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

Molecular Psychiatry volume 20, pages 1448–1459 (2015)Cite this article

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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.

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Acknowledgements

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 s.e.m., 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. We thank Emily Nichols for recruiting patients and data analysis. We also thank Dr Ryad Tamouza for providing DNA sample controls from Africa.

Author contributions

DYS, LJM, EM-G and JG-C performed the behavioral experiments with the help of SD. FM performed the in vivo electrophysiology and voltammetry with the help of DYS, LM and AG. DYS and LJM performed the anatomical experiments with the help of SB and EH. DYS, LJM and AB performed the biochemical measurements with the help of NH, PV and JC. MM and SL performed the in vitro electrophysiology experiments. The genetic studies were designed by SJ and performed by SJ with the help of FV, AH and FB. CBE, SC, FV and FB recruited subjects with severe addiction and unaffected controls. VFP and MAMP generated the VAChT mutant mice and helped with the manuscript. SEM designed the study and wrote the manuscript with the help of DYS, FM, RM, BG, MM and SJ.

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Author notes

  1. D Y Sakae, F Marti and S Lecca: These authors contributed equally to this work.

Authors and Affiliations

  1. Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France

    D Y Sakae, F Marti, S Lecca, L J Morel, A Besnard, N Heck, E Herzog, P Vanhoutte, J Caboche, B Giros, S Daumas, M Mameli & S El Mestikawy

  2. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France

    D Y Sakae, F Marti, L J Morel, A Besnard, N Heck, E Herzog, P Vanhoutte, J Caboche, B Giros, S Daumas & S El Mestikawy

  3. Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France

    D Y Sakae, F Marti, L J Morel, A Besnard, N Heck, E Herzog, P Vanhoutte, J Caboche, B Giros, S Daumas & S El Mestikawy

  4. Department of Psychiatry, Douglas Hospital Research Center, McGill University, Verdun, QC, Canada

    D Y Sakae, F Marti, L J Morel, A Gratton, L Moquin, B Giros & S El Mestikawy

  5. Institut du Fer à Moulin, Paris, France

    S Lecca & M Mameli

  6. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 839, Paris, France

    S Lecca & M Mameli

  7. Fondation FondaMental, Créteil, France

    F Vorspan, A Henrion, F Bellivier, B Giros, S Jamain & S El Mestikawy

  8. 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

    F Vorspan & F Bellivier

  9. Assistance Publique-Hôpitaux de Paris, GH Saint Louis—Lariboisière—F Widal, Service de Psychiatrie, Paris, France

    F Vorspan & F Bellivier

  10. Institut National de la Santé et de la Recherche Médicale (INSERM U955), Psychiatrie Translationnelle, Créteil, France

    F Vorspan, A Henrion, F Bellivier & S Jamain

  11. Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain

    E Martín-García, J Gutiérrez-Cuesta & R Maldonado

  12. Université Paris Est, Faculté de Médecine, Créteil, France

    A Henrion & S Jamain

  13. Assistance Publique-Hôpitaux de Paris, Hôpital H. Mondor—A Chenevier, Pôle de Psychiatrie, Créteil, France

    A Henrion & S Jamain

  14. Cellular Imaging Facility, Institut de Biologie Paris Seine (IBPS), Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Paris, France

    S Bolte

  15. Department of Anatomy and Cell Biology and Department of Physiology and Pharmacology, Robarts Research Institute, The University of Western Ontario, London, ON, Canada

    V F Prado & M A M Prado

  16. Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland

    C B Eap & S Crettol

  17. Department of Pharmaceutical Sciences, School of Pharmacy, University of Geneva, University of Lausanne, Geneva, Switzerland

    C B Eap

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  1. D Y Sakae
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  2. F Marti
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  25. M Mameli
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Correspondence to S Jamain or S El Mestikawy.

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Sakae, D., Marti, F., Lecca, S. et al. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Mol Psychiatry 20, 1448–1459 (2015). https://doi.org/10.1038/mp.2015.104

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