MOLECULAR MECHANISMS OF IBOGAINE ACTIVITY

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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.