N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats.

The present study examined the effect of N-tert-butyl-alpha-phenylnitrone (PBN) on 3,4-methylenedioxmathamphetamine (MDMA)-induced depletion of serotonin in the CNS. Rats were treated with two concurrent injections of MDMA (20 mg/kg, s.c.), PBN (50-400 mg/kg dissolved in ethanol, 50 mg/ml of 25% ethanol, i.p.), saline or 25% ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later. Rectal temperature was measured prior to and hourly following the drug injection for 5 h. Monoamine levels in the tissue were measured by HPLC. Density of the 5-HT transporters was assayed by [3H]paroxetine binding. Rectal temperature of rats increased after MDMA, decreased after PBN, ethanol, PBN plus ethanol, and MDMA plus ethanol, and was not significantly altered after MDMA plus PBN. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, striatum, and brain stem of rats decreased significantly after MDMA or MDMA plus ethanol, but not after MDMA plus PBN, PBN plus ethanol (PBN dissolved in ethanol), or ethanol as compared to the saline controls. Levels of 5-HT and 5-HIAA in the brain tissues of rats treated with MDMA plus PBN were elevated as compared to those treated with MDMA plus saline. Similar results were observed in the density of 5-HT transporters in the frontal cortex and hippocampus. These results indicate that scavenging of free radicals of MDMA metabolites or reactive oxygen species by PBN and with lowering of body temperature protected against MDMA-induced depletion of serotonin transmitter.