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, although zebrafish avoid higher concentrations of alcohol, they are attracted to low concentrations. Preexposure 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.

Alcohol use disorders are poorly understood, complex, multifactorial phenomena with a very large footprint within the global burden of diseases. Methods to study the development of addiction have primarily focused on contingent behaviors in rodents. Here, we report the development of an accessible, two-choice self-administration zebrafish assay (SAZA). Using this assay, we 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, and acute exposure to a deterrent decreased self-exposure to preferred concentration. A pigment mutant used in whole-brain imaging studies also displayed a similar relative preference profile but administrated substantially larger volumes of alcohol. The presence of a biphasic response (hormesis) in zebrafish validated a key aspect of vertebrate responses to alcohol. Our findings reveal the underappreciated usefulness of zebrafish in studying the neurogenetics of alcohol addiction and the discovery of novel alcohol deterrents.

The cover image is based on the Original Article Contingent stimulus delivery assay for zebrafish reveals a role for CCSER1 in alcohol preference by Fatima Megala Nathan et al., https://doi.org/10.1111/adb.13126.