PET Studies of Amphetamine Treatment of ADHD

描述（由申请人提供）：注意力缺陷/多动障碍（ADHD）是一种高度流行的神经精神障碍，影响3-5%的儿童和1-5%的成人。近60%被诊断患有多动症的成年人报告说，他们接受过药物治疗，通常是精神兴奋剂。安非他明是治疗多动症最常用的兴奋剂之一。安非他明最近被证明有可能破坏非人类灵长类动物（狒狒和松鼠猴）大脑中的多巴胺（DA）轴突末梢，其血浆浓度与ADHD患者相似。在这些研究中，安非他明是按照药物管理的时间表口服的，模拟了安非他明在ADHD治疗中的使用。这些临床前观察，再加上初步结果表明，成人ADHD患者先前接受安非他明治疗后，其标记结合电位（BP）下降bb0 WIN 35,428，不太可能与安非他明对DAT的急性作用有关，这引起了人们对安非他明治疗成人ADHD可能与脑多巴胺神经毒性风险相关的关注。拟议研究的目的是确定使用安非他明治疗成人多动症是否与脑多巴胺能神经毒性风险相关。为此，正电子发射断层扫描（PET）将用于测量先前接受安非他明治疗的成年ADHD患者脑DA轴突末端的两个结构元素，DAT和囊泡单胺转运蛋白2 （VMAT-2）。这一组的研究结果将与其他三组进行比较：1)从未接受过ADHD药物治疗的成人ADHD患者；2)接受过哌甲酯治疗的成人ADHD患者，已知其缺乏DA神经毒性潜能；3)年龄和性别匹配的健康成人从未接受过精神兴奋剂治疗。所有受试者都是年龄在18到40岁之间的成年人，在PET成像前至少两周（约是安非他命的30个半衰期）未使用中枢神经系统活性药物（包括处方兴奋剂）。我们假设，与所有三个对照组相比，以前接受过安非他明治疗的成人无药物ADHD患者的DAT和VMAT-2将持续下降。如果我们的假设是正确的，研究结果将对ADHD的治疗产生广泛的公共卫生影响。这项研究的发现也应该进一步阐明大脑DA系统在ADHD的病理生理和症状中的作用。公共卫生相关性：当前项目的总体目标是：“安非他明治疗成人多动症的PET研究”，目的是确定安非他明治疗成人多动症是否与脑多巴胺能神经毒性风险相关。这种担忧是基于对动物（包括非人类灵长类动物）的研究结果和对人类的初步数据表明，用于治疗多动症的安非他明对大脑多巴胺神经元有潜在的神经毒性。

DESCRIPTION (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent neuropsychiatric disorder, affecting 3-5% of children and 1-5% of adults. Nearly 60% of adults who are diagnosed with ADHD report that they have been treated with medications, generally psychostimulants. One of the most common stimulants used to treat ADHD is amphetamine. Amphetamine has recently been shown to have the potential to destroy dopamine (DA) axon terminals in the brain of non-human primates (baboons and squirrel monkeys) at plasma concentrations similar to those that develop in ADHD patients. In these studies, amphetamine was given orally according to a schedule of drug administration that simulated the use of amphetamine in ADHD treatment. These preclinical observations, coupled with preliminary results indicating that adult ADHD patients previously treated with amphetamine have decrements [11] WIN 35,428-labeled binding potential (BP) that are unlikely to be related to acute effects of amphetamine on the DAT, raise concern that amphetamine treatment of adult ADHD may be associated with a risk of brain dopamine neurotoxicity. The purpose of the proposed research is to determine if the use of amphetamine for the treatment of adult ADHD is associated with a risk of brain dopaminergic neurotoxicity. To this end, positron emission tomography (PET) will be used to measure two structural elements of brain DA axon terminals, the DAT and the vesicular monoamine transporter-type 2 (VMAT-2), in adult ADHD patients previously treated with amphetamine. Findings in this group will be compared to those three other groups: 1) Adults with ADHD who have never received pharmacological treatment for ADHD; 2) Adults with ADHD who have been treated with methylphenidate, which is known to lack DA neurotoxic potential; and 3) Age- and gender- matched healthy adults never treated with psychostimulants. All subjects will be adults between the ages of 18 and 40 who have been free of CNS-active drugs (including prescribed stimulants) for at least two weeks (approximately 30 half-lives of amphetamine) prior to PET imaging. We hypothesize that adult, drug-free ADHD patients who have been previously treated with amphetamine will have lasting decreases in the DAT and VMAT-2 compared to all three control groups. If our hypothesis is correct, findings will have broad public health implications for the treatment of ADHD. Findings from this research should also shed additional light on the role of brain DA systems in the pathophysiology and symptoms of ADHD. PUBLIC HEALTH RELEVANCE: The overall goal of the present project, entitled: "PET Studies of Amphetamine Treatment of Adult ADHD," is to determine if amphetamine treatment of adult ADHD is associated with the risk of brain dopaminergic neurotoxicity. This concern is based on findings in animals (including non-human primates) and pilot data in humans indicating that amphetamine, as used in the treatment of ADHD, has neurotoxic potential toward brain dopamine neurons.