title: Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.
abstract: Although the exact mechanism involved in the long-term depletion of brain serotonin (5-HT) produced by substituted amphetamines is not completely known, evidence suggests that oxidative and/or bioenergetic stress may contribute to 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-HT toxicity. In the present study, the effect of supplementing energy substrates was examined on the long-term depletion of striatal 5-HT and dopamine produced by the local perfusion of MDMA (100 microM) and malonate (100 mM) and the depletion of striatal and hippocampal 5-HT concentrations produced by the systemic administration of MDMA (10 mg/kg i.p. x4). The effect of systemic administration of MDMA on ATP levels in the striatum and hippocampus also was examined. Reverse dialysis of MDMA and malonate directly into the striatum resulted in a 55-70% reduction in striatal concentrations of 5-HT and dopamine, and these reductions were significantly attenuated when MDMA and malonate were co-perfused with nicotinamide (1 mM). Perfusion of nicotinamide or ubiquinone (100 microM) also attenuated the depletion of 5-HT in the striatum and hippocampus produced by the systemic administration of MDMA. Finally, the systemic administration of MDMA produced a 30% decrease in the concentration of ATP in the striatum and hippocampus. These results support the conclusion that MDMA produces a dysregulation of energy metabolism which contributes to the mechanism of MDMA-induced 5-HT neurotoxicity.
authors.affiliation: College of Pharmacy, University of Cincinnati, 3223, Eden Ave., Cincinnati, OH 45267, USA.
authors.forename: Altaf S
authors.initials: AS
authors.lastname: Darvesh
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gudelsky
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D008314:Malonates / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009536:Niacinamide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity*; D013997:Time Factors; D014451:Ubiquinone / Q000494:pharmacology
chemical_list: D008314:Malonates; D018490:Serotonin Agents; D014451:Ubiquinone; D009536:Niacinamide; D012701:Serotonin; D000255:Adenosine Triphosphate; C030290:malonic acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine