chrna3 modulates alcohol response.

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 personalised interventional strategies. Here, we used a two-choice self-administration zebrafish assay (SAZA) to isolate the function of nicotinic acetylcholine receptor (nAChR) subunit alpha3 (chrna3) in alcohol response. Juvenile zebrafish, of either sex, prior to complete sex differentiation, were examined in this study. They 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, while sedative effects became prominent at higher concentrations resulting in reduced locomotion and uncoordinated swimming. In contrast, these responses are blunted in chrna3 mutants. They exhibited prolonged alcohol self-administration, and increased gregariousness. Transcriptomic analyses suggest that glutamatergic and GABAergic neurotransmission alongside cholinergic signalling is impacted in the mutant brains. Our results thus suggest that chrna3 dysfunction has a systemic change with an increase in alcohol tolerance being one effect. These findings also highlight the use of non-rodent alternatives to understand the neurogenetics of development of AUD.Significance statement This study sheds light on how a specific gene, chrna3, influences the body's response to alcohol. Using a novel self-administration zebrafish assay (SAZA), we first discovered that zebrafish acute response to alcohol is biphasic. Changes in this chrna3 function can alter sensitivity and preference to alcohol. This is important because it helps elaborate on the genetic variance among people making them more, or less susceptible to alcohol dependence. Our findings also suggest that this gene plays a role in communication pathways within the brain, potentially impacting other related conditions. Ultimately, this work offers a new avenue for building empirically tested knowledge of genetic predisposition and paves the way for future personalised treatment plans.