PROJECT SUMMARY/ABSTRACT The parent award is focused on studying the mechanisms of novel psychoactive agents, with an emphasis on phenethylamines. Some of these agents are hallucinogenic and induce pronounced long term changes in dendritic branching and synaptic plasticity (termed as psychoplastogens). Even acute treatments with dimethyltryptamine (DMT), an agent from a related class (an indole-alkylamine) results in long term synaptic rewiring. The mechanisms behind these effects are the focus of significant interest for neuropsychiatric disorders and may have applications for dementia and Alzheimer’s disease (AD). Recent evidence indicates they may work via direct activation of TrkB, but most investigations have focused on traditional targets associated with these agents, such as 5-HT1A/2A, and few studies have used AD models. We propose to study binding partners of psychoplastogens and effects of kinase signaling and gene expression in human AD patients derived iPSCs via multi-omic analysis.

Project Narrative There is an ongoing substance abuse epidemic in western society. Synthetic psychoactive agents are among the newest, most popular, and least understood of the abused substances. This work focuses on the development of a new platform to understand bath salts and related agents to define novel therapeutic targets to treat toxicity and episodic lethality.