5,6-Dihydroxytryptamine, a serotonergic neurotoxin, is formed endogenously in the rat brain

Methamphetamine (MA) in high doses produces long-term toxic effects on the serotonergic system in the rat brain, including depletions of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid and reductions in 5-HT reuptake and tryptophan hydroxylase activity. In this study, the formation of 5,6-dihydroxytryptamine (5,6-DHT), a serotonergic neurotoxin, was observed in the rat hippocampus after a single 100 mg/kg injection of MA. The 5,6-DHT was detected by reverse-phase high-performance liquid chromatography with electrochemical detection in tissue samples taken 0.5-4 h after MA administration; the highest levels of 5,6-DHT (0.032 ng/mg wet tissue) were detected at 1 h. Following administration of MA, 5-HT was also depleted in the neocortex, but 5,6-DHT was not detected as frequently in this brain region as in the hippocampus. Comparisons were made between the long-term hippocampal 5-HT depletions seen either after an injection of MA or after intraventricular 5,6-DHT infusions and the levels of 5,6-DHT measured in the hippocampus shortly after each treatment. The amount of 5,6-DHT produced after MA administration appears to be adequate to cause the observed long-term 5-HT depletions. We suggest that 5,6-DHT formed from 5-HT may mediate the neurotoxic effects of MA on serotonergic nerve terminals.