In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine
María Isabel Colado, Esther O’shea, R Granados, Tracey K. Murray, A R Green
British Journal of Pharmacology July 1, 1997 DOI: 10.1038/sj.bjp.0701213 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Dark Agouti rats |
| Interventions | MDMA fenfluramine |
| Dose | 15 mg kg −1 (MDMA), 5 mg kg −1 (p-chloroamphetamine), 15 mg kg −1 (fenfluramine), 120 mg kg −1 (PBN) |
| Duration | At least 6 hours (acute free radical measurement), 7 days (neurotoxicity assessment) |
| Topics | MDMA Serotonin |
| Keywords | Microdialysis Striatum P-chloroamphetamine Pharmacology Hippocampus Dopamine Neurotoxicity 3,4-dihydroxyphenylacetic acid In vivo Cortex anatomy Biochemistry Homovanillic acid |
| Citations | 175 |
| Key findings | MDMA and PCA cause neurotoxic damage to serotonin neurons by increasing free radical formation, whereas fenfluramine induces damage through a different mechanism not involving free radicals. |
Abstract
Administration of 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) to several species results in a long lasting neurotoxic degeneration of 5‐hydroxytryptaminergic neurones in several regions of the brain. We have now investigated whether this degeneration is likely to be the result of free radical‐induced damage. Free radical formation can be assessed by measuring the formation of 2,3‐ and 2,5‐dihydroxybenzoic acid (2,3‐DHBA and 2,5‐DHBA) from salicylic acid. An existing method involving implantation of a probe into the hippocampus and in vivo microdialysis was modified and validated. Administration of MDMA (15 mg kg −1 , i.p.) to Dark Agouti (DA) rats increased the formation of 2,3‐DHBA (but not 2,5‐DHBA) for at least 6 h. Seven days after this dose of MDMA, the concentration of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) was reduced by over 50% in hippocampus, cortex and striatum, reflecting neurotoxic damage. There was no change in the concentration of dopamine or 3,4‐dihydroxyphenylacetic acid (DOPAC) in the striatum. p ‐Chloroamphetamine (PCA), another compound which produces a neurotoxic loss of cerebral 5‐HT content, when given at a dose of 5 mg kg −1 also significantly increased the formation of 2,3‐DHBA (but not 2,5‐DHBA) in the dialysate for over 4.5 h. post ‐injection starting 2 h after treatment. In contrast, fenfluramine administration (15 mg kg −1 , i.p.) failed to increase the 2,3‐DHBA or 2,5‐DHBA concentration in the dialysate. A single fenfluramine injection nevertheless also markedly decreased the concentration of 5‐HT and 5‐HIAA in the hippocampus, cortex and striatum seven days later. When rats pretreated with fenfluramine (15 mg kg −1 , i.p.) seven days earlier were given MDMA (15 mg kg −1 , i.p.) no increase in 2,3‐DHBA was seen in the dialysate from the hippocampal probe. This indicates that the increase in free radical formation following MDMA is occurring in 5‐HT neurones which have been damaged by the prior fenfluramine injection. Administration of the free radical scavenging agent α‐phenyl‐N‐tert‐butyl nitrone (PBN; 120 mg kg −1 , i.p.) 10 min before and 120 min after an MDMA (15 mg kg −1 , i.p.) injection prevented the acute rise in the 2,3‐DHBA concentration in the dialysate and attenuated by 30% the long term damage to hippocampal 5‐HT neurones (as indicated by a smaller MDMA‐induced decrease in both the concentration of 5‐HT and 5‐HIAA and also the binding of [ 3 H]‐paroxetine). These data indicate that a major mechanism by which MDMA and PCA induce damage to 5‐hydroxytryptaminergic neurones in rat brain is by increasing the formation of free radicals. These probably result from the degradation of catechol and quinone metabolites of these substituted amphetamines. In contrast, fenfluramine induces damage by another mechanism not involving free radicals; a proposal supported by some of our earlier indirect studies. We suggest that these different modes of action render untenable the recent suggestion that MDMA will not be neurotoxic in humans because fenfluramine appears safe at clinical doses.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 57
- The pharmacology of the acute hyperthermic response that follows administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats British Journal of Pharmacology 2002
- A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain British Journal of Pharmacology December 1, 2001
- Agony and ecstasy: a review of MDMA effects and toxicity European Psychiatry August 1, 2000
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
- Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT Synapse 2001
and 52 more in the library
Cites 23
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- 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. Journal of Pharmacology and Experimental Therapeutics September 1, 1987
- 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans Addiction May 1, 1994
- (±3,4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates JAMA July 1, 1988
- Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") Journal of Neuroscience August 1, 1995
and 18 more in the library