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Nicotine consumption is regulated by a human polymorphism in dopamine neurons

Molecular Psychiatry volume 19, pages 930–936 (2014)Cite this article

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Abstract

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5−/− mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

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Acknowledgements

We would like to thank Stefania Tolu for helpful comments on the manuscript. This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique CNRS UMR 3571, UMR 7102 and ATIP programme, the Agence Nationale pour la Recherche (ANR Neuroscience, Neurologie et Psychiatrie 2009, and ANR BLANC 2012), la Fondation pour la Recherche Médicale (FRM, équipe 2013 PF), fondation pour la the Neuropole de Recherche Francilien (NeRF) of Ile de France, the Bettencourt Schueller Foundation, National Cancer Institute INCa BIO-SILC programme, Ecole des Neurosciences de Paris (ENP), FP7 ERANET Neuron NICO-GENE network, LabEx GENMED funded by ANR, and NIH grants DA029157 and U19CA148127. This work was supported by the Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy. The laboratories of Philippe Faure, Uwe Maskos and Bertrand Lambolez are part of the École des Neurosciences de Paris Ile-de-France RTRA network. PF and UM are members of the Laboratory of Excellence, LabEx Bio-Psy.

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Author notes

  1. C Morel, L Fattore, U Maskos and P Faure: These authors contributed equally to this work.

Authors and Affiliations

  1. Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France

    C Morel, F Marti & P Faure

  2. CNR Neuroscience Institute, Cagliari, National Research Council, Italy, Cittadella Universitaria, Monserrato, Italy

    L Fattore

  3. Institut Pasteur, Unité Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France

    S Pons & U Maskos

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

    Y A Hay & B Lambolez

  5. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    M De Biasi

  6. McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada

    M Lathrop

  7. Fondation Jean Dausset, CEPH, Paris, France

    M Lathrop

  8. Department of Biomedical Sciences, University of Cagliari Cittadella Universitaria, Monserrato, Italy

    W Fratta

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Correspondence to U Maskos or P Faure.

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Morel, C., Fattore, L., Pons, S. et al. Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol Psychiatry 19, 930–936 (2014). https://doi.org/10.1038/mp.2013.158

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