Neuropharmacology of Response Inhibition in Comorbid ADHD and Nicotine Dependence

描述（由申请人提供）：被诊断为注意缺陷多动障碍（ADHD）的个体比一般人群吸烟更多，在更年轻的年龄开始使用，并且报告更难以戒烟。此外，我们实验室最近的证据表明，多动症固有的冲动性和反应抑制在吸烟行为的开始中起着重要而独特的作用，更符合本项目的目的，在吸烟的维持和戒烟后的复发中。虽然戒断诱导的尼古丁和多巴胺能神经传递的改变可能会破坏与反应抑制相关的额纹状体和顶叶回路，但在ADHD或非ADHD吸烟者中，研究戒断诱导的反应抑制缺陷的可能机制的实验工作很少。因此，本应用程序的总体目标是使用神经影像学，神经药理学和分子遗传学技术来研究ADHD和非ADHD吸烟者戒断诱导的反应抑制缺陷的神经生物学基础。20名患有ADHD的吸烟者和20名没有ADHD的吸烟者将在以下条件下进行Go/No-Go任务期间进行成像：1)照常吸烟，2)戒烟24小时，3)戒烟24小时+哌醋甲酯（MPH）。我们假设，与平常吸烟相比，24小时戒烟会导致反应抑制减弱，并破坏与任务相关的大脑激活。与非ADHD吸烟者相比，ADHD吸烟者的这些影响更大。我们进一步假设，在戒烟期间服用MPH将恢复反应抑制的表现和大脑指标，并且MPH的效果在患有ADHD的吸烟者中更大。除上述目的外，我们将初步评估多巴胺受体D4 7-repeat等位基因对戒烟和MPH给药后任务相关脑激活的调节作用。本研究结果将揭示ADHD和尼古丁依赖共病的神经药理学机制。此外，拟议的项目将提供实质性的神经生物学基础，在此基础上可以开发新的治疗这种共病的方法。最后，由于冲动和相关结构在非临床样本中与吸烟和其他成瘾密切相关，我们的方法将更广泛地阐明物质使用和滥用。公共卫生相关性：在美国，吸烟是导致死亡和残疾的主要可预防原因，患有注意缺陷多动障碍（ADHD）的人吸烟的比例高得不成比例。冲动和抑制过度学习行为的相关问题可能会导致ADHD患者吸烟的增加。这项研究将有助于更好地了解ADHD和尼古丁依赖的神经和遗传基础，并为开发新的治疗方法提供信息。

DESCRIPTION (provided by applicant): Individuals diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) smoke more than the general population, initiate use at a younger age, and report more difficulty trying to quit. Moreover, recent evidence from our laboratory suggests the impulsivity and response inhibition inherent in ADHD play an important and unique role in the initiation of smoking behavior, and more pertinent to the aims of this project, in the maintenance of smoking and in relapse following attempts to quit. Though abstinence-induced changes in nicotinic and dopaminergic neurotransmission likely disrupt fronto-striatal and parietal circuits associated with response inhibition, little experimental work has been done to investigate possible mechanisms underlying abstinence-induced response inhibition deficits among either ADHD or non-ADHD smokers. Thus, the overarching goal of the present application is to use neuroimaging, neuropharmacological and molecular genetic techniques to study the neurobiological basis of abstinence-induced deficits in response inhibition in ADHD and non-ADHD smokers. Twenty smokers with ADHD and 20 smokers without ADHD will undergo imaging during a Go/No-Go task under the following conditions: 1) smoking as usual, 2) 24 hr smoking abstinence, and 3) 24 hr smoking abstinence + methylphenidate (MPH). We hypothesize that compared to smoking as usual, 24 hr smoking abstinence will result in decrements in response inhibition and disruption of task-related brain activation. These effects will be greater in ADHD as compared to non-ADHD smokers. We further hypothesize that MPH administration during abstinence will restore performance and brain indices of response inhibition and that the magnitude of the effect of MPH will be greater among smokers with ADHD. In addition to the above aims, we will preliminarily evaluate the moderating effects of the dopamine receptor D4 7-repeat allele on task-related brain activation following smoking abstinence and MPH administration. The findings of this study will shed new light on the neuropharmacological mechanisms underlying comorbid ADHD and nicotine dependence. Moreover, the proposed project will provide a substantive neurobiological foundation on which new treatments for this comorbidity can be developed. Finally, since impulsivity and related constructs have been strongly associated with smoking and other addictions in non-clinical samples, our approach will shed light on substance use and abuse more broadly.PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. and individuals with Attention Deficit Hyperactivity Disorder (ADHD) smoke at disproportionately high rates. Impulsivity and the related problem of inhibiting over-learned behaviors may contribute to greater smoking among individuals with ADHD. The proposed research will lead to a better understanding of the neural and genetic basis of comorbid ADHD and nicotine dependence and inform the development of new treatments.