MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature.

1. 3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') decreases the 5-HT concentration, [3H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase. We have now evaluated the validity of these parameters as a reflection of neurotoxicity. 2. Male DA rats were administered MDMA (12.5 mg kg(-1), i.p.) and killed up to 32 weeks later. 5-HT content and [3H]-paroxetine binding were measured in the cortex, hippocampus and striatum. Parallel groups of treated animals were administered NSD-1015 for determination of in vivo tryptophan hydroxylase activity and 5-HT turnover rate constant. 3. Tissue 5-HT content and [3H]-paroxetine binding were reduced in the cortex (26-53%) and hippocampus (25-74%) at all time points (1, 2, 4, 8 and 32 weeks). Hydroxylase activity was similarly reduced up to 8 weeks, but had recovered at 32 weeks. The striatal 5-HT concentration and [3H]-paroxetine binding recovered by week 4 and hydroxylase activity after week 1. In all regions, the reduction in 5-HT concentration did not result in an altered 5-HT synthesis rate constant. 4. Administering MDMA to animals when housed at 4 degrees C prevented the reduction in [3H]-paroxetine binding and hydroxylase activity observed in rats housed at 22 degrees C, but not the reduction in 5-HT concentration. 5. These data indicate that MDMA produces long-term damage to serotoninergic neurones, but this does not produce a compensatory increase in 5-HT synthesis in remaining terminals. It also highlights the fact that measurement of tissue 5-HT concentration may overestimate neurotoxic damage.