The psychotropic amphetamine derivatives 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) have been used for recreational and therapeutic purposes in man. In rats, these drugs cause large reductions in brain levels of serotonin (5-HT). This study employs immunocytochemistry to characterize the neurotoxic effects of these compounds upon monoaminergic neurons in the rat brain. Two weeks after systemic administration of MDA or MDMA (20 mg/kg, s.c., twice daily for 4 d), there is profound loss of serotonergic (5-HT) axons throughout the forebrain; catecholamine axons are completely spared. Regional differences in drug toxicity are exemplified by partial sparing of 5-HT axons in hippocampus, lateral hypothalamus, basal forebrain, and in some areas of neocortex. The terminals of 5-HT axons are selectively ablated, while axons of passage and raphe cell bodies are spared. Thickened preterminal fibers exhibit increased staining due to damming-up of neurotransmitter and other axonal constituents. Fine 5-HT axon terminals are extremely vulnerable to these drugs, whereas terminal-like axons with large varicosities survive, raising the possibility that some 5-HT axons may be resistant to the neurotoxic effects. At short survivals, visualization of greatly swollen, fragmented 5-HT axons provides anatomic evidence for degeneration of 5-HT projections. The results establish that MDA and MDMA produce structural damage to 5-HT axon terminals followed by lasting denervation of the forebrain. Both drugs have similar effects, but MDA produces a greater reduction of 5-HT axons than does MDMA at the same dosage. The selective degeneration of 5-HT axons indicates that these drugs may serve as experimental tools to analyze the organization and function of 5-HT projections. Caution should be exercised until further studies determine whether these compounds may be hazardous in man.
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.
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