chrna3 modulates biphasic response to alcohol
Alcohol use disorders (AUDs) are complex phenomena governed by genetics, neurophysiology, environment, and societal structures. New methods to understand the underlying neurogenetics are valuable for designing better prevention and interventional strategies. Here, we used a novel, two-choice self-administration zebrafish assay (SAZA) to isolate the function of nicotinic acetylcholine receptor (nAChR) subunit alpha3 ( chrna3 ) in alcohol response. Juvenile zebrafish exhibited a biphasic response when self-administering alcohol that transitioned from attraction to aversion within minutes, suggesting they can regulate exposure to alcohol. This inverted U-shaped self-administration mirrored the effect alcohol has on shoaling behaviour. Exposure to low concentration of alcohol reduced anxiety-like behaviours characterised by decrease in shoal cohesion, while sedative effects became prominent at higher concentrations resulting in reduced locomotion and uncoordinated swimming. In contrast, chrna3 mutants displayed blunted responses, exhibiting prolonged alcohol self-administration, and increased gregariousness when compared to wild-type fish. These findings suggest that chrna3 dysfunction increased tolerance to alcohol. In humans, genetic variants that decrease CHRNA3 function may increase the likelihood of developing alcohol dependence. Thus, our results provide new insights into chrna3 function, as a potential target for pharmacological manipulation, and highlight the use of non-rodent alternatives to study the neurogenetics of development of AUD.