title: Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments.
abstract: Evidence links alterations in α5-containing nicotinic receptors (α5*-nAChRs) to nicotine addiction. Notably, the rs16969968 polymorphism in the α5 gene (α5SNP) increases the risk for heavy smoking and impairs nicotine-rewarding properties in mice. Additional work is needed to understand how native and polymorphic α5*-nAChRs contribute to processes associated with the risk for nicotine addiction.
  
  
  
  We aimed at understanding the contribution of α5*-nAChRs to endophenotypes like increased responses to novelty and anxiety, known to promote vulnerability to addiction, and to the response of the dopamine and serotonin systems to nicotine.
  
  
  
  Behavioural phenotypes were investigated in mice lacking the α5 gene (α5(-/-)). Nicotine injections were performed to test the consequences of nicotine exposure on the phenotypes identified. Dopamine and serotonin signalling were assessed using in vivo microdialysis and electrophysiology. We used lentiviral vectors to compare the consequences of re-expressing either the α5 wild-type allele or the α5SNP in specific brain areas of α5(-/-) mice.
  
  
  
  α5(-/-) mice did not exhibit high responses to novelty but showed decreased novelty-induced rearing behaviour together with high anxiety. Exposure to high doses of nicotine rescued these phenotypes. We identified altered spontaneous and nicotine-elicited serotonin and dopamine activity in α5(-/-) mice. Re-expression of α5 in the ventral tegmental area and hippocampus rescued rearing and anxiety levels in α5(-/-) mice, respectively. When expressing the α5SNP instead, this resulted in a knockout-like phenotype for both behaviours.
  
  
  
  We propose that altered α5*-nAChR cholinergic signalling contributes to emotional/behavioural impairments that may be alleviated by nicotine consumption.
authors.affiliation: Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, 75724 cedex15, France. morgane.besson@pasteur.fr.
authors.forename: Morgane
authors.initials: M
authors.lastname: Besson
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Physiology and Neurosciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Guiducci
authors.affiliation: Neurobiologie de la Prise de Décision, Neuro-PSI, CNRS UMR 9197, Orsay, 91405, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Granon
authors.affiliation: Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud XI, Chatenay-Malabry, 91290, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud XI, Chatenay-Malabry, 91290, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Guiard
authors.affiliation: Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud XI, Chatenay-Malabry, 91290, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Repérant
authors.affiliation: Neurobiologie des processus adaptatifs, Neurophysiologie et Comportement, Université Pierre et Marie Curie, Paris, 75005, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Faure
authors.affiliation: Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, 75724 cedex15, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pons
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Physiology and Neurosciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.affiliation: Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud XI, Chatenay-Malabry, 91290, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, 75724 cedex15, France.
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012201:Reward; D012701:Serotonin / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000235:genetics; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D004298:Dopamine; D009538:Nicotine; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D012701:Serotonin; C523972:CHRNA5 protein, mouse
keywords: Addiction; Anxiety; Lentiviral vector; Mice; Monoamines; Nicotine; Nicotinic receptors; Novelty; Polymorphism; Vulnerability