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 退化，应该作为一个模型系统，研究机制， 大脑中的神经元兴奋性毒性。伊波替尼，一种致幻吲哚 已被提议用于治疗药物成瘾的生物碱， 选择性变性的浦肯野细胞在旁索条纹内 小脑蚓部我们假设这种现象不是通过 通过药物对浦肯野细胞的直接作用：毒性是由于 而不是ibogain诱导的兴奋性传入激活， 小脑和神经元损伤的独特模式是由 小脑回路的独特结构我们将测试 伊波加因诱导的神经变性是由过量的 浦肯野细胞活性和由于释放引起的胞质Ca 2+蓄积 内源性兴奋性氨基酸从攀缘纤维和平行 纤维突触终末。该项目将（I）描述解剖 伊博替尼诱发小脑变性的特征;（2）确定 无论退化是由于持续的浦肯野细胞活性， 通过特定的小脑传入神经释放兴奋性氨基酸; （3）分析了iboclavin兴奋下位神经元的机制 橄榄色导致浦肯野细胞变性。康贝特人将以 不同谷氨酸受体亚型在介导 伊博替林的兴奋性毒性作用。诱导的神经元激活 将通过测量c-Fos的诱导来评估伊波替尼，并通过 神经元活动的其它参数（热休克蛋白诱导和 细胞色素氧化酶活性）。对这一模型系统的分析应有助于 阐明表现震颤和共济失调相关的临床疾病 小脑变性，并加强我们对内源性 兴奋性毒性机制如果伊波替尼能调节其抗成瘾作用 主要是通过小脑，这表明小脑可能 在药物成瘾的病因学中很重要， 这是旨在评估小脑在大脑中作用的研究的基础。 获得成瘾行为。这一职能可能反映了 小脑在学习中的作用及其对脑干的强大输出 网状结构澄清伊波加因诱导的变性应 有助于更好地理解成瘾机制， 合理使用伊波替尼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.