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Repeated Exposure to MDMA Triggers Long-Term Plasticity of Noradrenergic and Serotonergic Neurons

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Repeated Exposure to MDMA Triggers Long-Term Plasticity of Noradrenergic and Serotonergic Neurons Molecular Psychiatry (2014) 19, 823–833 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons C Lanteri1,2,3, EL Doucet1,2,3, SJ Herna´ndez Vallejo4, G Godeheu1,2,3, A-C Bobadilla1,2,3, L Salomon5, L Lanfumey6 and J-P Tassin1,2,3 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 À 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 a1B-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 a2A-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 a2A-adrenergic and 5-HT1A receptor binding, but a long-lasting downregulation of Gai 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 a2A-adrenergic and 5-HT1A autoreceptors has an important role in the physiopathology of addictive behaviors. Molecular Psychiatry (2014) 19, 823–833; doi:10.1038/mp.2013.97; published online 20 August 2013 Keywords: a2A-adrenergic autoreceptors; behavioral sensitization; Gi proteins; 5-HT1A autoreceptors; MDMA; neuroplasticity INTRODUCTION of MDMA and prevents the development of behavioral sensitiza- 22,23 3,4-Methylenedioxymethamphetamine (MDMA), commonly tion. Also, self-administration of MDMA is abolished in mice known as ‘ecstasy’, is a substituted amphetamine with psychos- lacking the serotonin transporter (serotonin transporter KO 24 timulant and hallucinogenic properties. This illicit drug is mice), whereas mice lacking 5-HT2A receptors (5-HT2A KO mice) extensively consumed by teenagers and young people in clubs are insensitive to MDMA-induced reinforcement and cue-induced 25 and rave parties, despite the increasing evidence of its putative reinstatement of MDMA-seeking behaviors. neurotoxicity1–3 and its adverse effects on mental health. Indeed, Recently, we identified a new kind of neural plasticity that may chronic use of MDMA has been associated with many psychiatric be involved in the long-term behavioral effects of drugs of abuse. disorders including anxiety, depression or psychosis,4–6 and may Indeed, we showed that repeated administration of amphetamine, lead to addiction in vulnerable individuals.7 cocaine, morphine, ethanol or nicotine þ monoamine oxidase In rodents, MDMA induces locomotor hyperactivity and inhibitor induces long-lasting sensitization of noradrenergic and 26–29 repeated injections result in behavioral sensitization.8–10 This serotonergic neurons in C57BL/6J mice. Molecular mechanisms long-lasting phenomenon is thought to have a critical role in the underlying this phenomenon remain however unknown. development of compulsive drug seeking and drug taking, as well The main purpose of this study was to investigate the long-term as in cue-induced relapse.11,12 effects of a repeated MDMA exposure on noradrenergic and Studies of the brain circuits underlying addictive behaviors have serotonergic transmissions. The reactivity of noradrenergic and focused on the mesolimbic dopaminergic system,13,14 as it was serotonergic neurons was investigated by in vivo microdialysis in shown that all drugs of abuse, including MDMA, increase the prefrontal cortex (PFC) and behavioral effects were recorded in extracellular dopamine levels in the nucleus accumbens of parallel. The mechanisms underlying MDMA-induced changes were rodents.15–18 However, several in vitro studies indicate that MDMA then investigated at the molecular, physiological and behavioral shows higher affinity for both norepinephrine and serotonin levels. transporters than for dopamine transporter.19–21 Moreover, growing evidence suggests that the involvement of MATERIALS AND METHODS both noradrenergic and serotonergic systems in MDMA-induced Subjects addictive behaviors may have been seriously underestimated. The Animals were 2–3 months old (26–32 g) C57BL/6J male mice (Charles River, pharmacological blockade of either a1-adrenergic or 5-hydroxy- L’Arbresle, France). They were housed eight per cage and maintained on a tryptamine (5-HT)2A receptors reduces the hyperlocomotor effects 12 h light/dark cycle with food and water available ad libitum. Seven 1Laboratoire de Physiopathologie des Maladies du Syste`me Nerveux Central, CNRS UMR 7224, Paris, France; 2Inserm UMR S952, Paris, France; 3Universite´ Pierre et Marie Curie, 7–9 quai Saint Bernard, 75252 Paris, France; 4Inserm U1016, Institut Cochin, Paris, France; 5CNRS UMR 7148, Colle`ge de France, Paris, France and 6Inserm UMR S894, Centre de Psychiatrie et de Neurosciences, Paris, France. Correspondence: Dr C Lanteri, Laboratoire de Physiopathologie des Maladies du Syste`me Nerveux Central, CNRS UMR 7224, Universite´ Pierre et Marie Curie, 7–9 quai Saint Bernard, 75252 Paris, France. E-mail: [email protected] Received 2 August 2012; revised 28 June 2013; accepted 10 July 2013; published online 20 August 2013 Sensitization of noradrenergic and serotonergic neurons with MDMA C Lanteri et al 824 hundred mice were used in this study (300 mice for the microdialysis PFC, the LC or the DRN through the dialysis probe and cortical samples experiments, 256 mice for the behavioral experiments, 80 mice for the were collected for 200 min. In local experiments, the concentration of neuroendocrine experiments and 64 mice for the molecular experiments). dexmedetomidine and F13640 was gradually increased every 40 min (i.e. Each mouse was naive at the beginning of each experiment and was not every two samples). used repeatedly for the different tests. Animal experimentation was conducted in accordance with the guidelines for care and use of Biochemistry. Dialysate samples (20 ml) were injected every 30 min experimental animals of the European Economic Community (86/809). through a rheodyne valve in the mobile phase circuit with a refrigerated automatic injector (Triathlon; Spark Holland, Emmen, The Netherlands). Drugs High-performance liquid chromatography was performed with a reverse- phase column (80 Â 4.6 mm; 3 mm particle size; HR-80; ESA, Chelmsford, 3,4-Methylenedioxymethamphetamine (MDMA) hydrochloride, D-amphe- MA, USA). The mobile phase (for NE analysis: 0.1 M NaH PO , 0.1 mM EDTA, tamine sulfate, p-chloroamphetamine (PCA) hydrochloride, prazosin 2 4 2.75 mM octane sulfonic acid, 0.25 mM triethylamine, 3% methanol, pH 2.9; hydrochloride, WAY-100635 (N-[2-[4-(2-[O-methyl-3H]methoxyphenyl)-1- for 5-HT analysis: 0.1 M NaH PO , 0.1 mM EDTA, 2.75 mM octane sulfonic piperazinyl]ethyl]-N-2-pyridinyl) cyclohexane carboxamide trihydrochlor- 2 4 acid, 0.25 mM triethylamine, 15% methanol, 5% acetonitrile, pH 2.9; and for ide) hydrochloride and efaroxan hydrochloride were purchased from DA analysis: 0.1 M NaH2PO4, 0.1 mM EDTA, 2.75 mM octane sulfonic acid, Sigma-Aldrich (L’Isle d’Abeau-Chesne, France). Dexmedetomidine hydro- À 1 0.25 mM triethylamine, 6% methanol, pH 2.9) was delivered at 0.7 ml min chloride was purchased from Tocris Bioscience (Bristol, UK). SR46349B by an ESA-580 pump. An ESA coulometric detector (Coulochem II 5100A, hemifumarate was a generous gift from Sanofi-Aventis (Paris, France) and with a 5014B analytical cell; Eurosep Instruments, Cergy, France) was F13640 was kindly supplied by Pierre Fabre Laboratories (Castres, France). used for electrochemical detection. The conditioning electrode was set All drugs were dissolved in saline (0.9% NaCl) except prazosin, which was at –0.175 mV and the detecting electrode was set at þ 0.175 mV. dissolved and sonicated in water (50% of final volume), and then completed with saline and SR46349B, which was dissolved and sonicated Histology. At the end of the experiment, a blue dye was infused through in saline plus lactic acid (0.1%), and then finally neutralized with 10 M 1 10 the microdialysis probe. Then, the brain was quickly removed and NaOH. Doses are expressed as salts. MDMA was given at 10 mg kg À . À 1 À 1 26 immediately frozen at À 30 1C using isopentane cooled by dry ice and D-amphetamine was given at 2 mg kg and PCA at 7 mg kg . Doses of 1 1 serial coronal slices were cut on a microtome to ensure the accurate probe prazosin (1 mg kg À ) and SR46349B (1 mg kg À ) were identical to those 26 implantation. used in previously reported experiments. Efaroxan was given at 2.5 mg kg À 1 and WAY-100635 was given at 1 mg kg À 1. The dose of F13640 given
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