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

Rationale: Evidence links alterations in \u3b15-containing nicotinic receptors (\u3b15*-nAChRs) to nicotine addiction. Notably, the rs16969968 polymorphism in the \u3b15 gene (\u3b15SNP) increases the risk for heavy smoking and impairs nicotine-rewarding properties in mice. Additional work is needed to understand how native and polymorphic \u3b15*-nAChRs contribute to processes associated with the risk for nicotine addiction. Objectives: We aimed at understanding the contribution of \u3b15*-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 \u3b15 gene (\u3b15 12/ 12). 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 \u3b15 wild-type allele or the \u3b15SNP in specific brain areas of \u3b15 12/ 12 mice. Results: \u3b15 12/ 12 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 \u3b15 12/ 12 mice. Re-expression of \u3b15 in the ventral tegmental area and hippocampus rescued rearing and anxiety levels in \u3b15 12/ 12 mice, respectively. When expressing the \u3b15SNP instead, this resulted in a knockout-like phenotype for both behaviours. Conclusions: We propose that altered \u3b15*-nAChR cholinergic signalling contributes to emotional/behavioural impairments that may be alleviated by nicotine consumption