NEUROCOGNITIVE EFFECTS OF NICOTINE DEPRIVATION AND DOPAMINE GENES

描述（由申请方提供）：拟议研究的总体目标是检查急性尼古丁剥夺对慢性吸烟者行为抑制性自我调节的神经认知机制的影响，并确定这些影响是否由多巴胺相关基因调节。烟草使用被认为是死亡和发病的唯一最可预防的原因;然而，戒烟治疗的效率仍然不高，主要是由于戒烟最初几天内复发率高。研究表明，尼古丁剥夺会削弱行为的抑制性自我控制，这可能是导致尼古丁依赖复发风险和易感性的关键因素。然而，人们对尼古丁剥夺诱导的去抑制的神经认知机制以及对这种效应的可能遗传影响知之甚少。我们假设尼古丁剥夺影响认知控制和行为自我调节的前额叶脑功能，并且这些剥夺诱导的缺陷的易感性的个体差异受到特定多巴胺相关基因的影响。为了验证这些假设，我们提出了一项基于人类实验室的对照实验研究，该研究将整合认知神经科学和药物基因组学方法，以实现以下特定目标：1）检查尼古丁剥夺对前额叶事件相关脑电位（ERP）和认知控制性能指标的急性影响，包括反应抑制，动作监测，2）研究儿茶酚-O-甲基转移酶（COMT）基因对吸烟剥夺的主观、行为和神经认知效应的个体差异的影响。为达致这些目标，我们会：（i）对一组慢性吸烟者进行前瞻性基因型分析（估计n=140）的COMT多态性，并选择三个相等（n=30）的基因型组，（ii）进行单盲、受试者内、交叉研究，其中参与者将在剥夺和非剥夺条件下接受测试在两个单独的实验室会议中，以及（iii）测试基因型与剥夺交互作用对自我报告、行为和神经认知变量的影响，同时控制重要的协变量。预计这项研究将提供试点和可行性数据，为后续的R 01应用程序的发展，重点是遗传和神经认知因素的吸烟复吸。 公共卫生相关性：烟草使用被认为是美国最可预防的死亡和疾病原因，每年都有许多吸烟者试图戒烟。然而，戒烟治疗的疗效仍然有限，主要是由于戒烟后最初几天内复吸率很高。人们对这种自我控制失败和无法抵制吸烟冲动的生物和行为因素知之甚少。更好地了解导致吸烟复吸的遗传和神经生物学因素可以为行为和药物治疗提供新的靶点，最终可以提高戒烟成功率。

DESCRIPTION (provided by applicant): The overall goal of the proposed study is to examine the effects of acute nicotine deprivation on neurocognitive mechanisms of inhibitory self-regulation of behavior in chronic smokers and to determine whether these effects are moderated by dopamine-related genes. Tobacco use is recognized as the single most preventable cause of mortality and morbidity; however, the efficiency of smoking cessation treatment remains modest, primarily due to high rates of relapse within the first days of abstinence. Research suggests that nicotine deprivation can weaken inhibitory self-control of behavior, which may be a crucial factor contributing to relapse risk and susceptibility to nicotine dependence. However, little is known about neurocognitive mechanisms underlying nicotine deprivation-induced disinhibition and possible genetic influences on such effects. We hypothesize that nicotine deprivation affects prefrontal brain function underlying cognitive control and self-regulation of behavior, and that individual differences in susceptibility to these deprivation-induced deficits are influenced by specific dopamine-related genes. To test these hypotheses, we propose a controlled, human laboratory-based experimental study that will integrate cognitive neuroscience and pharmacogenomic methods to pursue the following Specific Aims: 1) to examine acute effects of nicotine deprivation on prefrontal event-related brain potentials (ERPs) and performance indicators of cognitive control, including response inhibition, action monitoring, and decision making and 2) to examine the effects of the catechol-O-methyltransferase (COMT) gene on individual differences in subjective, behavioral, and neurocognitive effects of smoking deprivation. To achieve these aims, we will: (i) genotype prospectively a group of chronic smokers (estimated n=140) for the COMT polymorphism and select three equal (n=30) genotype groups, (ii) conduct a single-blind, within-subject, crossover study, in which participants will be tested under deprived and non-deprived conditions in two separate laboratory sessions, and (iii) test for genotype by deprivation interaction effects on self-report, behavioral, and neurocognitive variables while controlling for important covariates. It is expected that this study will provide pilot and feasibility data for the development of a subsequent R01 application focusing on genetic and neurocognitive factors underlying smoking relapse. PUBLIC HEALTH RELEVANCE: Tobacco use is recognized as the single most preventable cause of death and disease in the United States, and many smokers attempt to quit every year. However, the efficacy of smoking cessation treatments remains modest, primarily due to the high rate of relapse to smoking within the first days of abstinence. Little is known about biological and behavioral factors underlying this failure of self-control and inability to resist smoking urges. A better understanding of the genetic and neurobiological factors contributing to smoking relapse can suggest new targets for behavioral and pharmacological treatment, which can ultimately lead to improved rates of successful quitting.