Neurotoxicity of MDMA and Related Compounds: Anatomic Studiesa

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.

Study at a glance

Abstract

The cytotoxic effects of amphetamine derivatives were studied by immunocytochemistry to identify the cellular compartments affected by these drugs, to obtain morphologic evidence of neuronal degeneration, and to assess the potential for regeneration. The substituted amphetamines, MDA, MDMA, PCA, and fenfluramine, all release serotonin and cause acute depletion of 5-HT from most axon terminals in forebrain. (1) Unequivocal signs of axon degeneration were seen at 36-48 hour survivals: 5-HT axons exhibited increased caliber, huge, swollen varicosities, fragmentation, and dilated proximal axon stumps. (2) Fine 5-HT axon terminals were persistently lost after drug administration, while beaded axons and raphe cell bodies were spared. These two types of 5-HT axons, which arise from separate raphe nuclei and form distinct ascending projections, are differentially vulnerable to psychotropic drugs. (3) From 2-8 months after treatment, there was progressive serotonergic re-innervation of neocortex along a fronto-occipital gradient. Longitudinal 5-HT axons grew into layers I and VI from rostral to caudal, before sprouting into middle cortical layers; this bilaminar pattern of growth simulates perinatal development of 5-HT innervation. This study demonstrates differential vulnerability of 5-HT projections, evidence for axonal degeneration, and sprouting of 5-HT axons leading to re-innervation of forebrain. While the sprouting axons are anatomically similar to the type that was damaged, it is not known whether a normal pattern of innervation is re-established.