Identification of <i>slit3</i> as a locus affecting nicotine preference in zebrafish and human smoking behaviour.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32209227.
- Also identified by DOI 10.7554/eLife.51295 and PMC identifier 7096180.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 F<sub>3</sub> sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F<sub>0</sub> fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F<sub>3</sub> fish, one in the <i>slit3</i> gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human <i>SLIT3</i> locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of <i>slit3</i> 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 <i>htr1aa</i> 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.
Medical subject headings
- Conditioning, Classical
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins
- Nicotine
- Tobacco Smoking
- Zebrafish Proteins