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 <i>CHRNA5</i> have been identified as risk factors in human genetic studies. Whether the <i>CHRNA5</i> 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 <i>chrna5</i>-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, <i>chrna5</i> mutants exhibited greater behavioral changes, but reduced transcriptomic changes compared with wild-type siblings, suggesting an impaired homeostatic regulation following drug exposure. <i>chrna5</i> 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.