Although the mode of action of psychostimulant drugs implicates catecholamine transmitters in ADHD, andrelated pediatric neuropsychiatric disorders, very little is known about the precise biochemical changes thatmediate sympatomatic features of the disorders and/or how emerging genetic determinants contribute tothose changes. We will investigate the neuro-chemical and -pharmacological basis of responseinhibition and working memory in vervets (Chlorocebus aethiops). Building upon solid evidence for highlyheritable 'trait' impulsivity in captive vervets, we will first determine the relationship between ecologicallyrelevant measures of impulsivity and laboratory measures of cognitive control. We will further explore thedopamine receptor mechanisms contributing to impulsivity and poor executive functions, using behavioralpharmacological and post mortem neurochemical techniques. The hypotheses that low cortical dopaminergictone is correlated with poor response inhibition and that dopamine D4 agonists will improve responseinhibition will be tested. We will then utilize utilize a newly discovered genetic model to evaluate therelationship between a particular candidate gene for ADHD and response inhibition. We will compare vervetsthat carry different numbers of 48 bp repeats in exon 3 of the dopamine D4 receptor; the 5 repeatpolymorphism is associated with greater behavioral impulsivity than the 6 repeat version. We hypothesizethat the 5 repeat version is associated with low cortical dopaminergic tone and genomic downregulation ofthe dopamine D4 receptor. Through these studies, we aim to delineate the role for dopamine D4 receptors inimpulsivity and response inhibition and to uncover its potential as a new pharmacotherapy for ADHD. We willalso provide new information about the potential mediating influences of dopamine D4 genetic variants onclinical responses to catecholaminergic drugs. The accomplishment of these goals could lead to substantialbenefits for public health by releaving a major burden on the scholastic accomplishment of children and theworkplace efficiency of adults.
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