Immunocytochemical evidence for serotonergic neurotoxicity of N-ethyl-methylenedioxyamphetamine (MDE)

N-ethyl-3,4-methylenedioxyamphetamine (MDE) is one of a group of substituted amphetamines which have effects on several serotonergic markers such as tissue levels of serotonin and activity of tryptophan hydroxylase. In this study we have compared its effects on the rat brain with those of p-chloroamphetamine (PCA) using serotonin immunocytochemistry with a primary 5-HT antibody and a secondary avidin-biotin-HRP antibody. Two weeks after multiple (40 mg/kg x 8), but not single, injections of MDE there was a pronounced reduction in the number of serotonin-immunoreactive axons seen. This reduction was most marked in areas innervated extensively by serotonergic axons with varicosities of the fine type (e.g., posterior cerebral cortex and area CA1 of hippocampus). The reduction was quantitatively less than but qualitatively similar to that produced by a single dose of PCA (10 mg/kg). In material from short (3 day) survival animals, a large number of morphologically highly abnormal forms could be seen, suggestive of degenerating axons. A parallel series of sections prepared using tyrosine hydroxylase immunocytochemistry showed no differences between saline controls and PCA- or MDE-treated animals. We conclude that multiple systemic injections of MDE reduce the number of serotonin-immunoreactive fibers in the rat brain 2 weeks after treatment.