MOLECULAR MECHANISMS OF IBOGAINE ACTIVITY

这是对临床医生的科学家发展奖的请求。 伊波甘是一种致幻的吲哚生物碱，已被提出用于 戒毒治疗。它也会产生选择性的退化。 给药时小脑蠕虫内浦肯野细胞的数量 对老鼠来说是系统性的。伊博加因引起神经细胞病变的机制 损害尚未确定。我们认为ibogaine，就像结构上的 类似的吲哚骆驼蓬碱能强烈激活下丘脑的神经元 橄榄核，导致释放过量的 谷氨酸样兴奋性氨基酸神经递质，导致 浦肯野细胞兴奋性毒性变性。 本提案的目标是(1)描述 通过检查细胞骨架蛋白和神经元变性 脑缺血后连续间期神经元钙调节机制的研究 Ibogaine治疗；(2)确定神经元的时间关系 神经胶质细胞的损伤和激活及其可能的作用 一氧化氮的产生；(3)检验伊波甘引起的假说 兴奋性中毒性浦肯野细胞变性的病理改变 细胞内钙调节和(4)确定电生理。 伊波甘对培养的浦肯野和下橄榄细胞的影响。 伊博甘诱导的细胞学和分子生物学变化分析 提供对兴奋性毒性神经元变性机制的洞察 并可能导致适用于多种形式的治疗干预 中枢神经系统损伤。伊波甘的作用机制评估-- 神经元的诱导激活可能有助于更好地理解 致幻药物和成瘾行为背后的神经机制， 有可能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.