RECOVERY FROM METHAMPHETAMINE INDUCED NEURODEGENERATION

描述：（申请人摘要） 甲基苯丙胺 (METH) 是一种强效精神运动兴奋剂，具有很高的 对人类的潜在滥用。 冰毒也是一种神经毒素，影响 主要是大脑多巴胺（DA）和血清素系统。 滥用的可能性 冰毒及其神经毒性作用使冰毒成为一种重要的药物 人类长期使用可能会导致长期变化的观点 脑神经化学。 本提案中的实验将集中于 纹状体和细胞核突触前 DA 功能的体内变化 用神经毒性剂量的冰毒治疗的大鼠的伏隔核（NAc）。 的 实验将检验冰毒将产生持久的假设， DA 溢出和摄取的功能变化，其幅度和 这些变化的持续时间取决于动物的年龄，并且 这些变化可以通过最近发现的方法来预防或逆转 多巴胺能神经营养因子 胶质细胞系衍生神经营养因子 （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图（钙依赖性） 纹状体中 DA 和 DA 清除（摄取）的溢出以及对照 NAc 和冰毒治疗动物。 将进行体内微透析 确定基础水平，以及钾和 d-苯丙胺诱发（钙 DA 和 DA 代谢物的独立）溢出，以确认和扩展 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 神经毒性剂量的冰毒后大鼠的溢出和吸收。 第三个 一组实验将检查 METH 治疗期间大鼠的年龄 影响 DA 溢出和吸收变化的幅度和持续时间。 影响的严重程度和恢复时间将在 青年（3-4 个月大）和中年（12 个月大）动物。 在 第四组实验 GDNF，一种强效多巴胺能神经营养剂 药剂，将直接注射到年轻人的大脑中， 中年大鼠在神经毒性之前和之后的不同时间点 冰毒剂量。 GDNF 减少或预防 METH 诱发的能力 突触前 DA 功能的变化以及加速能力 恢复，将通过体内电化学和微透析进行监测。 组织 DA 水平将在所有实验结束时确定为 神经毒性损伤程度的衡量标准。 希望 从这些实验中获得的信息将增加我们的理解 与滥用冰毒相关的可能的长期后果。

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.