MECHANISM OF IBOGAINE INDUCED PURKINJE CELL DEGENERATION

这个项目将描述一个新发现的浦肯野细胞的例子 退行性变应作为研究其机理的模型系统 大脑中的神经元兴奋毒性。Ibogaine，一种致幻吲哚 已被提议用于治疗药物成瘾的生物碱，导致 矢状面旁横纹中浦肯野细胞的选择性变性 小脑蠕虫。我们假定这一现象不是居中的。 通过药物对浦肯野细胞的直接作用：毒性是由于 取而代之的是伊波甘诱导的兴奋性传入神经的激活 小脑和神经元损伤的独特模式是由 小脑回路的独特组织。我们将测试 伊波甘诱导的神经退行性变是过量的假说 浦肯野细胞活性与胞内钙离子释放的蓄积 攀爬纤维和平行纤维中内源兴奋性氨基酸的含量 纤维突触终末。这个项目将(I)描述解剖结构。 伊波甘所致小脑变性的特点；(2)测定 变性是否由持续的浦肯野细胞活动引起 通过特殊的小脑传入释放兴奋性氨基酸； (3)分析ibogaine兴奋下层的机制。 橄榄导致浦肯野细胞退化。我们将确定 不同谷氨酸受体亚型在介导大鼠脑缺血再灌注损伤中的作用 伊波甘的兴奋毒性作用。大鼠脑内神经细胞的激活作用 伊博加因将通过测量c-Fos的诱导进行评估，并通过 神经元活动的其他参数(热休克蛋白诱导和 细胞色素氧化酶活性)。对这一模式系统的分析应该有助于 阐明与震颤和共济失调相关的临床疾病 与小脑退行性变增强我们对内源性的认识 兴奋毒性机制。如果伊波加因调节其抗成瘾作用 主要通过小脑，这表明小脑可能 在药物成瘾的病因学中很重要，其结果可能形成 一项旨在评估小脑在脑内的作用的研究基础 成瘾行为的习得。这一功能可能反映了 学习中的小脑及其对脑干的强大输出 网状结构。澄清伊波甘诱导的退变应 有助于更好地理解成瘾机制，并 合理使用伊波甘及相关药物治疗成瘾。

This project will characterize a newly discovered example of Purkinje cell degeneration that should serve as a model system to study mechanisms of neuronal excitotoxicity in the brain. Ibogaine, an hallucinogenic indole alkaloid that has been proposed for treatment of drug addiction, causes selective degeneration of Purkinje cells in parasagittal stripes within the cerebellar vermis. We postulate that this phenomenon is not mediated by a direct action of the drug upon Purkinje cells: the toxicity is due instead to ibogaine-induced activation of excitatory afferents to cerebellum and the distinctive pattern of neuronal damage is determined by the unique organization of cerebellar circuitry. We will test the hypothesis that ibogaine-induced neurodegeneration results from excessive Purkinje cell activity and accumulation of cytosolic Ca2+ due to release of endogenous excitatory amino acids from climbing fiber and parallel fiber synaptic terminals. This project will (I) characterize the anatomic features of cerebellar degeneration induced by ibogaine; (2) determine whether the degeneration results from sustained Purkinje cell activity due to release of excitatory amino acids by particular cerebellar afferents; and (3) analyze the mechanisms by which ibogaine excites the inferior olive leading to Purkinje cell degeneration. We will determine the contribution of different glutamate receptor subtypes in mediating the excitotoxic effects of ibogaine. The neuronal activation induced by ibogaine will be assessed by measuring induction of c-Fos and confirmed by other parameters of neuronal activity (Heat Shock Protein induction and Cytochrome Oxidase activity). Analysis of this model system should help to elucidate clinical disorders which manifest tremor and ataxia associated with cerebellar degeneration and enhance our understanding of endogenous excitotoxic mechanisms. If ibogaine mediates its anti-addictive effects primarily via the cerebellum, this would suggest that the cerebellum may be important in the etiology of drug addiction and the results could form a basis for studies designed to evaluate a role for the cerebellum in the acquisition of addictive behavior. This function may reflect the role of the cerebellum in learning and its powerful output to the brainstem reticular formation. Clarification of ibogaine-induced degeneration should contribute to a better understanding of addictive mechanisms and to rational use of ibogaine and related drugs in treating addiction.