The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity.
3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are ring-substituted amphetamine derivatives with stimulant and hallucinogenic properties. The recreational use of these amphetamines, especially MDMA, is prevalent despite warnings of irreversible damage to the central nervous system. MDA and MDMA are primarily serotonergic neurotoxicants. Because (1) neither MDA nor MDMA produces neurotoxicity when injected directly into brain, (2) intracerebroventricular (i.c.v.) administration of some major metabolites of MDA and MDMA fails to reproduce their neurotoxicity, (3) alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-MeDA are metabolites of both MDA and MDMA, (4) alpha-MeDA and N-methyl-alpha-MeDA are readily oxidized to the corresponding ortho-quinones, which can undergo conjugation with glutathione (GSH), and (5) quinone thioethers exhibit a variety of toxicologic activities, we initiated studies on the potential role of thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA in the neurotoxicity of MDA and MDMA. Our studies have revealed that the thioether conjugates stimulate the acute release of serotonin, dopamine, and norepinephrine and produce a behavioral response commensurate with the "serotonin syndrome." Direct injection of the conjugates into rat brain also produces long-term depletions in serotonin (5-HT) concentrations, elevations in GFAP expression, and activation of microglial cells. The data are consistent with the view that thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA contribute to the neurotoxicity of the parent amphetamines.
Monks
Terrence J
TJ
Center for Cellular and Molecular Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-1074, USA. scouser@pharmacy.arizona.edu
Jones
Douglas C
DC
Bai
Fengju
F
Lau
Serrine S
SS
D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002396:Catechols / Q000378:metabolism; D006213:Hallucinogens / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D013287:Illicit Drugs / Q000009:adverse effects / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism
D002396:Catechols; D006213:Hallucinogens; D013287:Illicit Drugs; D017382:Reactive Oxygen Species; D013440:Sulfides; D015104:3,4-Methylenedioxyamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine