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Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour

García-González, J; Brock, AJ; Parker, MO; Riley, RJ; Joliffe, D; Sudwarts, A; Teh, M-T; ... Brennan, CH; + view all (2020) Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour. eLife , 9 , Article e51295. 10.7554/eLife.51295. Green open access

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Abstract

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

Type: Article
Title: Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.51295
Publisher version: http://dx.doi.org/10.7554/eLife.51295
Language: English
Additional information: © 2020, García-González et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: acoustic startle, conditioned place preference, gene association, neuroscience, nicotine, slit3, smoking, zebrafish
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology
URI: https://discovery.ucl.ac.uk/id/eprint/10122924
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