Morgane Besson1, Stefania Guiducci2, Sylvie Granon3, Jean-Philippe Guilloux4, Bruno Guiard4, Christelle Repérant4, Philippe Faure5, Stéphanie Pons6, Giuseppe Cannazza7, Michele Zoli2, Alain M Gardier4, Uwe Maskos6. 1. Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, 75724 cedex15, France. morgane.besson@pasteur.fr. 2. Department of Biomedical, Metabolic and Neural Sciences, Section of Physiology and Neurosciences, University of Modena and Reggio Emilia, Modena, 41121, Italy. 3. Neurobiologie de la Prise de Décision, Neuro-PSI, CNRS UMR 9197, Orsay, 91405, France. 4. Neuropharmacologie des troubles anxieux-dépressifs et neurogénèse, Université Paris-Sud XI, Chatenay-Malabry, 91290, France. 5. Neurobiologie des processus adaptatifs, Neurophysiologie et Comportement, Université Pierre et Marie Curie, Paris, 75005, France. 6. Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, CNRS UMR 3571, Institut Pasteur, Paris, 75724 cedex15, France. 7. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
Abstract
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We propose that altered α5*-nAChR cholinergic signalling contributes to emotional/behavioural impairments that may be alleviated by nicotine consumption.
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We propose that altered α5*-nAChR cholinergic signalling contributes to emotional/behavioural impairments that may be alleviated by nicotine consumption.
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