Contingent-behavior assay to study the neurogenetics of addiction shows zebrafish preference for alcohol is biphasic

Alcohol use disorders are complex, multifactorial phenomena with a large footprint within the global burden of diseases. Here, we report the development of an accessible, two-choice self-administration zebrafish assay (SAZA) to study the neurobiology of addiction. Using this assay, we first demonstrated that, while zebrafish avoid higher concentrations of alcohol, they are attracted to low concentrations. Pre-exposure to alcohol did not change this relative preference, but acute exposure to an alcohol deterrent approved for human use decreased alcohol self-administration. A pigment mutant used in whole-brain imaging studies displayed a similar relative alcohol preference profile, however, mutants in CCSER1, a gene associated with alcohol dependence in human genetic studies, showed a reversal in relative preference. The presence of a biphasic response (hormesis) in zebrafish validated a key aspect of vertebrate responses to alcohol. SAZA adds a new dimension for discovering novel alcohol deterrents, and studying the neurogenetics of addiction using the zebrafish.