The
indole alkaloids ibogaine and
harmaline are
beta-carboline derivatives that cause both
hallucinations and
tremor. Reports that
ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of
opiate and
cocaine addiction. In this study,
ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of
ibogaine have been proposed. We recently found that
ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. Based on those findings, the present study was conducted to investigate whether
ibogaine may cause neuronal injury or degeneration. The results demonstrate that,
after treatment with
ibogaine or
harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal
proteins microtubule-associated
protein 2 and
calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced
silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both
ibogaine and
harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an
excitatory amino acid from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells.