Translational Research to Enhance Cognitive Control

尽管精神兴奋剂药物的作用模式与儿茶酚胺递质在多动症和相关的儿童神经精神疾病中的作用有关，但人们对介导这些疾病交感症状特征的精确生化变化和/或新出现的遗传决定因素如何促成这些变化知之甚少。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”冲动性的确凿证据，我们将首先确定冲动性的生态相关测量和认知控制的实验室测量之间的关系。我们将利用行为药理学和死后神经化学技术进一步探索多巴胺受体对冲动和执行功能低下的影响机制。低皮质多巴胺能张力与不良反应抑制相关的假设，以及多巴胺D4激动剂将改善反应抑制的假设将被验证。然后，我们将利用新发现的遗传模型来评估ADHD特定候选基因与反应抑制之间的关系。我们将比较在多巴胺D4受体外显子3中携带不同数量的48 bp重复序列的受试者；5重复多态性比6重复多态性与更大的行为冲动相关。我们假设5重复版本与低皮质多巴胺能张力和多巴胺D4受体的基因组下调有关。通过这些研究，我们旨在描述多巴胺D4受体在冲动和反应抑制中的作用，并揭示其作为ADHD新药物治疗的潜力。我们还将提供关于多巴胺D4基因变异对儿茶酚胺能药物临床反应的潜在介导影响的新信息。这些目标的实现可以减轻儿童学业成绩和成人工作效率的沉重负担，从而为公共卫生带来实质性利益。

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.