The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

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• dc.contributor.author Sakae, Diana Yaeca
• dc.contributor.author Martín García, Elena, 1975-ca
• dc.contributor.author Gutiérrez Cuesta, Javierca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author El Mestikawy, Salahca
• dc.date.accessioned 2016-01-22T15:43:08Z
• dc.date.available 2016-05-01T02:00:03Z
• dc.date.issued 2015
• dc.description.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.ca
• dc.description.sponsorship This research was supported by funds from ANR (ANR-09-MNPS-033, ANR-13-SAMA-0005-01), Équipe FRM DEQ20130326486, FRC, Brain Canada Multi-Investigator Research Initiative, Djavad Mowafaghian Foundation, ERANET-Neuron Joint Transnational Call for "European Research Projects on Mental Disorders", INSERM, CNRS and UPMC. The research teams of SEM, SJ, MM, JC-PV, BG and FB are members of the Bio-Psy Laboratory of Excellence; this work was therefore supported by French state funds managed by the ANR within the Investissements d'Avenir program under reference ANR-11-IDEX-0004-02. DYS was funded by the École des Neurosciences de Paris. This work was also supported by the City of Paris and Inserm Atip-Avenir to MM. FV was supported by grants from the Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie (MILDT, 2006); the Département de la Recherche Clinique et du Développement-Assistance Publique Hôpitaux de Paris (DRCD-APHP,OST07013); and from the Programme Hospitalier de Recherches Cliniques (PHRC program,AOM10165). The Cellular Imaging and Flow Cytometry Facility is supported by the Conseil Régional Ile-de-France.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Sakae YS, Marti F, Lecca S, Vorspan F, Martín-García E, Morel LJ et al. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Molecular Psychiatry. 2015;20(11):1448-59. DOI: 10.1038/mp.2015.104ca
• dc.identifier.doi http://dx.doi.org/10.1038/mp.2015.104
• dc.identifier.issn 1359-4184
• dc.identifier.uri http://hdl.handle.net/10230/25641
• dc.language.iso engca
• dc.publisher Nature Publishing Groupca
• dc.relation.ispartof Molecular Psychiatry. 2015;20(11):1448-59
• dc.rights © Nature Publishing Group. http://dx.doi.org/10.1038/mp.2015.104ca
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Addiction
• dc.subject.keyword Nucleus accumbens
• dc.subject.keyword Cholinergic interneurons (TANs)
• dc.subject.keyword Co-transmission
• dc.subject.keyword Acetylcholine
• dc.subject.keyword Glutamate
• dc.subject.keyword Vesicular acetylcholine transporter (VAChT)
• dc.subject.keyword Vesicular glutamate transporter type 3 (VGLUT3)
• dc.subject.other Cocaïnaca
• dc.title The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbensca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca