The role of extracellular serotonin and MDMA in the sensitizing effects of MDMA

Behav Brain Res. 2022 Jul 26;430:113936. doi: 10.1016/j.bbr.2022.113936. Epub 2022 May 20.


MDMA is a non-selective monoamine releasing stimulant with potent serotonergic effects - a pharmacological effect not typically associated with drugs of misuse or efficacious reinforcers. Nonetheless, MDMA is misused by humans and self-administered by laboratory animals. We have previously shown that repeated exposure to MDMA sensitized both the locomotor activating and reinforcing effects of MDMA in rats. Because repeated MDMA exposure often results in decreased markers of serotonin neurotransmission, it is possible that this might underlie the sensitizing effects of MDMA. This was examined in the current study. Male Sprague-Dawley rats were stereotaxically implanted with guide cannula in the medial striatum. They were then pre-treated with saline (n = 11) or MDMA (10 mg/kg, i.p.; n = 10), once daily for five days. Two-days later, all rats received ascending doses of MDMA (0.0, 5.0, 10.0, mg/kg, i.p.) administered at 2 hr intervals, during which locomotor activity was measured and microdialysis samples were collected. Microdialysates were analyzed using liquid chromatography-mass spectrometry and the concentrations of serotonin and MDMA were quantified. Acute MDMA administration produced dose-dependent increases in locomotor activity, which was significantly enhanced by MDMA pre-treatment. Acute MDMA also produced dose-dependent increases in medial-striatal serotonin and MDMA, but this was not impacted by MDMA pre-treatment. These results suggest that the sensitizing effects of MDMA are not due to changes in MDMA-produced synaptic overflow of serotonin in the medial striatum or the absorption/elimination of systemically administered MDMA. More likely candidates are alterations in serotonin receptor mechanisms and/or dopamine neurotransmission following repeated exposure.

Keywords: LCMS; MDMA; Microdialysis; Sensitization; Serotonin; Striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine / pharmacology
  • Male
  • N-Methyl-3,4-methylenedioxyamphetamine* / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Agents / pharmacology
  • Serotonin*


  • Serotonin Agents
  • Serotonin
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine