Attention deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by marked impulsivity, hyperactivity, and impaired working memory. ADHD is estimated to affect 3-7% of school-age individuals in the United States alone, with a significant percentage of these cases persisting through adulthood. Although the pathophysiology of ADHD is not completely understood, disruption of the dopamine system appears to play a central role. Specifically, polymorphisms and elevated levels of the dopamine transporter (DAT) have been found in both adolescents and adults with ADHD. Elevated DAT levels are also found in the spontaneously-hypertensive rat, a well characterized animal model of ADHD. The primary medications utilized in the treatment of ADHD, methylphenidate and amphetamine, produce much of their therapeutic effects through blockade of DAT. Thus, alteration of DAT levels or function significantly contributes to the behavioral abnormalities and treatment of ADHD. Although genetic factors account for a large percentage of ADHD, an estimated 20-40% of cases do not appear to have a primary genetic etiology, suggesting that environmental factors may contribute to ADHD. Accordingly, exposure to environmental agents that alter the proper development of the dopaminergic system and enhance DAT levels may contribute to development of behaviors associated with ADHD. Our laboratory and others have demonstrated that repeated exposure of adult mice to the pyrethroid pesticide, deltamethrin, increases striatal DAT levels. We now have evidence that gestational and lactational exposure of mice to deltamethrin, at doses 4 to 40-fold below the developmental no-observable adverse effect level (NOAEL), causes longterm up-regulation of DAT and hyperactivity in adolescent mice. Therefore, the purpose of this proposal is to determine the effects of developmental pyrethroid exposure on the dopamine system and whether alterations of the dopamine system result in a behavioral phenotype similar to that of ADHD. ? ?
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