RECOVERY FROM METHAMPHETAMINE INDUCED NEURODEGENERATION

描述：(申请人摘要) 甲基苯丙胺(冰毒)是一种有效的精神运动兴奋剂，具有很高的 有可能在人类身上受到虐待。冰毒也是一种神经毒素，影响 主要是脑多巴胺(DA)和5-羟色胺系统。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 认为人类长期使用可能会导致长期的变化的观点 脑神经化学。这项计划中的实验将集中在 纹状体和核内突触前DA功能的活体变化 神经毒性剂量的冰毒处理大鼠的伏隔核(NAC)。这个 实验将检验冰毒将产生持久的， DA溢出和摄取的功能变化，即大小和 这些变化的持续时间将取决于动物的年龄，以及 这些变化可以通过最近发现的 多巴胺能神经营养因子胶质细胞源性神经营养因子 (GDNF)。最初的一组实验将确定短期(1 1周)冰毒处理对大鼠DA溢出和摄取的影响。活体内 电化学将被用来定位钾诱导的(钙依赖) 对照组纹状体和NAc中DA和DA清除(摄取)的溢出 以及冰毒处理过的动物。将进行体内微透析，以 测定基础水平，以及钾和d-苯丙胺诱发的(钙 独立)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恢复的时间进程(1周至1年)的技术 大鼠在神经毒性剂量冰毒后的溢出和摄取。第三 一系列实验将检验大鼠在冰毒治疗期间的年龄 影响DA溢出和摄取变化的幅度和持续时间。 影响的严重性和恢复的时间进程将在#年进行 幼年(3-4个月大)和中年(12个月大)动物。在……里面 第四组实验GDNF，一种有效的多巴胺能神经营养物质 将被直接注射到年轻人的大脑中 中年大鼠神经毒性作用前后不同时间点的变化 剂量的冰毒。GDNF减少或预防冰毒诱导的能力 突触前DA功能的变化，以及加速的能力 恢复情况，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测定为 一种神经毒性损伤程度的测量方法。希望这一天 从这些实验中得到的信息将增加我们的理解 与冰毒滥用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.