Substance use disorders are neurobehavioral disorders in which afflicted individuals continue to use a substance despite its adverse effects on their lives. Opioids and cocaine use were responsible for 70% and 22%,respectively, of drug overdose deaths in the US alone in 2019. While there are FDA-approved treatments foropioid use disorders, no such therapeutics are available for cocaine addiction. Opioids have a well-characterizedmechanism of action in the brain. However, cocaine targets multiple neurotransmitter pathways, and themolecular basis of addiction has not been elucidated. A significant challenge in discovering new therapeutics forcocaine use disorders (CUD) is the need to perform behavioral assays on animals to determine if a candidatedrug reduces or abolishes addictive behavior. The need for behavioral assays in rodents is not compatible withhigh-throughput drug discovery screens. NemaLife, Inc. has developed a microfluidic platform that enables high-throughput in vivo screening using thenematode Caenorhabditis elegans. Video data recorded by our platform is automatically processed by our AIanalysis pipeline NemaStudio.ai for metrics such as live/dead and animal activity. This Phase 1 project willimplement additional machine learning algorithms into NemaStudio.ai to classify worm behavior. This newfunctionality will enable us to perform high-throughput behavioral profiling of animals. This form of behavioralprofiling using worm models of CUD is expected to rapidly identify new treatments for cocaine addiction. Aim 1 - Develop high-throughput AI-assisted behavioral profiling assays for cocaine use disorders. Inthis aim, we will take existing worm CUD paradigms and optimize them for our microfluidic platform. Specifically,we will create microfluidic chip-based versions of cue-conditioned place preference and self-administration CUDparadigms. Once these assays are developed, we will collect large datasets of animal behavior either on or offcocaine. This data will then be used to train NemaStudio.ai to classify and quantify addictive behaviors in animalsexposed to cocaine and form our behavioral profiling pipeline. Aim 2 - Identify potential CUD therapeutics from a targeted library of psychedelic compounds. Withour screening pipeline in place, we will examine whether psychedelic compounds, which are known to have anti-addiction properties, might represent a new source of treatments for CUD. We will screen a variety of psychedeliccompounds, select the top candidates, and perform RNA-seq on psychedelic-treated and untreated CUDanimals. This data will help identify possible mechanisms of action by which these candidates reduce/abolishthe effects of cocaine addiction in the worm. Our data-driven insights will enable targeted rodent studies for pre-clinical validation of the hit compounds. In sum, this work leverages AI tools to build a high throughput in vivodrug discovery platform to accelerate the development of new therapeutics for CUD.
Public Health Relevance Statement: Project Narrative
There has been a significant increase in the global number of people suffering from substance use disorders,
with the two major causes of drug overdose deaths being opioid and cocaine use. While FDA-approved
treatments exist for opioid use disorders, no such remedies are available for cocaine addiction. Our Phase 1
project combines NemaLife's microfluidic in vivo screening platform with new AI tools to perform high-throughput
behavioral screens to identify new therapeutics for cocaine addiction.
Project Terms: