Amphetamine derivatives such as MDA, MDMA, PCA, and fenfluramine cause serotonin (5-HT) release and acute depletion of 5-HT from most axon terminals in the forebrain. Within 36–48 hours, signs of axon degeneration appear, including swollen varicosities and fragmentation. Fine 5-HT axon terminals are persistently lost, while beaded axons and raphe cell bodies are spared, indicating differential vulnerability of two types of 5-HT axons arising from separate raphe nuclei. Over 2–8 months, progressive serotonergic re-innervation of the neocortex occurs along a fronto-occipital gradient, with longitudinal axons growing into layers I and VI before sprouting into middle layers, resembling perinatal development. It is unknown whether a normal innervation pattern is re-established.
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.