AGING AND VULNERABILITY TO 6HYDROXYDOPAMINE

这份申请来自一位新的研究人员，旨在进行研究 主题16-感觉和运动加工。黑质纹状体多巴胺(DA) 大脑系统已被证明在控制中起着重要作用 运动的力量。黑质纹状体多巴胺神经元逐渐丧失 在人类正常衰老期间，许多老年人表现出一种或 帕金森氏症的症状更多，而不是得了这种病。 这可能表明，有帕金森症状的老年人可能 黑质纹状体DA的丢失比正常情况下更严重。尽管这项事业 对于老年人正常发生的中脑DA细胞的丢失 尚不清楚，动物研究表明，年龄较大的DA神经元 动物可能更容易受到各种神经毒素的影响。 本申请中的实验的目的也是 确定老年动物的黑质纹状体DA系统是否更多 对多巴胺能毒素6的神经毒性作用敏感 羟基多巴胺(6-OHDA)，并开始建立衰老模型 部分缺乏多巴胺的大脑。它被假设为 老年大鼠黑质纹状体DA系统对 6-OHDA对小鼠黑质纹状体DA系统的神经毒性作用 老鼠。最初的一系列实验将产生一种剂量- 幼年成年动物对多巴胺耗竭效应的反应曲线 6-OHDA。雄性Fischer-344只大鼠(4个月大)将被给予一只， 右侧脑室注射6-羟基多巴胺。这个 检查剂量分别为0、50、100、150和200杯6-OHDA 注射。三周后，将测量多巴胺和代谢物水平 在纹状体、伏隔核、黑质和内侧 前额叶皮质。根据这些实验的结果，一剂 6-OHDA可将纹状体DA水平降低约50% 在幼年成年大鼠中给三岁的大鼠；4个月，18 几个月，24个月大。三周后，这些老鼠将成为 将进行麻醉和活体电化学实验 在大脑的两边绘制出钾诱导的溢出 DA，以及随后纹状体中DA的清除。紧随其后的是 实验，将测量死后DA和代谢物的水平 以确定6-OHDA对整个组织的消耗程度。这个 这些实验的结果将有助于确定黑质纹状体 DA系统对衰老大鼠脑内神经毒性更敏感 6-OHDA的影响，并将开始确定在 衰老与年轻大脑中突触前多巴胺能功能的比较 作为对神经毒性侮辱的回应。

This application is from a new investigator and is aimed at research topic 16 - sensory and motor processing. The nigrostriatal dopamine (DA) system of the brain has been shown to play a major role in the control of movement. A gradual loss of nigrostriatal dopamine neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkinson's disease without having the disease. This may indicate that older people that have parkinsonian signs may have a greater than normal loss of nigrostriatal DA. Although the cause for the normally occurring loss of midbrain DA cells in the elderly is not known, animal studies have indicated that the DA neurons of older animals may be more vulnerable to the effects of various neurotoxins. The purpose of the experiments in the present application is too determine if the nigrostriatal DA system of older animals is more sensitive to the neurotoxic effects of the dopaminergic toxin 6- hydroxydopamine (6-OHDA), and to begin to develop a model of the aging brain that is partially depleted of DA. It is hypothesized that the nigrostriatal DA system in older rats will be more sensitive to the neurotoxic effects of 6-OHDA than the nigrostriatal DA system of younger rats. The initial set of experiments will be to generate a dose- response curve in young adult animals for the DA-depleting effects of 6-OHDA. Male Fischer-344 rats (4 months old) will be given a single, unilateral injection of 6-OHDA into the right lateral ventricle. The doses examined will be 0, 50, 100, 150, and 200 mug of 6-OHDA per injection. Three weeks later, DA and metabolite levels will be measured in the striatum, nucleus accumbens, substantia nigra, and medial prefrontal cortex. Based on the results of these experiments, a dose of 6-OHDA that reduces striatal DA levels by approximately 50 percent in young adult rats will given to rats of three ages; 4 months, 18 months, and 24 months old. Three weeks later the rats will be anesthetized and in vivo electrochemistry experiments will be carried out on both sides of the brain to map out potassium-evoked overflow of DA, and subsequent clearance of DA, in the striatum. Following the experiments, post-mortem levels of DA and metabolites will be measured to determine the extent of whole tissue depletion by the 6-OHDA. The results of these experiments will help determine if the nigrostriatal DA system of the aging rat brain is more susceptible to the neurotoxic effects of 6-OHDA, and will begin to determine possible differences in presynaptic dopaminergic functioning in the aging versus younger brain in response to a neurotoxic insult.