Translational Research to Enhance Cognitive Control

增强认知控制的转化研究

• 批准号: 7915207
• 负责人: JAMES T. MCCRACKEN
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7915207
• 关键词: Adult; Agonist; Animal Model; Attention deficit hyperactivity disorder; Behavioral; Biochemical; Candidate Disease Gene; Catecholamines; Chemicals; Child; Childhood; Clinical; Disease; Dopamine; Dopamine Receptor; Down-Regulation; Exons; Genetic Determinism; Genetic Models; Genetic Polymorphism; Genomics; Goals; Impulsivity; Laboratories; Lead; Measures; Mediating; Pharmaceutical Preparations; Pharmacotherapy; Public Health; Role; Short-Term Memory; Solid; Techniques; Testing; Translational Research; Workplace; base; cognitive control; dopamine D4 receptor; executive function; genetic variant; improved; neurochemistry; neuropsychiatry; psychostimulant; response; trait

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.

尽管精神刺激药物的作用方式暗示了ADHD中的儿茶酚胺发射器以及相关的儿科神经精神疾病，但对介导疾病的同性恋特征的精确生化变化和/或出现的遗传确定性如何有助于这些变化的精确生化变化知之甚少。我们将研究ADHD的潜在动物模型中反应抑制和工作记忆的神经化学和药理学基础。在坚实的证据表明高度遗传的“性状”冲动性的基础上，我们将首先确定冲动性与认知控制的实验室措施之间的生态相关度量之间的关系。我们将进一步探索使用行为药理和验尸神经化学技术的多巴胺受体机制，导致冲动性和执行功能不佳。低皮质多巴胺能张力与反应抑制不良相关的假设，多巴胺D4激动剂将改善反应抑制作用。然后，我们将利用新发现的遗传模型来评估特定候选基因的多动症和响应抑制之间的关系。我们将比较多巴胺D4受体外显子3中携带48 bp重复序列的受试者；与6个重复版本相比，5个重复多态性与更大的行为冲动有关。我们假设5个重复版本与多巴胺能张力低皮质多巴胺能和多巴胺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，并发现其作为多动症的新药物疗法的潜力。我们还将提供有关多巴胺D4遗传变异对儿茶酚胺能药物的临床反应的潜在介导影响的新信息。实现这些目标可能会通过重大负担儿童的学术成就和成人的工作场所效率来给公共卫生带来重大利益。