MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons.
This study investigates a number of parameters that influence the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT) neurons in brain. Both the dose and number of injections of MDMA affect the degree of neurotoxicity on 5-HT axons and terminals as assessed by decreases in the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and the density of 5-HT uptake sites. Repeated systemic administration of various doses of MDMA (5-20 mg/kg twice daily for 4 consecutive days) results in dose-dependent decreases in 5-HT, 5-HIAA and 5-HT uptake sites. Increasing the number of injections of MDMA resulted in progressively greater reductions in 5-HT and 5-HIAA which occurred prior to decreases in 5-HT uptake sites. In contrast, no significant changes were observed in the density of norepinephrine uptake sites following single or repeated injections of 20 mg/kg MDMA. With respect to neuronal regeneration, following an initial 90% loss of 5-HT uptake sites after treatment with MDMA, the recovery of these sites occurred over a protracted period of time; a marked 25% reduction was seen at 6 months and the concentration of 5-HT uptake sites returned to control levels at 12 months following treatment with MDMA. Pretreatment with the selective 5-HT uptake blocker, citalopram, prior to each injection of MDMA prevented the neurotoxic effects of MDMA on the 5-HT parameters described above suggesting that active uptake of MDMA or a MDMA-related substance into brain 5-HT neurons was involved in the neurotoxic actions of the drug. In addition, the neurodegenerative effects of MDMA on 5-HT neurons exhibited some species specificity as comparable decreases in cerebral cortical 5-HT, 5-HIAA and 5-HT uptake sites were observed in rat and guinea pig while no significant changes in any of these serotonergic parameters were seen in mouse brain.
D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009410:Nerve Degeneration / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity
D000662:Amphetamines; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine