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.
