NEUROCOGNITIVE EFFECTS OF NICOTINE DEPRIVATION AND DOPAMINE GENES

描述(申请人提供)：这项拟议研究的总体目标是研究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受到多巴胺相关基因的调节。烟草使用被认为是导致死亡和发病的最可预防的单一原因；然而，戒烟治疗的效率仍然不高，主要是因为戒烟头几天的复发率很高。研究表明，尼古丁剥夺会削弱行为的抑制性自我控制，这可能是导致复发风险和尼古丁依赖易感性的关键因素。然而，人们对尼古丁剥夺引起的去抑制的神经认知机制以及可能的遗传影响知之甚少。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脑功能，个体对这些剥夺诱导的缺陷的敏感性差异受到特定的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实验室的对照实验研究，它将结合认知神经科学和药物基因组学方法来追求以下特定目标：1)检测尼古丁剥夺对前额叶事件相关脑电位(ERPs)和认知控制绩效指标(包括反应抑制、动作监控和决策)的急性影响；2)检测儿茶酚氧位甲基转移酶(COMT)基因对吸烟剥夺的主观、行为和神经认知影响的个体差异。为了实现这些目标，我们将：(I)前瞻性地对一组慢性吸烟者(估计n=140)进行COMT基因多态的分型，并选择三个相等的(n=30)分型组；(Ii)进行单盲、受试者内、交叉研究，在两个不同的实验室会议中对参与者进行剥夺和非剥夺条件下的测试；以及(Iii)通过剥夺交互作用对自我报告、行为和神经认知变量的影响进行测试，同时控制重要的协变量。预计这项研究将为后续R01应用的开发提供试点和可行性数据，重点关注导致吸烟复发的遗传和神经认知因素。 与公共健康相关：在美国，烟草使用被认为是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，戒烟治疗的效果仍然不大，主要是因为戒烟的头几天内复吸率很高。对于这种自我控制失败和无法抵抗吸烟冲动背后的生物和行为因素，人们知之甚少。更好地了解导致吸烟复发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目标，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.