Repurposing FDA-Approved Drugs to Target Chronic Alcohol Tolerance - Abstract Alcohol Use Disorder (AUD) is a complex brain disease characterized by excessive alcohol consumption, leading to severe consequences and chronic tolerance, where increasing amounts of alcohol are needed to achieve the same effects. Understanding the mechanisms of chronic tolerance is crucial for developing effective treatments yet remains challenging. Compounds targeting serotonin signaling, such as psychedelics, have shown potential for treating AUD. However, their mechanisms of action are not fully understood, and drugs with histories of abuse or controversy face significant challenges in gaining clinical acceptance, often requiring additional time and costs for regulatory approval. To surmount this hurdle, we propose the development of a rapid and reliable platform for the evaluation and repurposing of compounds, including FDA-approved drugs, for the treatment of AUD and comorbidities. We employ the nematode Caenorhabditis elegans as an AUD model, effectively replicates key features of AUD, providing valuable insights into its neural and molecular underpinnings. Our goal is to identify compounds that suppress chronic ethanol tolerance and dependence. Using the FDA- approved drug library, we will conduct in vivo phenotypic screening in C. elegans, focusing on behaviors linked to ethanol and serotonin tolerance. Additionally, we will identify the molecular components within the serotonergic system that influence these behaviors. Our high-throughput (HTP) locomotor activity tracking system will facilitate reliable data acquisition and comprehensive assessment of chemical impacts, accelerating the development of novel AUD therapeutics. In summary, our innovative approach combines endophenotypic screening with the repurposing of FDA- approved drug libraries. This strategy offers a rapid and efficient means of gaining insights into AUD mechanisms, ultimately advancing the development of novel therapeutics for this intricate disorder and its associated comorbidities.
