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

Nirmal S. Bhide, Jack W. Lipton, Jacobi I. Cunningham, Bryan K. Yamamoto, Gary A. Gudelsky

Research output: Contribution to journalArticle

18 Scopus citations


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 (SERTir), and the reduction in SERTir 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.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalBrain research
StatePublished - Aug 25 2009



  • MDMA
  • Neuroprotection
  • Neurotoxicity
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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