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, [ 3 H]‐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 [ 3 H]‐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 [ 3 H]‐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 [ 3 H]‐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°C prevented the reduction in [ 3 H]‐paroxetine binding and hydroxylase activity observed in rats housed at 22°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.British Journal of Pharmacology (2006) 148 , 778–785. doi: 10.1038/sj.bjp.0706783