RGD Reference Report - A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats. - Rat Genome Database

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A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats.

Authors: Forget, Benoit  Scholze, Petra  Langa, Francina  Morel, Carole  Pons, Stephanie  Mondoloni, Sarah  Besson, Morgane  Durand-de Cuttoli, Romain  Hay, Audrey  Tricoire, Ludovic  Lambolez, Bertrand  Mourot, Alexandre  Faure, Philippe  Maskos, Uwe 
Citation: Forget B, etal., Curr Biol. 2018 Oct 22;28(20):3244-3253.e7. doi: 10.1016/j.cub.2018.08.044. Epub 2018 Oct 4.
RGD ID: 14694852
Pubmed: PMID:30293722   (View Abstract at PubMed)
DOI: DOI:10.1016/j.cub.2018.08.044   (Journal Full-text)

Tobacco addiction is a chronic and relapsing disorder with an important genetic component that represents a major public health issue. Meta-analysis of large-scale human genome-wide association studies (GWASs) identified a frequent non-synonymous SNP in the gene coding for the α5 subunit of nicotinic acetylcholine receptors (α5SNP), which significantly increases the risk for tobacco dependence and delays smoking cessation. To dissect the neuronal mechanisms underlying the vulnerability to nicotine addiction in carriers of the α5SNP, we created rats expressing this polymorphism using zinc finger nuclease technology and evaluated their behavior under the intravenous nicotine-self-administration paradigm. The electrophysiological responses of their neurons to nicotine were also evaluated. α5SNP rats self-administered more nicotine at high doses and exhibited higher nicotine-induced reinstatement of nicotine seeking than wild-type rats. Higher reinstatement was associated with altered neuronal activity in several discrete areas that are interconnected, including in the interpeduncular nucleus (IPN), a GABAergic structure that strongly expresses α5-containing nicotinic receptors. The altered reactivity of IPN neurons of α5SNP rats to nicotine was confirmed electrophysiologically. In conclusion, the α5SNP polymorphism is a major risk factor for nicotine intake at high doses and for relapse to nicotine seeking in rats, a dual effect that reflects the human condition. Our results also suggest an important role for the IPN in the higher relapse to nicotine seeking observed in α5SNP rats.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Chrna5Ratbehavioral response to nicotine  IMP  RGD 
Chrna5Ratcellular response to nicotine  IMP  RGD 
Chrna5Ratregulation of neuronal action potential  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Chrna5Ratimpaired behavioral response to nicotine  IMP  RGD 
Chrna5em18PasRatimpaired behavioral response to nicotine  IMP  RGD 
LE-Chrna5em18PasRatimpaired behavioral response to nicotine  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Chrna5  (cholinergic receptor nicotinic alpha 5 subunit)
Chrna5em18Pas  (cholinergic receptor, nicotinic, alpha 5 (neuronal); ZFN induced mutant 18,Pas)

Strains
LE-Chrna5em18Pas  (NA)

Objects referenced in this article
Gene Chrna5em20(D398N)Pas cholinergic receptor, nicotinic, alpha 5 (neuronal); ZFN induced mutant 20,Pas Rattus norvegicus
Strain LE-Chrna5em20(D398N)Pas null Rattus norvegicus

Additional Information