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Journal of Neuroscience, Vol 8, 2788-2803, Copyright © 1988 by Society for Neuroscience
Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity
E O'Hearn, G Battaglia, EB De Souza, MJ Kuhar and ME Molliver
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
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.
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