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.

中文翻译：

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将split3确定为影响斑马鱼尼古丁偏好和人类吸烟行为的场所

为了促进吸烟遗传学研究，我们确定了针对尼古丁偏好的诱变斑马鱼筛查是否可以预测影响吸烟行为的基因座。在30个经过筛选的F ₃兄弟姐妹组中，每个组均来自单独的乙基-硝基脲诱变的F ₀鱼，其中两个显示尼古丁偏爱增加或减少。在F ₃鱼携带的25个失活突变中，slit3基因中的一个突变与杂合子个体中尼古丁的偏好增加隔离。对来自英国（n = 863）和芬兰（n = 1715）的队列中人SLIT3基因座进行了重点SNP分析，发现了与香烟消费和戒烟可能性相关的两个变异。split3的特征突变幼虫和成年鱼显示出对多巴胺能和5-羟色胺能拮抗剂氨磺必利的敏感性降低，已知会影响与人类成瘾有关的惊吓反射，并且突变幼虫中的htr1aa mRNA表达增加。没有发现对神经元寻路的影响。这些发现揭示了SLIT3在影响斑马鱼对烟碱和人类吸烟的反应途径的发展中的作用。