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.

Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments / Besson, Morgane; Guiducci, Stefania; Granon, Sylvie; Guilloux, Jean Philippe; Guiard, Bruno; Repérant, Christelle; Faure, Philippe; Pons, Stéphanie; Cannazza, Giuseppe; Zoli, Michele; Gardier, Alain M.; Maskos, Uwe. - In: PSYCHOPHARMACOLOGY. - ISSN 0033-3158. - STAMPA. - 233:18(2016), pp. 3297-3314. [10.1007/s00213-016-4362-2]

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

GUIDUCCI, Stefania;CANNAZZA, Giuseppe;ZOLI, Michele;MASKOS, UWE
2016-01-01

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.
6-lug-2016
233
18
3297
3314
Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments / Besson, Morgane; Guiducci, Stefania; Granon, Sylvie; Guilloux, Jean Philippe; Guiard, Bruno; Repérant, Christelle; Faure, Philippe; Pons, Stéphanie; Cannazza, Giuseppe; Zoli, Michele; Gardier, Alain M.; Maskos, Uwe. - In: PSYCHOPHARMACOLOGY. - ISSN 0033-3158. - STAMPA. - 233:18(2016), pp. 3297-3314. [10.1007/s00213-016-4362-2]
Besson, Morgane; Guiducci, Stefania; Granon, Sylvie; Guilloux, Jean Philippe; Guiard, Bruno; Repérant, Christelle; Faure, Philippe; Pons, Stéphanie; Cannazza, Giuseppe; Zoli, Michele; Gardier, Alain M.; Maskos, Uwe
File in questo prodotto:
File Dimensione Formato  
Alterations in alpha5.pdf

non disponibili

Tipologia: Versione pubblicata dall'editore
Dimensione 4.63 MB
Formato Adobe PDF
4.63 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1116237
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 13
social impact