Developmental Pyrethroid Exposure and ADHD

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种临床异质性障碍，其特征是明显的冲动、多动和工作记忆受损。据估计，仅在美国，就有3-7%的学龄儿童患有多动症，而且这些病例中有很大一部分会持续到成年。尽管ADHD的病理生理机制尚未完全被理解，但多巴胺系统的破坏似乎起着核心作用。具体来说，多巴胺转运体（DAT）的多态性和升高水平在青少年和成人ADHD患者中都被发现。在自发性高血压大鼠中也发现了升高的DAT水平，这是一种典型的ADHD动物模型。用于治疗ADHD的主要药物，哌甲酯和安非他明，通过阻断DAT产生很大的治疗效果。因此，DAT水平或功能的改变对ADHD的行为异常和治疗有重要影响。虽然遗传因素占ADHD的很大比例，但估计有20-40%的病例似乎没有原发性遗传病因，这表明环境因素可能导致ADHD。因此，暴露于改变多巴胺能系统正常发育和提高DAT水平的环境因素可能有助于ADHD相关行为的发展。我们的实验室和其他实验室已经证明，成年小鼠反复接触拟除虫菊酯类杀虫剂，即溴氰菊酯，会增加纹状体DAT水平。我们现在有证据表明，小鼠在妊娠期和哺乳期暴露于溴氰菊酯，剂量低于发育不可观察到的不良反应水平（NOAEL）的4至40倍，会导致青春期小鼠DAT的长期升高和多动。因此，本研究的目的是确定发育性拟除虫菊酯暴露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于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.