Gene involved in nicotine addiction identified

Summary: Study implicated the Slit3 gene in nicotine addiction.

Source: Queen Mary University London

Researchers at Queen Mary University of London have shown that zebrafish can provide genetic clues to smoking, a complex human behavior.

By studying genetically-altered zebrafish they were able to pinpoint a human gene, Slit3, involved in nicotine addiction and also discover the ways in which it may act.

While zebrafish have been used extensively in genetic research, they’ve been used only in developmental models, such as identifying genes associated with disease, rather than to predict genes involved in a complex cognitive behaviour such as smoking.

Although smoking has long been known to have a genetic element, relatively little has been known about the genes involved since it has been difficult to identify them from human studies alone.

In a study published in eLife journal, the researchers tested families of genetically altered zebrafish for nicotine preference. When one family showed a much stronger nicotine preference compared to the others, the researchers identified all the mutations in the family, eventually narrowing down to a mutation in the Slit3 gene linked to the behaviour.

To see if the same gene affected nicotine preference in people, the researchers looked for association between variants in the human Slit3 gene and smoking behaviour, such as decreased or increased desire to smoke and how easy it was to quit, in groups of people in the UK and Finland. They found 3 variants in the human Slit3 gene that were significantly linked to smoking activity.

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To then learn more about how the Slit3 gene might be working, the researchers tested both mutant and wild type fish for sensitivity to a dopaminergic drug. The image is in the public domain.

To then learn more about how the Slit3 gene might be working, the researchers tested both mutant and wild type fish for sensitivity to a dopaminergic drug. In humans this drug affects the startle reflex – our physical reaction to a sudden loud noise – that is linked to addictions, including nicotine addiction. When tested with the startle reaction, the mutant fish showed decreased sensitivity to the drug. After testing various different receptors that might be involved in the reduced drug sensitivity, the researchers found that only one receptor was implicated – the serotonin receptor 5HT 1AA.

Caroline Brennan, Professor of Molecular Genetics at Queen Mary University of London, led the research. She explained: “This gives us a hypothesis for how the Slit3 gene works in humans. It is somehow altering the level of serotonin receptors present; and the differences in the levels are presumably then influencing sensitivity to nicotine addiction.”

Professor Brennan added: “As well as finding out more about the genes involved in nicotine addiction, most importantly, we’ve found an easier way of finding these genes in the future. Although zebrafish are a ‘lower’ organism, they have a similar genetic structure to humans and share 70% of genes with us. 84% of genes known to be associated with human disease have a zebrafish counterpart; and while there has been scepticism regarding their usefulness in terms of human cognition, we have shown that they can give insight into the genetics of that as well.”

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Source:
Queen Mary University London
Media Contacts:
Samantha Rey – Queen Mary University London
Image Source:
The image is in the public domain.

Original Research: Open access
“Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour”. Judit García-González, Alistair J Brock, Matthew O Parker, Riva J Riley, David Joliffe, Ari Sudwarts, Muy-Teck Teh, Elisabeth M Busch-Nentwich, Derek L Stemple, Adrian R Martineau, Jaakko Kaprio, Teemu Palviainen, Valerie Kuan, Robert T Walton, Caroline H Brennan.
eLife doi:10.7554/eLife.51295.

Abstract

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

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.

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