3,4-methylenedioxymethamphetamine self-administration is abolished in serotonin transporter knockout mice

Biol Psychiatry. 2007 Sep 15;62(6):669-79. doi: 10.1016/j.biopsych.2006.11.005. Epub 2007 Feb 16.


Background: The neurobiological mechanism underlying the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA) remains unclear. The aim of the present study was to determine the contribution of the serotonin transporter (SERT) in MDMA self-administration behavior by using knockout (KO) mice deficient in SERT.

Methods: Knockout mice and wild-type (WT) littermates were trained to acquire intravenous self-administration of MDMA (0, .03, .06, .125, and .25 mg/kg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. Additional groups of mice were trained to obtain food and water to rule out operant responding impairments. Microdialysis studies were performed to evaluate dopamine (DA) and serotonin (5-HT) extracellular levels in the nucleus accumbens (NAC) and prefrontal cortex (PFC), respectively, after acute MDMA (10 mg/kg).

Results: None of the MDMA doses tested maintained intravenous self-administration in KO animals, whereas WT mice acquired responding for MDMA. Acquisition of operant responding for food and water was delayed in KO mice, but no differences between genotypes were observed on the last day of training. MDMA increased DA extracellular levels to a similar extent in the NAC of WT and KO mice. Conversely, extracellular concentrations of 5-HT in the PFC were increased following MDMA only in WT mice.

Conclusions: These findings provide evidence for the specific involvement of SERT in MDMA reinforcing properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Conditioning, Operant / physiology
  • Dopamine / metabolism
  • Extracellular Space / metabolism
  • Hallucinogens / administration & dosage*
  • Hallucinogens / pharmacology
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Knockout
  • Microdialysis
  • N-Methyl-3,4-methylenedioxyamphetamine / administration & dosage*
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Nucleus Accumbens / metabolism
  • Prefrontal Cortex / metabolism
  • Reinforcement, Psychology*
  • Reward
  • Self Administration*
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / physiology*


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