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

• Published in: British journal of pharmacology 1997-07, Vol.121 (5), p.889-900
• Main Authors: Colado, M I, O'Shea, E, Granados, R, Murray, T K, Green, A R
• Format: Article
• Language: English
• Subjects: 2,3‐dihydroxybenzoic acid; 3,4‐Methylenedioxymethamphetamine; 5‐hydroxytryptamine; Animals; Biogenic Monoamines - metabolism; Biological and medical sciences; Body Temperature - drug effects; Brain Chemistry - drug effects; Drug toxicity and drugs side effects treatment; ecstasy; fenfluramine; Fenfluramine - toxicity; Free Radical Scavengers - pharmacology; Free Radicals; Hippocampus - drug effects; Hippocampus - metabolism; hyperthermia; Male; Medical sciences; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine - toxicity; Nerve Degeneration - drug effects; neurodegeneration; p-Chloroamphetamine - toxicity; Paroxetine - metabolism; Pharmacology. Drug treatments; p‐chloroamphetamine; Rats; Serotonin Agents - toxicity; Serotonin Uptake Inhibitors - metabolism; Toxicity: nervous system and muscle; α‐phenyl‐N‐tert‐butyl nitrone
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701213

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 [3H]‐paroxetine). These data indicate that a major mec