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Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement

Molecular Psychiatry volume 18, pages 382–393 (2013)Cite this article

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Abstract

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

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Acknowledgements

We thank Benoît Forget and Henri Korn for helpful comments on the manuscript, and Jochen Roeper for help with slice electrophysiology. This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique CNRS URA 2182, UMR 7102, UMR 5287 and ATIP programme, the Agence Nationale pour la Recherche (ANR Neuroscience, Neurologie et Psychiatrie 2005 and 2009, and ANR BLANC 2009), Neuropôle IdF, INSERM U960, the RTRA Ecole des Neurosciences de Paris and the Bettencourt Schueller Foundation. The research leading to these results has received funding from the European Union Seventh Framework Programme under Grant no. HEALTH-F2-2008-202088 (‘NeuroCypres’ project to U.M.). ST acknowledges financial support from Fondation de la Recherche Médicale (FRM), and Pasteur-Weizmann.

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Author notes

  1. S Tolu, R Eddine, F Marti, P Faure and U Maskos: These authors contributed equally to this work.

Authors and Affiliations

  1. Département de Neuroscience, Institut Pasteur, Unité Neurobiologie intégrative des systèmes cholinergiques, Paris, France

    S Tolu, S Pons, M Besson & U Maskos

  2. CNRS, URA2182, Paris, France

    S Tolu, S Pons, M Besson, J-P Changeux & U Maskos

  3. Université P. et M. Curie, CNRS UMR 7102, Neurobiologie des Processus Adaptatifs, Equipe Neurophysiologie et comportement, Paris, France

    R Eddine, F Marti & P Faure

  4. Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Talence, France

    V David, M Baudonnat & M Husson

  5. Center for Neural Science, New York University, New York, NY, USA

    M Graupner

  6. EA3544 Pharmacologie des troubles anxio-dépressifs et Neurogenèse, Univ Paris-Sud, Fac Pharmacie, Châtenay-Malabry, France

    C Reperant, J Zemdegs & A M Gardier

  7. Université P. et M. Curie, INSERM UMRS 952, CNRS UMR 7224, Physiopathologie des Maladies du Système Nerveux Central, Equipe Signalisation Intracellulaire et Neuroadaptations, Paris, France

    C Pagès & J Caboche

  8. Université P. et M. Curie, CNRS UMR 7102, Neurobiologie des Processus Adaptatifs, Equipe Réseau cortical et couplage neurovasculaire, Paris, France

    Y A H Hay & B Lambolez

  9. Group for Neural Theory, LNC INSERM U960, DEC ENS, Paris, France

    B Gutkin

  10. Collège de France, Paris, France

    J-P Changeux

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  1. S Tolu
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  2. R Eddine
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Correspondence to P Faure or U Maskos.

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Tolu, S., Eddine, R., Marti, F. et al. Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement. Mol Psychiatry 18, 382–393 (2013). https://doi.org/10.1038/mp.2012.83

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