METHAMPHETAMINE AND DOPAMINE TRANSPORTERS

描述：(申请人摘要) 甲基苯丙胺(冰毒)滥用的发生率在过去几年里急剧上升。 过去几年：因此，其对中枢单胺能的神经化学作用 神经元值得研究。大剂量冰毒对啮齿动物和 灵长类导致单胺能系统的短期和长期缺陷。 这个实验室最近报告了一项新的发现，即冰毒管理 导致多巴胺转运体(DAT)快速且可逆的下降 与多巴胺终末退化不同的功能。因为 DAT对于清除神经元外环境中的多巴胺是必不可少的， DAT的这种快速和可逆的变化可能是 重要性。因此，这一假设将被检验为冰毒和 通过以下方式以可逆方式有选择地改变DAT的性质和功能 实现以下具体目标： A.通过以下方式评估冰毒效应对DAT的选择性：1)确认 这种现象不是由于多巴胺神经元变性造成的；2)比较 甲基对DAT的作用及其对囊泡单胺和谷氨酸的影响 转运蛋白；以及3)评估大脑区域和物种差异 冰毒对DAT的影响。 B.阐明冰毒对DAT可逆作用的本质 研究：1)冰毒处理是否改变DAT蛋白结构；2) 多巴胺D2受体调节DAT功能；3)从头合成蛋白质是 DAT恢复所必需的；以及4)抗氧化剂在以下情况下恢复DAT活性 冰毒管理部门。 C.通过评估受冰毒影响的DAT的功能后果 冰毒损伤的DAT对体内及后续多巴胺再摄取的影响 在体外摄取冰毒。 D.评估冰毒对DAT的影响是否对冰毒具有选择性 DAT对：1)阻断多巴胺再摄取的药物(可卡因， 诺米芬辛)，或增加多巴胺的释放(即苯丙胺、MDMA、MDE和 芬氟拉明)；以及2)促进多巴胺合成的药物(L-多巴)。 这些研究的结果将阐明快速和 可逆性冰毒引起DAT活性下降。对这一点的理解 这一现象对其作用机制有重要影响。 冰毒和其他精神刺激剂，以及生理调节 多巴胺能系统。这样的理解有助于更好地发展 治疗药物滥用和多巴胺相关的神经病学和 精神障碍。

DESCRIPTION: (Applicant's Abstract) The incidence of methamphetamine (METH) abuse has risen sharply over the past few years: hence, its neurochemical effects on central monoaminergic neurons warrant investigation. High-dose METH administration to rodents and primates results in short- and long-term deficits in monoaminergic systems. This laboratory reported recently the novel finding that METH administration causes a rapid and reversible decrease in dopamine transporter (DAT) function which is distinct from degeneration of dopamine terminals. Because DAT are essential for clearing dopamine from the extraneuronal environment, this rapid and reversible change in DAT may be a regulatory phenomenon of importance. Hence, the hypothesis will be tested that METH acutely and selectively alters the nature and function of DAT in a reversible manner by achieving the following Specific Aims: A. Assess the selectivity of the METH effect on DAT by: 1) confirming that this phenomenon is not due to dopamine neuronal degeneration; 2) comparing METH actions on DAT with effects on vesicular monoamine and glutamate transporters; and 3) assessing brain regional and species differences in the METH effect on DAT. B. Elucidate the nature of the reversible effect of METH on DAT by investigating whether: 1) METH treatment alters DAT protein structure; 2) dopamine D2 receptors modulate DAT function; 3) de novo protein synthesis is necessary for DAT recovery; and 4) antioxidants restore DAT activity after METH administration. C. Demonstrate functional consequences of METH-affected DAT by assessing the effect of METH-impaired DAT on dopamine reuptake in vivo, and subsequent uptake of METH in vitro. D. Evaluate whether the METH effect on DAT is selective to METH by assessing the response of DAT to: 1) agents that block dopamine reuptake (cocaine, nomifensine), or increase dopamine release (i.e., amphetamine, MDMA, MDE and fenfluramine); and 2) an agent which increases dopamine synthesis (L-dopa). Results of these studies will elucidate the importance of the rapid and reversible METH-induced decrease DAT activity. An understanding of this phenomenon has important implications regarding the mechanism of action of METH and other psychostimulants, as well as for the physiological regulation of dopaminergic systems. Such understanding could help develop better strategies for treating drug abuse and dopamine-related neurological and psychiatric disorders.