3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated production of hydrogen peroxide in an in vitro model: the role of dopamine, the serotonin-reuptake transporter, and monoamine oxidase-B.
3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been shown to induce long-term deficits in serotonergic function in animal models. Several studies have suggested that dopamine (DA) uptake into serotonin (5-HT) terminals by the 5-HT reuptake transporter (SERT) and subsequent deamination by monoamine oxidase-B (MAO-B) leads to the formation of hydrogen peroxide and may be major contributors to this serotonergic toxicity. In the present study, when human choriocarcinoma (JAR) cells were exposed to MDMA (1.2 mM) for 6h, followed by treatment with DA (0.1 mM), hydrogen peroxide production increased over a 24 h period, peaking at 420% over baseline and decreasing cell viability by 30%. DA alone increased hydrogen peroxide production 84% over baseline, but did not significantly decrease cell viability. Incubation of MDMA treated cells with the SERT inhibitor, fluoxetine (500 nM) or the MAO-B inhibitor, L-deprenyl (0.1 mM) for 30 min prior to DA, significantly blocked free radical production and cell death. These findings support the hypothesis that the deamination of DA by MAO-B within the serotonergic cell can lead to hydrogen peroxide formation and ultimately cell death.
Hrometz
Sandra L
SL
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA.
Brown
Andrew W
AW
Nichols
David E
DE
Sprague
Jon E
JE
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002822:Choriocarcinoma; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D004347:Drug Interactions; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000502:physiology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011247:Pregnancy; D012642:Selegiline / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
D004298:Dopamine; D005473:Fluoxetine; D006213:Hallucinogens; D006861:Hydrogen Peroxide; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009419:Nerve Tissue Proteins; D012642:Selegiline; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human