MITOCHONDRIAL DYSFUNCTION AND METHAMPHETAMINE TOXICITY

描述（改编自申请人的摘要） 甲基苯丙胺是一种滥用药物，高剂量会导致中毒， 纹状体中的多巴胺能末梢以及其他神经成分。的 尽管氧化应激， 多巴胺和体温过高被假设在毒性 结果。一些研究表明，线粒体功能障碍可能在 在甲基苯丙胺诱导的神经毒性机制中发挥作用，但这 没有被直接检查。因此，在本申请中，我们建议 研究暴露导致线粒体功能障碍的假设， 高剂量的甲基苯丙胺是一个关键步骤， 神经毒性我们将集中讨论一个基本问题， 甲基苯丙胺通过直接作用引起线粒体功能障碍 甲基苯丙胺，间接作用，如细胞质多巴胺增加，或 两者的结合，导致DA末端损伤或细胞死亡。我们 建议在各种体外和体内模型中检查这一点， 每个系统的独特特性的优势。越来越复杂 系统，我们将检查线粒体功能和细胞活力， 急性和慢性暴露于甲基苯丙胺（1）分离的线粒体和 突触体，（2）细胞培养，（3）皮质-纹状体-中脑器官型 培养物，和（4）体内大鼠模型。在大鼠模型中，除了 线粒体的功能分析，我们还将研究线粒体蛋白 修饰和潜在的治疗方法，以提高线粒体 功能和限制毒性。我们知道滥用安非他明的人， 即使是偶尔的酗酒者，也有增加发展的风险， 对中枢神经系统造成永久性损伤。这也可能使他们在以后的生活中 神经系统疾病，如帕金森氏病。这个项目的最终目标 研究将确定新的目标和治疗方法， 干预以预防甲基苯丙胺诱导的神经毒性。

DESCRIPTION (adapted from the applicant's abstract) Methamphetamine is a drug of abuse and in high doses causes toxicity to dopaminergic terminals in striatum as well as other neural components. The mechanism associated with this toxicity is not known although oxidative stress, dopamine, and hyperthermia have been hypothesized to play a role in the toxic outcome. Several studies have suggested that mitochondrial dysfunction may play a role in the mechanism of methamphetamine-induced neurotoxicity, but this has not been examined directly. Therefore, in this application, we propose to examine the hypothesis that mitochondrial dysfunction resulting from exposure to high doses of methamphetamine is a critical step in the resulting neurotoxicity. We will focus on the fundamental question of whether exposure to methamphetamine causes mitochondrial dysfunction by direct effects of methamphetamine, indirect effects such as increases in cytoplasmic dopamine, or a combination of both, resulting in DA terminal damage or cell death. We propose to examine this in a variety of in vitro and in vivo models taking advantage of the unique characteristics of each system. In increasingly complex systems, we will examine mitochondrial function and cell viability following acute and chronic exposure to methamphetamine in (1) isolated mitochondria and synaptosomes, (2) cell cultures, (3) cortico-striatal-mesenephalic organotypic cultures, and (4) the in vivo rat model. In the rat model, in addition to the functional analyses of mitochondria, we will also examine mitochondrial protein modifications and potential therapeutic approaches to enhance mitochondrial function and limit toxicity. We know that individuals who abuse amphetamines, even the occasional binge abuser, are at increased risk for the development of permanent damage to the CNS. This may also predispose them later in life to neurological disorders such as Parkinson's disease. The ultimate goal of this study will be to identify new targets and approaches for therapeutic intervention to prevent methamphetamine-induced neurotoxicity.