title: 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 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.
authors: 1] Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, CNRS UMR 7224, Paris, France [2] Inserm UMR S952, Paris, France [3] Université Pierre et Marie Curie, 7-9 quai Saint Bernard, 75252 Paris, France.
authors: C
authors: C
authors: Lanteri
authors: 1] Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, CNRS UMR 7224, Paris, France [2] Inserm UMR S952, Paris, France [3] Université Pierre et Marie Curie, 7-9 quai Saint Bernard, 75252 Paris, France.
authors: E L
authors: EL
authors: Doucet
authors: Inserm U1016, Institut Cochin, Paris, France.
authors: S J
authors: SJ
authors: Hernández Vallejo
authors: 1] Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, CNRS UMR 7224, Paris, France [2] Inserm UMR S952, Paris, France [3] Université Pierre et Marie Curie, 7-9 quai Saint Bernard, 75252 Paris, France.
authors: G
authors: G
authors: Godeheu
authors: 1] Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, CNRS UMR 7224, Paris, France [2] Inserm UMR S952, Paris, France [3] Université Pierre et Marie Curie, 7-9 quai Saint Bernard, 75252 Paris, France.
authors: A-C
authors: AC
authors: Bobadilla
authors: CNRS UMR 7148, Collège de France, Paris, France.
authors: L
authors: L
authors: Salomon
authors: Inserm UMR S894, Centre de Psychiatrie et de Neurosciences, Paris, France.
authors: L
authors: L
authors: Lanfumey
authors: 1] Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, CNRS UMR 7224, Paris, France [2] Inserm UMR S952, Paris, France [3] Université Pierre et Marie Curie, 7-9 quai Saint Bernard, 75252 Paris, France.
authors: J-P
authors: JP
authors: Tassin
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects* / Q000378:metabolism; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D059333:Central Nervous System Sensitization; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006213:Hallucinogens / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018817:N-Methyl-3,4-methylenedioxyamphetamine
references: Psychopharmacology (Berl). 2004 Dec;177(1-2):100-10
references: 15338099
references: Neuropsychopharmacology. 2005 Dec;30(12):2180-91
references: 15841107
references: J Pharmacol Exp Ther. 1991 Nov;259(2):820-5
references: 1682486
references: Science. 1980 Jan 18;207(4428):329-31
references: 7188649
references: Lancet. 2007 Mar 24;369(9566):1047-53
references: 17382831
references: J Neurosci. 1995 Nov;15(11):7181-8
references: 7472472
references: Nat Neurosci. 2009 Aug;12(8):1036-41
references: 19597494
references: J Pharmacol Exp Ther. 1994 Aug;270(2):741-51
references: 8071867
references: Addict Biol. 2009 Apr;14(2):119-29
references: 18811678
references: Science. 1982 Mar 12;215(4538):1394-6
references: 6278591
references: J Neurosci. 1987 Sep;7(9):2837-43
references: 3625275
references: Psychopharmacology (Berl). 2010 Mar;209(1):25-36
references: 20101393
references: Brain Res. 2001 Dec 13;922(1):9-20
references: 11730697
references: Neuropsychopharmacology. 2003 Mar;28(3):421-34
references: 12629522
references: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7476-81
references: 16648258
references: Neuropsychopharmacology. 1998 Jun;18(6):492-502
references: 9571657
references: Addiction. 2000 Aug;95 Suppl 2:S91-117
references: 11002906
references: Neuropsychopharmacology. 2004 Oct;29(10):1800-6
references: 15127086
references: Neuropsychopharmacology. 1998 Jan;18(1):26-40
references: 9408916
references: Anesthesiology. 1992 Jun;76(6):948-52
references: 1350889
references: J Neurosci. 2003 Mar 1;23(5):1879-85
references: 12629192
references: Neuropsychopharmacology. 2008 Jun;33(7):1724-34
references: 17805311
references: J Neurochem. 2008 Nov;107(4):1102-12
references: 18823368
references: J Neurosci. 2002 Apr 1;22(7):2873-84
references: 11923452
references: J Neurosci. 2009 Jan 28;29(4):987-97
references: 19176807
references: Synapse. 1995 Jan;19(1):56-65
references: 7709344
references: Proc Natl Acad Sci U S A. 1988 Jul;85(14):5274-8
references: 2899326
references: Cereb Cortex. 2005 Dec;15(12):1877-86
references: 15728739
references: Biochem Pharmacol. 2008 Jan 1;75(1):85-97
references: 17686465
references: Pharmacol Biochem Behav. 2008 Aug;90(2):208-17
references: 18403002
references: Clin Pharmacol Ther. 2011 Aug;90(2):246-55
references: 21677639
references: Mol Psychiatry. 2012 Jun;17(6):612-23
references: 21808255
references: Nat Neurosci. 2005 Nov;8(11):1445-9
references: 16251986
references: Brain Res. 2005 Sep 7;1055(1-2):143-8
references: 16098489
references: J Neurosci. 2004 Mar 17;24(11):2787-96
references: 15028772
references: Eur J Pharmacol. 1988 Aug 2;152(3):227-34
references: 2906000
references: Brain Res. 1992 Apr 17;577(2):351-5
references: 1606506
references: Synapse. 2001 Jan;39(1):32-41
references: 11071707
references: Int J Neuropsychopharmacol. 2011 Aug;14(7):927-40
references: 20942998
references: Neuropharmacology. 2002 Nov;43(6):945-58
references: 12423664
references: Psychopharmacology (Berl). 1989;99(3):352-6
references: 2574478
references: J Neurosci. 1987 Sep;7(9):2844-8
references: 3625276
references: Anesthesiology. 1989 Jul;71(1):75-9
references: 2568769
references: PLoS One. 2009 Nov 23;4(11):e7952
references: 19956756
references: Psychopharmacology (Berl). 2005 Apr;178(4):505-13
references: 15765263
references: Science. 2006 Feb 17;311(5763):1017-20
references: 16484499
references: J Neurosci. 1993 Jan;13(1):266-75
references: 8423473
references: Pharmacol Biochem Behav. 2007 Apr;86(4):622-30
references: 17363047
references: Biol Psychiatry. 2007 Sep 15;62(6):669-79
references: 17306775
references: Neuropsychopharmacology. 1998 Jun;18(6):469-79
references: 9571655
references: Psychopharmacology (Berl). 2007 Jan;189(4):489-503
references: 16220332
references: Science. 1997 Oct 3;278(5335):58-63
references: 9311927
references: Eur J Pharmacol. 1988 Sep 23;154(3):285-91
references: 3234483
references: Neuropharmacology. 1980 Apr;19(4):355-63
references: 6104308
references: J Neurochem. 1996 Jan;66(1):243-9
references: 8522960
references: PLoS One. 2012;7(5):e36476
references: 22574166
references: Neuron. 2008 Aug 14;59(3):486-96
references: 18701073
references: Neuroreport. 1999 Nov 8;10(16):3369-74
references: 10599847
references: Lancet. 1998 Oct 31;352(9138):1433-7
references: 9807990
references: J Biol Chem. 2012 Sep 7;287(37):31270-9
references: 22843681
references: J Neurosci. 1995 Nov;15(11):7189-95
references: 7472473
references: Eur J Neurosci. 2008 May;27(9):2433-43
references: 18461718
references: Nature. 1996 Jul 18;382(6588):255-7
references: 8717040
references: Lancet. 1991 Nov 23;338(8778):1335
references: 1682711
references: Proc Natl Acad Sci U S A. 1980 Mar;77(3):1696-700
references: 6246501
references: Science. 1985 Sep 6;229(4717):986-8
references: 4023719
references: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9950-5
references: 9275232
references: Nature. 1983 Sep 8-14;305(5930):140-2
references: 6225026
references: Science. 1997 Jun 27;276(5321):2048-50
references: 9197269
references: Nature. 2001 May 31;411(6837):583-7
references: 11385572
references: J Pharmacol Exp Ther. 2009 Oct;331(1):35-44
references: 19589951
references: Lancet. 1991 Dec 14;338(8781):1520
references: 1683934
references: Brain Res Brain Res Rev. 1993 Sep-Dec;18(3):247-91
references: 8401595
references: BMC Pharmacol. 2006 Mar 03;6:6
references: 16515684
references: J Neurochem. 1990 Sep;55(3):1079-82
references: 2117048
references: Neuropharmacology. 1987 Nov;26(11):1657-61
references: 2448703
references: Neuropsychopharmacology. 2003 Jan;28(1):63-72
references: 12496941
references: Brain Res. 1992 Feb 7;571(2):330-7
references: 1377088
references: Mol Pharmacol. 2006 Sep;70(3):1013-21
references: 16772521
references: Neuropsychopharmacology. 2012 May;37(6):1465-73
references: 22353758