Translational Research to Enhance Cognitive Control

尽管精神刺激性药物的作用模式与ADHD和相关的儿科神经精神障碍有关，但人们对调节这些障碍的共同特征的确切生化变化和/或新出现的遗传决定因素如何导致这些变化知之甚少。我们将在一个潜在的ADHD动物模型中研究反应抑制和工作记忆的神经化学和药理学基础。基于高度可遗传的“特质”冲动的确凿证据，我们将首先确定与生态相关的冲动衡量标准和认知控制实验室衡量标准之间的关系。我们将利用行为药理学和死后神经化学技术，进一步探索导致冲动和执行功能低下的多巴胺受体机制。低皮质多巴胺能张力与较差的反应抑制相关，以及多巴胺D4激动剂将改善反应抑制的假设将得到检验。然后，我们将利用一个新发现的遗传模型来评估ADHD的特定候选基因与反应抑制之间的关系。我们将对多巴胺D4受体外显子3携带不同数量48BP重复的受试者进行比较；与6重复版本相比，5重复多态与更大的行为冲动相关。我们假设5个重复版本与皮质多巴胺能张力降低和多巴胺D4受体的基因组下调有关。通过这些研究，我们旨在阐明多巴胺D4受体在冲动和反应抑制中的作用，并揭示其作为治疗ADHD的新药物的潜力。我们还将提供有关多巴胺D4基因变异对儿茶酚胺能药物临床反应的潜在中介影响的新信息。这些目标的实现可以减轻儿童学业成就和成年人工作效率的主要负担，从而为公共卫生带来实质性的好处。

Although the mode of action of psychostimulant drugs implicates catecholamine transmitters in ADHD, and related pediatric neuropsychiatric disorders, very little is known about the precise biochemical changes that mediate sympatomatic features of the disorders and/or how emerging genetic determinants contribute to those changes. We will investigate the neuro-chemical and -pharmacological basis of response inhibition and working memory in a potential animal model for ADHD. Building upon solid evidence for highly heritable "trait" impulsivity, we will first determine the relationship between ecologically relevant measures of impulsivity and laboratory measures of cognitive control. We will further explore the dopamine receptor mechanisms contributing to impulsivity and poor executive functions, using behavioral pharmacological and post mortem neurochemical techniques. The hypotheses that low cortical dopaminergic tone is correlated with poor response inhibition and that dopamine D4 agonists will improve response inhibition will be tested. We will then utilize a newly discovered genetic model to evaluate the relationship between a particular candidate gene for ADHD and response inhibition. We will compare subjects that carry different numbers of 48 bp repeats in exon 3 of the dopamine D4 receptor; the 5 repeat polymorphism is associated with greater behavioral impulsivity than the 6 repeat version. We hypothesize that the 5 repeat version is associated with low cortical dopaminergic tone and genomic downregulation of the dopamine D4 receptor. Through these studies, we aim to delineate the role for dopamine D4 receptors in impulsivity and response inhibition and to uncover its potential as a new pharmacotherapy for ADHD. We will also provide new information about the potential mediating influences of dopamine D4 genetic variants on clinical responses to catecholaminergic drugs. The accomplishment of these goals could lead to substantial benefits for public health by releaving a major burden on the scholastic accomplishment of children and the workplace efficiency of adults.