Increased anxiety and "depressive" symptoms months after MDMA ("ecstasy") in rats: drug-induced hyperthermia does not predict long-term outcomes

Psychopharmacology (Berl). 2003 Aug;168(4):465-74. doi: 10.1007/s00213-003-1452-8. Epub 2003 Apr 17.


Rationale: There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour.

Objective: The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration.

Method: Male Wistar rats were treated with MDMA (4x5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28 degrees C) or a low ambient temperature (16 degrees C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC.

Results: MDMA treatment caused a clear and consistent hyperthermia at 28 degrees C and hypothermia at 16 degrees C. Months later, rats pre-treated with MDMA at either 16 or 28 degrees C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28 degrees C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28 degrees C. Dopamine in the striatum was also depleted in rats given MDMA.

Conclusions: These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / chemistry
  • Animals
  • Anxiety / chemically induced*
  • Biogenic Monoamines / chemistry
  • Cognition / drug effects*
  • Cognition / physiology
  • Corpus Striatum / chemistry
  • Depression / chemically induced*
  • Fever / chemically induced*
  • Hippocampus / chemistry
  • Interpersonal Relations
  • Male
  • Medical Futility
  • Motor Activity / drug effects
  • N-Methyl-3,4-methylenedioxyamphetamine / administration & dosage
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity*
  • Prefrontal Cortex / chemistry
  • Rats
  • Rats, Wistar
  • Time Factors


  • Biogenic Monoamines
  • N-Methyl-3,4-methylenedioxyamphetamine