Neuropharmacology of Response Inhibition in Comorbid ADHD and Nicotine Dependence

被诊断为注意缺陷多动障碍(ADHD)的人比一般人吸烟更多 人口，在更年轻的时候开始使用，并报告更难尝试戒烟。此外，最近的证据表明 来自我们实验室的研究表明，ADHD固有的冲动和反应抑制在 在启动吸烟行为方面的独特作用，更符合本项目的目标，在 保持吸烟，并在尝试戒烟后复发。尽管禁欲引起的变化 尼古丁和多巴胺能神经传递可能扰乱与以下相关的额纹状体和顶叶环路 对于反应抑制，几乎没有实验工作来研究可能的机制 戒断导致的反应抑制缺陷在ADHD或非ADHD吸烟者中。因此， 目前应用的主要目标是使用神经成像、神经药理学和分子 基因技术研究戒断诱导的反应抑制缺陷的神经生物学基础 多动症和非多动症吸烟者。20名患有ADHD的吸烟者和20名没有ADHD的吸烟者将接受 在以下情况下在进行/不进行任务期间进行成像：1)照常吸烟，2)24小时吸烟 戒烟，3)24小时戒烟，哌醋甲酯(MPH)。我们假设，相比于 像往常一样吸烟，24小时戒烟会导致反应抑制和干扰反应减少 与任务相关的大脑激活。与非ADHD吸烟者相比，ADHD患者的这些影响会更大。我们 进一步的假设是，在戒酒期间服用公共卫生将恢复表现和脑指数 反应抑制，在患有多动症的吸烟者中，mph的影响程度会更大。在……里面 除了上述目的外，我们还将初步评估多巴胺受体D4的调节作用 戒烟和服用公共卫生后任务相关脑激活的7个重复等位基因。这个 这项研究的发现将为揭示ADHD共病的神经药理学机制提供新的线索 和尼古丁依赖。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出治疗这种合并症的新方法。最后，由于冲动和相关 在非临床样本中，结构与吸烟和其他成瘾密切相关，我们的 这种方法将更广泛地揭示药物使用和滥用的情况。

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.