3,4-methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein

Synapse. 2004 Sep 15;53(4):240-8. doi: 10.1002/syn.20058.


Previous experiments conducted in this laboratory showed that administration of high-dose D-fenfluramine (D-FEN) and p-chloroamphetamine (PCA) decreased 5-HT transporter (SERT) binding and tissue 5-HT by 30-60% in caudate and whole brain tissue 2 days and 2 weeks after drug administration. However, protein expression as determined by Western blot analysis did not change in either tissue or time point, except for a 30% decrease in the caudate 2 days after PCA administration. In the present study, we studied the effect of MDMA and 5,7-dihydroxytryptamine (5,7-DHT) on tissue 5-HT levels and the protein expression level of SERT and glial fibrillary acidic protein (GFAP), a validated neurotoxicity marker.

Hypothesis: MDMA administration decreases SERT expression.

Methods: Two weeks after MDMA administration (7.5 mg/kg i.p., q 2 h x 3 doses) or 2 weeks after i.c.v. administration of 5,7,-DHT (150 microg/rat), male Sprague-Dawley rats were sacrificed and the caudate, cortex, and hippocampal tissue collected. Western blots for SERT and GFAP were generated using published methods. Tissue 5-HT levels were determined by HPLC coupled to electrochemical detection.

Results: MDMA treatment decreased tissue 5-HT in cortex, hippocampus, and caudate by about 50%. However, MDMA treatment had no significant effect on expression level of SERT and GFAP in any brain region. In contrast, 5,7-DHT reduced tissue 5-HT by more than 90%, decreased SERT protein expression by 20-35%, and increased GFAP by 30-39%.

Conclusion: These data suggest the MDMA treatment regimen used here does not cause degeneration of 5-HT nerve terminals. Viewed collectively with our previous results and other published data, these data indicate that MDMA-induced persistent 5-HT depletion may occur in the absence of axotomy.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • 5,7-Dihydroxytryptamine / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Chemistry / drug effects*
  • Brain Chemistry / physiology
  • Carrier Proteins / drug effects*
  • Carrier Proteins / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Glial Fibrillary Acidic Protein / drug effects*
  • Glial Fibrillary Acidic Protein / metabolism
  • Homovanillic Acid / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Membrane Glycoproteins / drug effects*
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins*
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Nerve Tissue Proteins / drug effects*
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurotoxins / pharmacology
  • Norepinephrine / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Carrier Proteins
  • Glial Fibrillary Acidic Protein
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neurotoxins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • 3,4-Dihydroxyphenylacetic Acid
  • 5,7-Dihydroxytryptamine
  • Serotonin
  • Hydroxyindoleacetic Acid
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Norepinephrine
  • Homovanillic Acid