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

Esther O’shea, Laura Orío, Isabel Escobedo, Verónica Sánchez, Jorge Camarero, Alfred Richard Green, María Isabel Colado

British Journal of Pharmacology June 12, 2006 DOI: 10.1038/sj.bjp.0706783 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Observational cohort Peer reviewed
Population Male DA rats
Intervention MDMA
Dose 12.5 mg kg−1, i.p.
Duration Up to 32 weeks
Topics MDMA Serotonin
Keywords Neurotoxicity Term time 5-HT Receptor Pharmacology Biochemistry
Citations 57
Key findings MDMA produces long-term damage to serotoninergic neurons in rat forebrain, but tissue serotonin concentration may overestimate the extent of neurotoxic damage.

Abstract

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. 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. 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. 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. 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

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study Year Design Participants
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats 1998 Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA 1999 Observational cohort

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MDMA Serotonin