AGING AND VULNERABILITY TO 6HYDROXYDOPAMINE

衰老和对 6 羟基多巴胺的脆弱性

• 批准号: 2751212
• 负责人: WAYNE A CASS
• 金额: $ 7.29万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2751212
• 关键词: 6 hydroxydopamine; aging; brain metabolism; corpus striatum; developmental neurobiology; disease /disorder model; dopamine; drug administration rate /duration; high performance liquid chromatography; laboratory rat; model design /development; neurotoxicology; nucleus accumbens; potassium channel; prefrontal lobe /cortex; substantia nigra

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.

这个应用程序是从一个新的调查员，旨在研究 主题16 -感觉和运动处理。黑质纹状体多巴胺（DA） 大脑的一个系统已经被证明在控制中起着重要的作用。 的运动。 黑质纹状体多巴胺神经元逐渐丧失， 在人类的正常衰老过程中，许多老年人表现出一种或 更多的帕金森病的迹象，而没有这种疾病。 这可能表明有帕金森症状的老年人可能 黑质纹状体DA的损失比正常情况下更大。虽然原因 老年人中脑DA细胞的正常丢失， 动物研究表明，老年人的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 对多巴胺能毒素6- 羟基多巴胺（6-OHDA），并开始开发衰老模型， 大脑中的DA部分耗尽。据推测， 老年大鼠的黑质纹状体DA系统将对 6-OHDA的神经毒性作用比年轻的黑质纹状体DA系统 大鼠 最初的实验将产生一个剂量- 年轻成年动物中DA消耗效应的反应曲线 6-OHDA。 雄性Fischer-344大鼠（4月龄）将给予单次， 将6-OHDA单侧注射到右侧脑室。 的 检查的剂量为0、50、100、150和200 μ g 6-OHDA/ 注射 三周后，将测量DA和代谢物水平 在纹状体、中脑核、黑质和内侧核中， 前额皮质 根据这些实验的结果， 6-OHDA可使纹状体DA水平降低约50% 在年轻的成年大鼠将给予三个年龄的大鼠; 4个月，18 一个月，一个24个月。 三个星期后，老鼠将 将进行麻醉和在体电化学实验 在大脑两侧绘制出钾诱发的溢出， DA，以及随后的DA清除。 后 在实验中，将测量DA和代谢物的死后水平 以确定6-OHDA对整个组织的消耗程度。 的 这些实验的结果将有助于确定黑质纹状体是否 衰老大鼠脑内DA系统对神经毒素更敏感 6-OHDA的影响，并将开始确定可能的差异， 老年人与年轻人大脑中的突触前多巴胺能功能 以应对神经毒性损伤。