Genetic analysis of psychoplasticity in C. elegans - PROJECT SUMMARY Growing clinical evidence suggests that psychedelics are effective in treating intractable psychiatric dis- eases, including depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD). These diseases are characterized by cortical neuron atrophy and dysfunction. New evidence indicates that psychedel- ics may reverse this process by acting as psychoplastogens, substances that induce neurons to form new branches and synaptic connections. There is now a concerted effort to enhance psychedelics for widespread therapeutic use. The prevailing paradigm in drug development has focused on seeking compounds that selectively target a single molecular site, known as the magic-bullet approach. However, the most effective psychiatric drugs seem to be superior precisely because they are polypharmacological, targeting multiple sites. Thus, defining the polypharmacology of psychedelics in relation to psychoplastogenicity is essential for their optimization. The overarching goal of the proposed research is to determine the degree of polypharmacology of rep- resentative psychedelics concerning behavior and psychoplasticity using the classical genetic organism, C. ele- gans. Psychedelics primarily activate serotonin receptors (5-HTRs). Mammals have seven families of 5-HTRs. C. elegans has six 5-HTR genes encoding orthologs of five mammalian families, indicating significant conserva- tion. We aim to evaluate the degree of polypharmacology of representative psychedelics in terms of behavior and psychoplasticity. Regarding behavior, we have established that DOI reduces the probability of immobility and increases fast forward locomotion in C. elegans, akin to DOI-induced hyperactivity in mice. Regarding psy- choplasticity, we have preliminary evidence of this phenomenon in C. elegans, particularly in the PVD neurons, which have an intricate, grid-like dendritic arbor commonly used to study molecular mechanisms of dendritogen- esis. This research is innovative as it significantly departs from conventional rodent models, in utilizing the invertebrate genetic model, C. elegans, to explore mechanisms of action. The research is significant as it could deepen our understanding of 5-HTR polypharmacology and establish a new in vivo platform for uncovering the genetic and molecular mechanisms of psychedelic action. This platform could also facilitate rapid, cost-effective screening of modified psychedelic compounds currently in development in academia and industry.
