RECOVERY FROM METHAMPHETAMINE INDUCED NEURODEGENERATION

描述：（申请人摘要） 甲基苯丙胺（METH）是一种强效的精神兴奋剂， 在人类中滥用的可能性。 METH也是一种神经毒素， 主要是脑多巴胺（DA）和血清素系统。 的滥用潜力 甲基苯丙胺及其神经毒性作用使其成为一种重要的药物， 人类长期使用可能导致长期变化的观点， 脑神经化学 本提案中的实验将集中在 纹状体和核中突触前DA功能的体内变化 神经毒性剂量的METH处理的大鼠的NAc。 的 实验将测试METH将产生持久， DA溢出和摄取的功能变化， 这些变化的持续时间将取决于动物的年龄， 这些变化可以通过最近发现的 多巴胺能神经营养因子 （GDNF）。 最初的一组实验将确定短期（1 周）METH治疗对大鼠DA溢出和摄取的影响。 体内 电化学将用于绘制钾诱发（钙依赖性） 对照组纹状体和NAc中DA溢出和DA清除（摄取） 和METH处理的动物。 将进行体内微透析， 确定基础水平，钾和d-苯丙胺诱发（钙 DA和DA代谢物的溢出，以确认和延长 电化学研究 第二组实验将使用相同的 检查DA恢复时间进程（1周至1年）的技术 溢出和摄取的大鼠神经毒性剂量的甲基。 第三 一组实验将检查在METH治疗期间大鼠的年龄如何 影响DA溢出和摄取变化的幅度和持续时间。 影响的严重程度和恢复的时间过程将在 年轻成年（3-4月龄）和中年（12月龄）动物。 在 第四组实验GDNF，一种强效多巴胺能神经营养剂 药剂，将被直接施用到年轻成年人的大脑中， 中年大鼠在神经毒性之前和之后的不同时间点， 剂量的甲基。 GDNF减少或阻止MET诱导的肿瘤细胞凋亡的能力， 突触前DA功能的变化，以及加速突触前DA功能的能力， 恢复，将用体内电化学和微透析监测。 组织DA水平将在所有实验结束时测定， 神经毒性损伤程度的量度。 希望广大 从这些实验中获得的信息将增加我们对 与滥用甲基苯丙胺相关的长期后果。

DESCRIPTION: (Applicant's Abstract) Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin, affecting primarily brain dopamine (DA) and serotonin systems. The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term changes in brain neurochemistry. The experiments in this proposal will focus on in vivo changes in presynaptic DA function in the striatum and nucleus accumbens (NAc) of rats treated with neurotoxic doses of METH. The experiments will test the hypotheses that METH will produce long-lasting, functional changes in DA overflow and uptake, that the magnitude and duration of these changes will be dependent on the age of the animals, and that these changes can be prevented or reversed by the recently discovered dopaminergic neurotrophic factor glial cell line derived neurotrophic factor (GDNF). The initial set of experiments will determine the short-term (1 week) effects of METH treatment on DA overflow and uptake in rats. In vivo electrochemistry will be used to map potassium-evoked (calcium dependent) overflow of DA and DA clearance (uptake) in the striatum and NAc of control and METH treated animals. In vivo microdialysis will be carried out to determine basal levels, and potassium-and d-amphetamine-evoked (calcium independent) overflow of DA and DA metabolites to confirm and extend the electrochemical studies. The second set of experiments will use the same techniques to examine the time course (1 week to 1 year) for recovery of DA overflow and uptake in rats following neurotoxic doses of METH. The third set of experiments will examine how the age of the rat during METH treatment affects the magnitude and duration of changes in DA overflow and uptake. The severity of effects and time course for recovery will be followed in young adult (3-4 months old) and middle-aged (12 months old) animals. In the fourth set of experiments GDNF, a potent dopaminergic neurotrophic agent, will be administered directly into the brain of young adult and middle-aged rats at various time points prior to, and after, neurotoxic doses of METH. The ability of GDNF to reduce or prevent METH-induced changes in presynaptic DA function, and the ability to accelerate recovery, will be monitored with in vivo electrochemistry and microdialysis. Tissue DA levels will be determined at the conclusion of all experiments as a measure of the extent of the neurotoxic lesions. It is hoped that the infor-mation derived from these experiments will increase our understanding of possible long-term consequences associated with METH abuse.