AMPHETAMINE INDUCED MONOAMINERGIC NEUROTOXICITY IN ANIMALS & HUMANS

该项目包括啮齿类动物、非人类灵长类动物和人类的体外和体内研究。各种苯丙胺类似物的单胺能神经毒性特性，包括（？）3，4-亚甲二氧基甲基苯丙胺，芬氟拉明，甲卡西酮，和甲基苯丙胺首先在体外和动物中确定，并确定了各种生物测定用于检测神经毒性的效用。 方法包括脑脊液测定单胺代谢物，直接神经化学评估单胺及其代谢物，它们的合成酶，和它们的转运。 如有指征，可使用荧光技术进行神经解剖学研究。 此外，最近开发的正电子发射断层扫描（PET）配体[11-C] McN 5652用于确定是否暴露于安非他明类似物与[11-C] McN 5652标记的5-HT转运蛋白的减少有关。 PET研究最初在非人灵长类动物中进行，适当时在人类中进行。 类似地，当确定各种安非他明类似物中的一种对动物中的多巴胺神经元具有神经毒性时，首先使用[11-C]WIN-35，428（一种选择性标记多巴胺转运蛋白的PET配体）在狒狒中进行PET研究。 如有必要，则在人体中进行研究。 最后，除了评估各种安非他明类似物的神经毒性潜力外，还在努力确定安非他明诱导的神经毒性损伤（如果存在）的功能后果。 为此，非人类灵长类动物和人类进行了一系列行为测试，以评估被认为是由单胺调节的功能领域。 在人类中，这些测试包括认知测试、睡眠研究、神经内分泌研究、人格评估、神经精神测试和疼痛测试。

This project includes studies in vitro and in vivo in rodents, in non-human primates, and in humans. The monoaminergic neurotoxic properties of a variety of amphetamine analogs, including (?) 3,4-methylenedioxymethamphetamine, fenfluramine, methcathinone, and methamphetamine are first determined in vitro and in animals, and the utility of various biological assays for the detection of neurotoxicity are determined. Methods include cerebrospinal fluid assay of monoamine metabolites, direct neurochemical assessment of monoamines and their metabolites, their synthetic enzymes, and their transporters. When indicated, neuroanatomical studies using immunohistofluorescent techniques are performed. Further, a recently developed positron emission tomography (PET) ligand [11-C]McN5652 is used to determine whether exposure to amphetamine analogs is associated with a reduction in [11-C]McN5652-labeled 5-HT transporters. PET studies are initially conducted in non-human primates and, when appropriate, are than conducted in humans. Similarly, when one of the various amphetamine analogs is determined to be neurotoxic to dopamine neurons in animals, PET studies are first conducted in baboons using [11-C]WIN-35,428, a PET ligand that selectively labels the dopamine transporter. If indicated, studies are then conducted in humans. Finally, in addition to assessment of the neurotoxic potential of various amphetamine analogs, efforts are being made to determine the functional consequences of amphetamine-induced neurotoxic injury, if it exists. To this end, non-human primates and humans undergo batteries of behavioral tests to evaluate functional spheres thought to be modulated by monoamines. In humans, these batteries include cognitive testing, sleep studies, neuroendocrine studies, personality evaluation, neuropsychiatric testing, and pain testing.