Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain

Brain Res. 2009 Aug 25;1286:32-41. doi: 10.1016/j.brainres.2009.06.042. Epub 2009 Jun 23.


Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA-induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 h for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERT(ir)), and the reduction in SERT(ir) also was completely attenuated in MDMA-preconditioned animals. Preconditioning with MDMA (10 mg/kg, ip) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not dopamine depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA-induced hyperthermia in rats previously exposed to MDMA contribute towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute towards neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT produced by subsequent MDMA administration. The mechanisms underlying preconditioning-induced neuroprotection for MDMA remain to be determined.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Blotting, Western
  • Brain / drug effects*
  • Brain / metabolism
  • Dopamine / metabolism
  • Drug Tolerance / physiology*
  • Fever / chemically induced
  • Methamphetamine / pharmacology
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Neuroprotective Agents / pharmacology*
  • RNA-Binding Proteins / biosynthesis
  • RNA-Binding Proteins / drug effects
  • Rats
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin / metabolism


  • Adrenergic Uptake Inhibitors
  • Neuroprotective Agents
  • RNA-Binding Proteins
  • Serotonin Uptake Inhibitors
  • Sert1 protein, rat
  • Serotonin
  • Methamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine