The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA ('ecstasy').
The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [3H]paroxetine binding in regions of the brain 7 days later, with a dose of 4 mg/kg having no degenerative effect. This dose was also without effect when given once daily for 4 days, but produced a marked loss of [3H]paroxetine binding and indole concentration ( approximately 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorectic effect of the drug being seen. These data demonstrate that MDMA-induced neurodegeneration is related to both the dose and frequency of administration and indicate that damage to 5-HT neurones can occur in the absence of a hyperthermic response to the drug. We suggest that damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted.
Departamento de farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
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O'Shea
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Granados
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Esteban
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Colado
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Green
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology*; D009411:Nerve Endings / Q000187:drug effects / Q000473:pathology*; D017374:Paroxetine / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity; D014018:Tissue Distribution
D018490:Serotonin Agents; D012701:Serotonin; D017374:Paroxetine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine