Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT

Brain Res. 2005 Sep 21;1056(2):168-75. doi: 10.1016/j.brainres.2005.07.009.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Brain / anatomy & histology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Chemistry / drug effects
  • Dopamine / metabolism
  • Drug Interactions
  • Energy Metabolism / drug effects*
  • Male
  • Malonates / pharmacology
  • Microdialysis / methods
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity*
  • Niacinamide / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Serotonin Agents / toxicity*
  • Time Factors
  • Ubiquinone / pharmacology


  • Malonates
  • Serotonin Agents
  • Ubiquinone
  • Niacinamide
  • Serotonin
  • Adenosine Triphosphate
  • malonic acid
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine