PET Studies of Amphetamine Treatment of ADHD

描述(申请人提供)：注意力缺陷/多动障碍(ADHD)是一种非常普遍的神经精神障碍，影响3-5%的儿童和1-5%的成年人。在被诊断为ADHD的成年人中，近60%的人表示他们曾接受过药物治疗，通常是精神刺激剂。用于治疗ADHD的最常见的兴奋剂之一是苯丙胺。安非他明最近被证明有可能破坏非人类灵长类动物(狒狒和松鼠猴子)大脑中的多巴胺(DA)轴突终末，其血浆浓度与ADHD患者的血浆浓度相似。在这些研究中，根据模拟苯丙胺在ADHD治疗中的使用情况的给药时间表，口服安非他明。这些临床前的观察，再加上初步结果表明，以前接受苯丙胺治疗的成人ADHD患者有35,428标记的结合电位(BP)下降，这不太可能与苯丙胺对DAT的急性影响有关，这引发了人们的担忧，即苯丙胺治疗成人ADHD可能与脑多巴胺神经毒性的风险有关。这项拟议研究的目的是确定使用苯丙胺治疗成人ADHD是否与脑多巴胺能神经毒性的风险有关。为此，正电子发射断层扫描(PET)将被用来测量两个结构元素的脑DA轴突终末，DAT和囊泡单胺转运体-2(VMAT-2)，在成人ADHD患者以前使用苯丙胺治疗。这一组的发现将与其他三组进行比较：1)从未接受过ADHD药物治疗的ADHD成年人；2)接受过哌醋甲酯治疗的ADHD成年人，已知这种药物缺乏DA神经毒性潜力；以及3)年龄和性别匹配的健康成年人从未接受过精神刺激药物治疗。所有受试者将是18至40岁的成年人，在PET成像之前至少两周没有服用中枢神经系统活性药物(包括处方兴奋剂)(大约30个苯丙胺半衰期)。我们假设，与所有三个对照组相比，以前接受过苯丙胺治疗的成年、非药物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的病理生理学和症状中的作用。公共卫生相关性：本项目的总体目标是：“成人ADHD苯丙胺治疗的PET研究”，目的是确定成人ADHD的苯丙胺治疗是否与大脑多巴胺能神经毒性的风险有关。这一担忧是基于动物(包括非人类灵长类动物)的发现和人类的试点数据，这些数据表明，用于治疗ADHD的苯丙胺对脑多巴胺神经元具有神经毒性潜力。

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.