METHAMPHETAMINE AND DOPAMINE TRANSPORTERS

描述：（申请人摘要） 2000年以来，甲基苯丙胺（METH）滥用的发生率急剧上升， 因此，其对中枢单胺能神经系统的神经化学作用 神经元值得研究。 对啮齿类动物给予高剂量甲基苯丙胺， 灵长类导致单胺能系统的短期和长期缺陷。 该实验室最近报告了一项新的发现， 导致多巴胺转运蛋白（DAT）的快速和可逆性降低 这一功能不同于多巴胺末梢的退化。 因为 DAT对于从神经元环境中清除多巴胺是必不可少的， DAT的这种快速和可逆的变化可能是一种调节现象， 重要性 因此，将检验METH急性和 选择性地以可逆的方式改变DAT的性质和功能， 实现以下具体目标： A.通过以下方式评估METH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; 2）比较 METH对DAT的作用与对囊泡单胺和谷氨酸的影响 转运蛋白;和3）评估大脑区域和物种差异， METH对DAT的影响 B。通过以下方式阐明METH对DAT的可逆作用的性质： 研究是否：1）METH处理改变DAT蛋白质结构; 2） 多巴胺D2受体调节DAT功能; 3）从头蛋白质合成是 必需的DAT恢复;和4）抗氧化剂恢复DAT活性后， METH给药。 C.通过评估 MET受损DAT对体内多巴胺再摄取的影响，以及随后的 体外摄取METH。 D.通过评估METH对DAT的影响是否对METH具有选择性， DAT对以下物质的反应：1）阻断多巴胺再摄取的药剂（可卡因， 诺米芬辛），或增加多巴胺释放（即，安非他明、MDMA、MDE和 芬氟拉明）;和2）增加多巴胺合成的药剂（L-多巴）。 这些研究的结果将阐明快速和 可逆的MET诱导的DAT活性降低。 理解本 这一现象对药物的作用机制具有重要意义。 METH和其他精神兴奋剂，以及用于生理调节 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神经系统疾病的策略， 精神疾病

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.