Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons

Mol Psychiatry. 2014 Jul;19(7):823-33. doi: 10.1038/mp.2013.97. Epub 2013 Aug 20.


3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') is a psychostimulant drug, widely used recreationally among young people in Europe and North America. Although its neurotoxicity has been extensively described, little is known about its ability to strengthen neural circuits when administered in a manner that reproduces human abuse (i.e. repeated exposure to a low dose). C57BL/6J mice were repeatedly injected with MDMA (10 mg kg(-1), intraperitoneally) and studied after a 4-day or a 1-month withdrawal. We show, using in vivo microdialysis and locomotor activity monitoring, that repeated injections of MDMA induce a long-term sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization. The development of this phenomenon, which lasts for at least 1 month after withdrawal, requires repeated stimulation of α(1B)-adrenergic and 5-hydroxytryptamine (5-HT)(2A) receptors. Moreover, behavioral and neuroendocrine assays indicate that hyper-reactivity of noradrenergic and serotonergic networks is associated with a persistent desensitization of somatodendritic α(2A)-adrenergic and 5-HT1A autoreceptor function. Finally, molecular analysis including radiolabeling, western blot and quantitative reverse transcription-polymerase chain reaction reveals that mice repeatedly treated with MDMA exhibit normal α(2A)-adrenergic and 5-HT(1A) receptor binding, but a long-lasting downregulation of Gαi proteins expression in both locus coeruleus and dorsal raphe nucleus. Altogether, our results show that repeated MDMA exposure causes strong neural and behavioral adaptations and that inhibitory feedback mediated by α(2A)-adrenergic and 5-HT(1A) autoreceptors has an important role in the physiopathology of addictive behaviors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Neurons / drug effects*
  • Adrenergic Neurons / metabolism
  • Adrenergic alpha-1 Receptor Agonists / pharmacology
  • Adrenergic alpha-2 Receptor Agonists / pharmacology
  • Animals
  • Central Nervous System Sensitization
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism
  • Down-Regulation / drug effects
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Hallucinogens / pharmacology*
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Male
  • Mice
  • Motor Activity / drug effects*
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Neuronal Plasticity / drug effects*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Serotonergic Neurons / drug effects*
  • Serotonergic Neurons / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Agonists / pharmacology


  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-2 Receptor Agonists
  • Hallucinogens
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-2
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT2 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • N-Methyl-3,4-methylenedioxyamphetamine