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Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments

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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.

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Acknowledgments

This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique UMR 3571& 7102, Agence Nationale pour la Recherche, Fondation pour la Recherche Médicale, Neuropole de Recherche Francilien of Ile de France, National Cancer Institute INCa BIO-SILC programme, Ecole des Neurosciences de Paris, EU FP7 ERANET Neuron NICO-GENE network, LabEx BIOPSY funded by ANR, Italian Ministry of Health RF2009-154961. We thank M. Soudant for lentivirus production, C. Morel for sharing vectorized mice and B. Forget for comments on the work and manuscript.

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Correspondence to Morgane Besson.

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Besson, M., Guiducci, S., Granon, S. et al. Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments. Psychopharmacology 233, 3297–3314 (2016). https://doi.org/10.1007/s00213-016-4362-2

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