"Neurochemical Alterations By Designer Drugs"

由于苯乙胺类药物的滥用和相关问题，如甲基苯丙胺 （方法），继续是美国和世界各地的一个主要问题，这是至关重要的，根据- 承受滥用这些精神兴奋剂所造成的短期和长期后果。特别 与本项目相关的是阐明单胺转运蛋白在急性和慢性炎症中的作用。 苯乙胺的作用。我们最近证明了METH治疗快速而深刻地 降低纹状体纯化囊泡中囊泡单胺转运蛋白-2（VMAT-2）的活性。这个VMAT- 2.急性转运蛋白反应（VATR）至少有两种不同的组分：一种（第一组分）， 发生在单次METH给药后，另一种（第二种组分）显然仅在多次给药后发生。 导致神经毒性的甲基苯丙胺。基于这些观察，我们假设， "VATR的第二种而不是第一种成分的表达与苯乙胺的出现有关， 诱导单胺神经毒性。"这一假设将通过实现以下具体目标来检验： a.测定并比较甲基苯丙胺诱导的纹状体VATR各成分的特征。我们将 研究和对比基本剂量、时间、动力学、解剖学和机械学的全部补充 单次（无毒）和多次（神经毒性）METH给药后VATR的特征。 B。阐明VATR各组成部分的功能意义。这将通过确定是否 VATR组分干扰囊泡单胺螯合和释放功能。 C.确定不同苯乙胺对VATR表达的影响（即，安非他明摇头丸 芬氟拉明和麻黄碱），单胺神经毒性特征与METH不同。这将确认 VATR组分如何与对单胺系统的各种影响以及 与这些不同的苯乙胺类似物相关的单胺毒性。

Because abuse and associated problems of the phenylethylamine drugs, such as methamphetamine (METH), continue to be a major concern in the United States and throughout the world, it is critical to under- stand the short- and long-term consequences resulting from abusing these psychostimulants. Of particular relevance to this project is the elucidation of the role of monoamine transporters to the acute andchronic effects of phenylethylamines. We recently demonstrated that METH treatments rapidly and profoundly reduce the activity of vesicular monoamine transporters-2 (VMAT-2) in striatal purified vesicles. This VMAT- 2 Acute Transporter Response (VATR) has at least two distinct components: one (1st component) that occurs after a single METH administration, and the other (2nd component) apparently only after multiple METH adminstrations that lead to neurotoxicity. Based on these observations, we hypothesize that "Expression of a 2nd, but not the 1st, component of the VATR is linked to occurrence of phenylethylamine- induced monoamine neurotoxicity." This hypothesis will be tested by achieving the following Specific Aims: A. Determine and compare the features of the components of the METH-induced striatal VATR. We will study and contrast the full complement of basic dose, temporal, kinetic, anatomical, and mechanistic features of the VATR after a single (nontoxic) and multiple (neurotoxic) METH administrations. B. Elucidate the funtional significance of the VATR components. This will be accomplished by determining if the VATR components interfere with vesicular monoamine sequestration and releasing functions. C. Determine the effects on VATR expression of diverse phenylethylamines (i.e., amphetamine, MDMA, fenfluramine, and ephedrine), with monoamine neurotoxcity profiles distinct from METH. This will identify how the VATR components link with the various effects on monoamine systems and different expressions of monoamine toxicity associated with these distinct phenylethylamine analogs.