The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

Ibogaine, an alkaloid causing hallucinations, tremor, and ataxia, leads to degeneration of Purkinje cells in the rat cerebellum in narrow parasagittal bands, accompanied by activated glial cells. Harmaline, a related alkaloid that excites inferior olivary neurons, produces the same pattern. The authors hypothesized that ibogaine excites inferior olive neurons, causing sustained glutamate release at climbing fiber synapses, mediating excitotoxic Purkinje cell death. Pharmacologically ablating the inferior olive in rats with 3-acetylpyridine before ibogaine administration almost completely prevented Purkinje cell degeneration and glial activation. This demonstrates ibogaine is not directly toxic but depends on an intact olivocerebellar projection. The unique circuitry of this projection provides high synaptic security, making Purkinje cells vulnerable to excitotoxic injury.

Study at a glance

Abstract

Ibogaine, an indole alkaloid that causes hallucinations, tremor, and ataxia, produces cerebellar neurotoxicity in rats, manifested by degeneration of Purkinje cells aligned in narrow parasagittal bands that are coextensive with activated glial cells. Harmaline, a closely related alkaloid that excites inferior olivary neurons, causes the same pattern of Purkinje cell degeneration, providing a clue to the mechanism of toxicity. We have proposed that ibogaine, like harmaline, excites neurons in the inferior olive, leading to sustained release of glutamate at climbing fiber synapses on Purkinje cells. The objective of this study was to test the hypothesis that increased climbing fiber activity induced by ibogaine mediates excitotoxic Purkinje cell degeneration. The inferior olive was pharmacologically ablated in rats by a neurotoxic drug regimen using 3-acetylpyridine, and cerebellar damage attributed to subsequent administration of ibogaine was analyzed using immunocytochemical markers for neurons and glial cells. The results show that ibogaine administered after inferior olive ablation produced little or no Purkinje cell degeneration or glial activation. That a lesion of the inferior olive almost completely prevents the neurotoxicity demonstrates that ibogaine is not directly toxic to Purkinje cells, but that the toxicity is indirect and dependent on integrity of the olivocerebellar projection. We postulate that ibogaine-induced activation of inferior olivary neurons leads to release of glutamate simultaneously at hundreds of climbing fiber terminals distributed widely over the surface of each Purkinje cell. The unique circuitry of the olivocerebellar projection provides this system with maximum synaptic security, a feature that confers on Purkinje cells a high degree of vulnerability to excitotoxic injury.