Neurochemical Alterations By Designer Drugs

描述（由申请人提供）：由于苯基乙胺类药物的滥用和相关问题，如甲基苯丙胺（冰毒），在美国和全世界仍然是一个主要问题，因此了解滥用这些精神兴奋剂造成的短期和长期后果至关重要。与本项目特别相关的是阐明单胺转运体对苯乙胺的急性和慢性影响的作用。我们最近证明，甲基苯丙胺治疗迅速而深刻地降低纹状体纯化囊泡中单胺转运体-2 （VMAT-2）的活性。这个VMAT- 2急性转运蛋白反应（VATR）至少有两个不同的组成部分：一个（第一个组成部分）

DESCRIPTION (provided by applicant): 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 understand 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 and chronic 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 administrations 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 functional 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 (that is, 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.