Role of chrna5 in multi-substance preference and phenotypes comorbid with the development of substance dependence

Addiction to nicotine and alcohol continues to be a leading cause of death and loss of productivity as measured in disability-adjusted life years. Polymorphisms in the nicotinic acetylcholine receptor subunit 5 (CHRNA5) have been identified as risk factors associated with nicotine dependence in human genetic studies and rodent models. Whether the chrna5 function is independently relevant to phenotypes associated with disorders comorbid with substance use, 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 that the chrna5 mutant fish exhibit an increased acute preference to both nicotine and alcohol in the Self-Administration Zebrafish Assay (SAZA). When subjected to multi-day exposures to either, chrna5 mutants exhibited greater behavioural change, but reduced transcriptomic changes compared to WT siblings, suggesting an impaired homeostatic regulation following drug exposure. Further, chrna5 mutants exhibited drug-independent changes in appetite and circadian rhythms, suggesting a genetic predisposition to disorders often comorbid with substance dependence. We expect these results to give new insights into the operation of genes whose normal function modulates vulnerability to multi-substance use and comorbid disorders.