title: Nicotine consumption is regulated by a human polymorphism in dopamine neurons.
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.
authors.affiliation: Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Morel
authors.affiliation: CNR Neuroscience Institute, Cagliari, National Research Council, Italy, Cittadella Universitaria, Monserrato, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fattore
authors.affiliation: Institut Pasteur, Unité Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Pons
authors.affiliation: Université P. et M. Curie, CNRS UMR 7102, Neurobiologie des Processus Adaptatifs, Equipe Réseau cortical et couplage neurovasculaire, Paris, France.
authors.forename: Y A
authors.initials: YA
authors.lastname: Hay
authors.affiliation: Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Marti
authors.affiliation: Université P. et M. Curie, CNRS UMR 7102, Neurobiologie des Processus Adaptatifs, Equipe Réseau cortical et couplage neurovasculaire, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Lambolez
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: De Biasi
authors.affiliation: 1] McGill University and Genome Quebec Innovation Centre, Montréal, QC, Canada [2] Fondation Jean Dausset, CEPH, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Biomedical Sciences, University of Cagliari Cittadella Universitaria, Monserrato, Italy.
authors.forename: W
authors.initials: W
authors.lastname: Fratta
authors.affiliation: Institut Pasteur, Unité Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France.
authors.forename: U
authors.initials: U
authors.lastname: Maskos
authors.affiliation: Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Faure
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012054:Reinforcement, Psychology; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects
chemical_list: D009538:Nicotine; D011978:Receptors, Nicotinic; C523972:CHRNA5 protein, mouse