Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour
Open Access
- 25 March 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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.Keywords
Funding Information
- Wellcome Trust (Clinical research fellowship WT 110284/Z/15/Z)
- National Institutes of Health (Project grant)
- Medical Research Council (G1000403)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (G1000053)
- Biotechnology and Biological Sciences Research Council (BB/M007863)
- National Institute for Health Research (PGfAR RP-PG-0609-10181)
- National Institute for Health Research (NIHR PGfAR RP-PG-0407-10398)
- National Institutes of Health (U01 DA 044400-03)
- National Institute for Health Research (NF-SI-0515-10076)
- Royal Society (Industry Fellows College)
- Academy of Finland (308248)
- Academy of Finland (312073)
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