title: The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.
abstract: Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.
authors.forename: D Y
authors.initials: DY
authors.lastname: Sakae
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Marti
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 839, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Lecca
authors.affiliation: Fondation FondaMental, Créteil, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U705, Centre National de la Recherche Scientifique (CNRS) UMR 8206, Université Paris Descartes, Université Denis Diderot, PRES Sorbonne Paris Cité, Paris, France.|Assistance Publique-Hôpitaux de Paris, GH Saint Louis-Lariboisière-F Widal, Service de Psychiatrie, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM U955), Psychiatrie Translationnelle, Créteil, France.
authors.forename: F
authors.initials: F
authors.lastname: Vorspan
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.
authors.forename: L J
authors.initials: LJ
authors.lastname: Morel
authors.affiliation: Fondation FondaMental, Créteil, France.|Institut National de la Santé et de la Recherche Médicale (INSERM U955), Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Hôpital H. Mondor-A Chenevier, Pôle de Psychiatrie, Créteil, France.
authors.forename: A
authors.initials: A
authors.lastname: Henrion
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Gutiérrez-Cuesta
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Besnard
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Heck
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Herzog
authors.affiliation: Cellular Imaging Facility, Institut de Biologie Paris Seine (IBPS), Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Bolte
authors.affiliation: Department of Anatomy and Cell Biology and Department of Physiology and Pharmacology, Robarts Research Institute, The University of Western Ontario, London, ON, Canada.
authors.forename: V F
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Department of Anatomy and Cell Biology and Department of Physiology and Pharmacology, Robarts Research Institute, The University of Western Ontario, London, ON, Canada.
authors.forename: M A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Fondation FondaMental, Créteil, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U705, Centre National de la Recherche Scientifique (CNRS) UMR 8206, Université Paris Descartes, Université Denis Diderot, PRES Sorbonne Paris Cité, Paris, France.|Assistance Publique-Hôpitaux de Paris, GH Saint Louis-Lariboisière-F Widal, Service de Psychiatrie, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM U955), Psychiatrie Translationnelle, Créteil, France.
authors.forename: F
authors.initials: F
authors.lastname: Bellivier
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neuroscience, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: C B
authors.initials: CB
authors.lastname: Eap
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neuroscience, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Crettol
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Vanhoutte
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Caboche
authors.affiliation: Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Gratton
authors.affiliation: Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Moquin
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.|Fondation FondaMental, Créteil, France.
authors.forename: B
authors.identifier: http://orcid.org/0000-0001-5876-9822
authors.initials: B
authors.lastname: Giros
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Daumas
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 839, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Mameli
authors.affiliation: Fondation FondaMental, Créteil, France.|Institut National de la Santé et de la Recherche Médicale (INSERM U955), Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Hôpital H. Mondor-A Chenevier, Pôle de Psychiatrie, Créteil, France.
authors.forename: S
authors.initials: S
authors.lastname: Jamain
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada.|Fondation FondaMental, Créteil, France.
authors.forename: S
authors.initials: S
authors.lastname: El Mestikawy
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000473:pathology*; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000235:genetics / Q000473:pathology; D012646:Self Administration; D015398:Signal Transduction / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D050496:Vesicular Glutamate Transport Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D018765:Dopamine Uptake Inhibitors; C460879:SLC17A8 protein, human; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D003042:Cocaine; D004298:Dopamine