Translational Research to Enhance Cognitive Control

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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.