Developmental Pyrethroid Exposure and ADHD

描述(申请人提供)：注意缺陷多动障碍(ADHD)是一种临床异质性疾病，以明显的冲动、多动和工作记忆受损为特征。据估计，仅在美国，ADHD就影响到3-7%的学龄儿童，其中相当大比例的病例会持续到成年。虽然ADHD的病理生理学机制还不完全清楚，但多巴胺系统的破坏似乎起到了核心作用。具体地说，在青少年和成人ADHD中都发现了多巴胺转运体(DAT)的多态和水平升高。在自发性高血压大鼠中也发现DAT水平升高，这是ADHD的典型动物模型。治疗ADHD的主要药物是哌醋甲酯和苯丙胺，它们的大部分疗效都是通过阻断DAT来实现的。因此，DAT水平或功能的改变对ADHD的行为异常和治疗具有重要意义。虽然遗传因素占ADHD的很大比例，但估计有20%-40%的病例似乎没有主要的遗传病因，这表明环境因素可能导致ADHD。因此，暴露在改变多巴胺能系统正常发育和提高DAT水平的环境介质中可能有助于ADHD相关行为的发展。我们的实验室和其他实验室已经证明，成年小鼠反复暴露于拟除虫菊酯杀虫剂溴氰菊酯，会增加纹状体DAT水平。我们现在有证据表明，孕期和哺乳期小鼠暴露于溴氰菊酯的剂量是发育不可观察到的不良反应水平(NOAEL)的4到40倍，会导致青春期小鼠DAT的长期上调和多动。因此，本研究的目的是确定拟除虫菊酯发育过程中对多巴胺系统的影响，以及多巴胺系统的改变是否会导致类似ADHD的行为表型。

DESCRIPTION (provided by applicant): 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.