MOLECULAR MECHANISMS OF IBOGAINE ACTIVITY

这是一个临床医生科学家发展奖的申请。 伊波替尼是一种致幻吲哚生物碱， 戒毒治疗它也会产生选择性退化 小脑蚓部的浦肯野细胞 系统性地对老鼠。伊波替尼引起神经元 损害没有得到证实。我们建议，像结构上一样， 与吲哚类似，强烈激活下丘脑神经元 橄榄核，导致释放过量的a 谷氨酸样兴奋性氨基酸神经递质，导致 浦肯野细胞的兴奋性毒性变性。 本提案的目标是（1）描述 通过检查细胞骨架蛋白和 神经元钙调节机制在连续的时间间隔后， （2）确定神经元的时间关系 损伤和胶质细胞活化以及胶质细胞的可能作用 一氧化氮的产生;（3）测试伊博替林引起的假设 兴奋性毒性浦肯野细胞变性通过病理改变 细胞内钙调节和（4）确定电生理 伊波替尼对培养的浦肯野细胞和下橄榄细胞的影响。 伊博替林引起的细胞学和分子生物学变化分析 深入了解兴奋毒性神经元变性的机制 并可能导致适用于许多形式的 中枢神经系统损伤评价伊波替尼的作用机制- 神经元的诱导激活可能会导致更好地理解 致幻药物和成瘾行为的神经机制， 潜在地提供改进的抗成瘾疗法。

This is a request for a Scientist Development Award for Clinicians. Ibogaine is an hallucinogenic indole alkaloid that has been proposed for treatment against drug addiction. It also produces selective degeneration of Purkinje cells in the vermis of the cerebellum when administered systemically to rats. The mechanism by which ibogaine causes neuronal damage is not established. We propose that ibogaine, like the structurally similar indole harmaline, intensely activates neuronS in the inferior olivary nucleus, leading to the release of excess quantities of a glutamate-like excitatory amino acid neurotransmitter, resulting in excitotoxic degeneration of Purkinje cells. The goals of this proposal are to (1) characterize the evolution of neuronal degeneration through examination of cytoskeletal proteins and neuronal calcium regulatory mechanisms at successive intervals after ibogaine treatment; (2) determine the temporal relationship of neuronal damage and glial activation and the possible contribution of glial cell nitric oxide production; (3) Test the hypothesis that ibogaine causes excitotoxic Purkinje cell degeneration through pathologic alterations of intracellular calcium regulation and (4) determine the electrophysiologic effects of ibogaine on cultured Purkinje and inferior olive cells. Analysis of cytologic and molecular changes induced by ibogaine should provide insight into the mechanisms of excitotoxic neuronal degeneration and may lead to therapeutic interventions applicable to many forms of central nervous system injury. Assessment of the mechanisms of ibogaine- induced activation of neurons may lead to better understanding of the neuronal mechanisms underlying hallucinogenic drugs and addictive behavior, potentially affording improved anti-addictive therapies.