Neuropharmacology of Response Inhibition in Comorbid ADHD and Nicotine Dependence

描述(由申请者提供)：被诊断为注意力缺陷多动障碍(ADHD)的人比普通人群吸烟更多，在更年轻的时候开始吸烟，并报告更难戒烟。此外，我们实验室的最新证据表明，ADHD固有的冲动和反应抑制在启动吸烟行为方面发挥着重要而独特的作用，更符合本项目的目标，在保持吸烟和戒烟尝试后复发方面更具针对性。尽管戒烟引起的尼古丁和多巴胺能神经传递的改变可能会扰乱与反应抑制相关的额叶-纹状体和顶叶环路，但在ADHD或非ADHD吸烟者中，几乎没有实验工作来研究戒烟诱导的反应抑制缺陷的可能机制。因此，本应用的总体目标是利用神经成像、神经药理学和分子遗传学技术来研究ADHD和非ADHD吸烟者禁欲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的吸烟者在Go/No-Go任务中接受成像，条件如下：1)照常吸烟，2)24小时戒烟，3)24小时戒烟哌醋甲酯(MPH)。我们假设，与平时吸烟相比，戒烟24小时会导致反应抑制减少和与任务相关的大脑激活中断。与非ADHD吸烟者相比，ADHD患者的这些影响会更大。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数，并且mph的影响在患有ADHD的吸烟者中将更大。除了上述目标外，我们还将初步评估多巴胺受体D4 7-重复等位基因对戒烟和服用MPH后任务相关脑激活的调节作用。这项研究的发现将为揭示ADHD和尼古丁依赖共病的神经药理学机制提供新的线索。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治疗这种合并症的新方法。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揭示物质使用和滥用。公共健康相关性：吸烟是美国和注意力缺陷多动障碍(ADHD)吸烟率极高的人死亡和残疾的主要可预防原因。冲动和抑制过度学习行为的相关问题可能会导致ADHD患者更多地吸烟。这项拟议的研究将有助于更好地理解ADHD和尼古丁依赖的共病神经和遗传基础，并为新治疗方法的开发提供信息。

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.