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，在年轻时开始使用，并报告更难尝试戒烟。此外，最近的证据表明， 我们实验室的研究表明，ADHD固有的冲动性和反应抑制在ADHD中起着重要的作用， 在吸烟行为的启动中起着独特的作用，与本项目的目标更相关， 维持吸烟和尝试戒烟后复发。虽然禁欲引起的变化， 烟碱和多巴胺能神经传递可能会破坏额-纹状体和顶叶回路， 反应抑制，很少有实验工作已经做了调查可能的机制， 注意力缺陷多动障碍或非注意力缺陷多动障碍吸烟者之间的禁欲诱导的反应抑制缺陷。因此 本申请的首要目标是使用神经成像、神经药理学和分子生物学技术来研究神经系统的功能。 遗传学技术来研究戒断引起的反应抑制缺陷的神经生物学基础， ADHD和非ADHD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 在以下条件下进行Go/No-Go任务期间成像：1）照常吸烟，2）24小时吸烟 戒烟24小时+哌醋甲酯（MPH）。我们假设， 像往常一样吸烟，24小时戒烟将导致反应抑制和干扰的减少， 与任务相关的大脑激活与非ADHD吸烟者相比，这些影响在ADHD中更大。我们 进一步假设，在禁欲期间给予MPH将恢复表现和大脑指数， 反应抑制，MPH的影响程度在患有ADHD的吸烟者中更大。在 除了上述目的，我们将初步评估多巴胺受体D4的调节作用， 7-重复等位基因对戒烟和MPH给药后任务相关脑激活的影响。的 这项研究的结果将为共病ADHD的神经药理学机制提供新的线索 尼古丁依赖此外，拟议的项目将提供一个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并发症的新方法。最后，由于冲动和相关的 在非临床样本中，构建体与吸烟和其他成瘾密切相关， 这一方法将更广泛地揭示药物使用和滥用问题。

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.