Investigating pharmacotherapies for alcohol use disorder using Drosophila melanogaster.

Background: Drosophila melanogaster provides a powerful whole-organism approach for the therapeutic discovery of treatments for many disorders due to the ability to perform high-throughput drug studies with detailed molecular and cellular mechanisms. While Drosophila has been critical for identifying novel molecular and neural circuit mechanisms underlying alcohol responses, few studies assess the use of Drosophila for the investigation and discovery of pharmacological targets of alcohol use disorder (AUD). Determining appropriate doses that impact alcohol consumption and memory for alcohol reward without affecting acute locomotor responses is key to identifying effective AUD medications such as naltrexone, acamprosate, and topiramate. This pipeline can then be used to test novel pharmacotherapies, including γ-secretase inhibitors (such as dibenzazepine and compound E) as potential treatments for AUD.

Methods: To validate Drosophila as an effective model for studying pharmacological therapies for AUD, we identified nondisruptive drug doses in flies using feeding and locomotive assays. Then, we assessed their impact on ethanol consumption and conditioned preference in cue-induced alcohol-seeking after 1 or 3 days of training.

Results: Naltrexone and acamprosate significantly reduced ethanol food preference and 3-day conditioned preference, while topiramate did not. γ-secretase inhibitors dibenzazepine and compound E significantly decreased conditioned preference after 3 days.

Conclusion: Drosophila is a valuable model organism for identifying and characterizing new AUD pharmacotherapies.