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

Abstract

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 α1B-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 α2A-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 α2A-adrenergic and 5-HT1A 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 α2A-adrenergic and 5-HT1A autoreceptors has an important role in the physiopathology of addictive behaviors.

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Acknowledgements

This work was supported by Université Pierre et Marie Curie (UPMC), Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS) and Institut National de la Santé et de la Recherche Médicale (Inserm). We thank Drs Francis Colpaert (†) and Pierre Sokollof (Laboratoires Pierre Fabre, Castres, France) for kindly providing us F13640. We also thank Dr Marie-Pascale Martres and Caroline Chevarin for her help with radiolabeling experiments; Dr Marie Picot and Nicolas ‘boubou’ Bouveyron for their precious advices on western blot experiments; and Carole Jacq for her help with behavioral experiments. CL would like to thank Vanessa Houades for her support. This work is dedicated to the memory of Iderlinda Deus de Sousa.

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Correspondence to C Lanteri.

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CL and JPT designed the study. CL, ELD, SJHV, GG, ACB and LS performed research. CL, ELD, SJHV, ACB, LL and JPT analyzed the data. CL wrote the manuscript.

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Lanteri, C., Doucet, E., Hernández Vallejo, S. et al. Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons. Mol Psychiatry 19, 823–833 (2014). https://doi.org/10.1038/mp.2013.97

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Keywords

  • α2A-adrenergic autoreceptors
  • behavioral sensitization
  • Gi proteins
  • 5-HT1A autoreceptors
  • MDMA
  • neuroplasticity

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