MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning

Behav Neurosci. 2009 Oct;123(5):1076-84. doi: 10.1037/a0016716.


3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Exploratory Behavior / drug effects*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Injections, Intraperitoneal
  • Male
  • Maze Learning / drug effects*
  • N-Methyl-3,4-methylenedioxyamphetamine / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Stress, Physiological*
  • Stress, Psychological / physiopathology*


  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • N-Methyl-3,4-methylenedioxyamphetamine