholine receptor genes have been associated with smoking behavior. In addition, nicotine increases dopamine release in many brain areas, including those relevant to attentional control. Indeed, a number of dopamine-related genotypes have been associated with both smoking behavior and attention, albeit in opposing directions. We propose to examine nicotinic-related and dopaminergic genotypes as moderators of nicotine deprivation effects on behavioral and neural indices of attentional control. Two well established tasks (oddball and N-back) will be included to assess attentional control and working memory. These tasks have been studied extensively using event-related brain potential (ERP) methodology. ERP may provide a more sensitive index of cognitive-attentional differences relative to strictly behavioral measures. Eighty-six (43 men) smokers will attend two laboratory sessions following overnight smoking deprivation. In a double-blind and counterbalanced fashion, participants will smoke four nicotine-containing cigarettes throughout one session, and four denicotinized cigarettes during the other. During both sessions, participants will complete the executive attention-related tasks, including concurrent ERP data collection. We hypothesize that the deprived condition will be associated with lower attentional control and working memory, and that genotypes indicative of reduced dopaminergic and nicotinic cholinergic activity will moderate nicotine deprivation induced decrements in attentional control and working memory. We expect to utilize the information gained from this exploratory/developmental research to develop and evaluate smoking cessation and relapse prevention treatment programs. For instance, there are a number of apparently safe and non-addictive nicotine-related compounds believed to improve cognition; these may provide additional support for cessation among smokers with genotypes suggestive of greater vulnerability to withdrawal induced attentional deficits. PUBLIC HEALTH RELEVANCE: The purpose of this research is to better understand disturbances in attentional control resulting from nicotine withdrawal, including genetic moderation of these effects. This research may lead to practical applications, such as matching of individual genetic profiles and cognitive characteristics with appropriate behavioral and pharmacotherapy smoking cessation treatments.