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

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.

Behavioral Effects of Developmental Exposure to JWH-018 in Wild-Type and Disrupted in Schizophrenia 1 (disc1) Mutant Zebrafish

“…Defective habituation is also associated with neuropsychiatric disorders, such as schizophrenia [ 23 ]. In zebrafish assays of response to acoustic startle, a progressive reduction in mean distance travelled with stimulus number gives an indication of habituation [ 24 , 25 ].…”

Differential impact of dose-range glyphosate on locomotor behavior, neuronal activity, glio-cerebrovascular structures, and transcript regulations in zebrafish larvae

“…Nevertheless, the possibility of a binary mixture toxicity associated with PTU and the varying glyphosate concentrations cannot be completely excluded. Regarding our behavioral analyses we here acknowledge that, while 4 dpf zebrafish embryos do not respond to an acoustic startle, 5 dpf zebrafish do (Best et al, 2008;Bhandiwad et al, 2013;Zeddies and Fay, 2005) and they were used by others when testing chemicals (García-González et al, 2020;Wolman et al, 2011).…”

Behavioral effects of developmental exposure to JWH-018 in wild type and disrupted in schizophrenia 1 (disc1) mutant zebrafish

“…Conditioned place preference (CPP), where drug exposure is paired with specific environmental cues, is commonly used as a measure of drug-induced reinforcement and reward [56]. Previous studies have shown that zebrafish show a robust CPP to nicotine [57–60] . Here, we show developmental exposure to 0.15 μM nicotine lead to altered sensitivity of the drug-induced reinforcement and reward as measured in CPP (See [57] for methodology on the CPP assay). Fish that were not developmentally treated with nicotine showed a small increase in preference when conditioned with 5 μM nicotine.…”

“…Conditioned place preference (CPP), where drug exposure is paired with specific environmental cues, is commonly used as a measure of drug-induced reinforcement and reward [56]. Previous studies have shown that zebrafish show a robust CPP to nicotine [57–60] .…”

“…Here, we show developmental exposure to 0.15 μM nicotine lead to altered sensitivity of the drug-induced reinforcement and reward as measured in CPP (See [57] for methodology on the CPP assay). Fish that were not developmentally treated with nicotine showed a small increase in preference when conditioned with 5 μM nicotine.…”