Serotonergic psychedelic 5-MeO-DMT alters plasticity-related gene expression and generates anxiolytic effects in stressed mice
OpenAlex – December 28, 2023
Source: OpenAlex
Summary
A single high dose of the psychedelic 5-MeO-DMT significantly altered gene expression in key brain regions, impacting immediate early genes like Arc and Zif268. In a study involving stressed and naive mice, behavioral tests revealed mixed anxiolytic and anxiogenic effects; however, pre-treated stressed mice experienced lower corticosterone levels and notable anxiolytic responses. Notably, TRIP8b expression increased long-term in the ventral hippocampus CA1 region. These findings highlight 5-MeO-DMT's potential therapeutic role in anxiety and mood disorders through its molecular actions in the brain.
Abstract
Abstract Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. One lesser studied psychedelic, the 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), is suggested to have anxiolytic effects yet a comprehensive mechanism of action is still lacking. Here, we investigated the effects of a single high-dose of the short-acting 5-MeO-DMT on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus - DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 hr, 5 hrs or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA and vCA1, while only NR2A expression was altered after 5 hrs in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 hr or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior.