Disruption of chrna5 blunts aversion and adaptive transcriptomic responses to nicotine and alcohol

Addiction to nicotine and alcohol continues to be a leading cause of death and loss of productivity. Polymorphisms in CHRNA5 have been identified as risk factors in human genetic studies. Whether the CHRNA5 function is independently relevant to phenotypes associated with substance abuse and if genetic factors influence subsequent outcomes when exposure to psychoactive substances happens at an early age, are questions of interest. We generated a stable mutant line in zebrafish using the CRISPR-Cas9 technique. We found the chrna5-mutant fish exhibited an increased acute preference to both nicotine and alcohol in the self-administration zebrafish assay (SAZA). When subjected to multi-day exposures to either drug, chrna5 mutants exhibited greater behavioral changes, but reduced transcriptomic changes compared with wild-type siblings, suggesting an impaired homeostatic regulation following drug exposure. chrna5 mutants also exhibited drug-independent changes in appetite and circadian rhythms. We expect these results to give new insights into genetic predisposition that modulates vulnerability to nicotine and alcohol abuse.