Effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: implications for MDMA neurotoxicity

J Neurochem. 2010 Feb;112(4):951-62. doi: 10.1111/j.1471-4159.2009.06515.x. Epub 2009 Nov 30.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a popular recreational drug used worldwide. This study aimed to determine the effects of this compound on the expression of nerve terminal serotonergic markers in rats. Experiment 1 investigated MDMA-induced changes in levels of the serotonin transporter (SERT) and the vesicular monoamine transporter 2 (VMAT-2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Adult male Sprague-Dawley rats were administered 100 mg/kg DSP-4 or saline 1 week prior to either an MDMA (10 mg/kg x 4) or saline binge. Two weeks following the binge treatment, the DSP-4/MDMA group unexpectedly showed little change in hippocampal VMAT-2 protein expression compared with DSP-4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA-treated animals. Furthermore, animals treated with binge MDMA (Experiment 2) showed a striking decrease in SERT gene expression (and a lesser effect on VMAT-2) measured by quantitative RT-PCR in pooled dorsal and median raphe tissue punches, when compared with saline-treated controls. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers, thus questioning the need to invoke distal axotomy as an explanation of MDMA-related serotonergic deficits.

Publication types

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

MeSH terms

  • 5,7-Dihydroxytryptamine / pharmacology
  • Animals
  • Area Under Curve
  • Benzylamines / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Central Nervous System Stimulants / administration & dosage
  • Disease Models, Animal
  • Female
  • Gene Expression / drug effects
  • Hallucinogens / toxicity*
  • Male
  • Methamphetamine / administration & dosage
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity*
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / prevention & control
  • Neurotransmitter Uptake Inhibitors / pharmacology
  • Pregnancy
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Time Factors
  • Vesicular Monoamine Transport Proteins / metabolism*

Substances

  • Benzylamines
  • Central Nervous System Stimulants
  • Hallucinogens
  • Neurotransmitter Uptake Inhibitors
  • Serotonin Plasma Membrane Transport Proteins
  • Slc18a2 protein, rat
  • Vesicular Monoamine Transport Proteins
  • 5,7-Dihydroxytryptamine
  • Serotonin
  • Methamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • DSP 4