ADHD Treatment & Amphetamine Neurotoxicity

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是一种常见的致残性神经精神疾病，影响3-7%的儿童和1-5%的成人。兴奋剂是治疗ADHD的主要药物。在用于治疗ADHD的各种兴奋剂药物中，安非他明是最常见的处方药之一，无论是儿童还是成人。大量数据表明，安非他明有可能破坏动物脑多巴胺（DA）轴突和轴突终末。尚未研究人类接受安非他明治疗ADHD可能引起类似安非他明诱导的DA神经毒性的可能性，主要是因为在动物中产生DA神经毒性作用的剂量高于治疗ADHD所用的剂量（以ing/kg计）。然而，最近在我们的实验室的初步研究结果表明，狒狒治疗与安非他明的口服给药方案类似，通常用于治疗多动症维持DA神经毒性的变化，在纹状体。初步数据还表明，狒狒中与脑DA神经毒性相关的安非他明血浆水平与用安非他明治疗ADHD的人类中报告的水平相当。拟议研究的目的是：1）确认我们在大量成年狒狒中的初步观察结果，并看看它们是否可以扩展到青春期动物; 2）确定狒狒的发现是否可以扩展到另一个非人类灵长类动物物种（松鼠猴，成年和青少年）已知以类似于人类的方式代谢安非他明;和3）测量非人灵长类动物中通过苯丙胺给药方案产生的苯丙胺血浆浓度，以便将与2种非人灵长类动物中DA神经毒性相关的苯丙胺水平和药代动力学特征与先前在人类中记录的那些进行比较。总之，拟议研究的结果将有助于确定是否有必要关注接受安非他明治疗ADHD的人类中可能的安非他明诱导的DA神经毒性，以及是否需要对人类ADHD队列中可能的安非他明诱导的DA神经毒性进行对照研究。

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a common and disabling neutopsychiatric disorder that afflicts 3-7% of children and 1-5% of adults. Stimulant drugs are the mainstay of treatment for ADHD. Of the various stimulant drugs used to treat ADHD, amphetamine is among the most often prescribed, both to children and adults. A significant body of data indicates that amphetamine has the potential to destroy brain dopamine (DA) axons and axon terminals in animals. The possibility that humans receiving amphetamine for the treatment of ADHD might incur similar amphetamine-induced DA ncurotoxicity has not been investigated, largely because the doses that produce DA neurotoxic effects in animals are higher, on a ing/kg basis, than the doses used in the treatment of ADHD. However, recent preliminary findings in our laboratory indicate that baboons treated with an oral dosing regimen of amphetamine similar to that used commonly to treat ADHD sustain DA neurotoxic changes in the striatum. Pilot data also indicate that plasma levels of .amphetamine associated with brain DA ncurotoxicity in baboons are on the order of those reported in humans treated with amphetamine for ADHD. The aims of the proposed studies are: 1) To confirm our preliminary observations in a larger number of adult baboons, and to see if they can be extended to adolescent animals; 2) To determine if findings in baboons can be extended to another non-human primate species (squirrel monkeys, adult and adolescent) known to metabolize amphetamine in a manner similar to humans ; and 3) To measure plasma concentrations of amphetamine engendered by dosing regimens of amphetamine in non-human primates, in order to compare the levels and pharmacokinctic profiles of amphetamine associated with DA ncurotoxicity in 2 non-human primate species with those previously documented in humans. Together, results of the proposed studies will help determine whether concern over possible amphetamineinduced DA neurotoxicity in humans receiving amphetamine for the treatment of ADHD is warranted, and if controlled studies of possible amphetamine-induced DA neurotoxicity in human ADHD cohorts are indicated.