Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress.

A single low dose of the psychedelic compound (R)-DOI, a selective 5-HT2A receptor partial agonist, can shift stress-coping behavior in male mice exposed to repeated social aggression. In the Stress Alternatives Model, mice that typically adopt reactive, vulnerable coping strategies (Stay) showed increased escape behavior, more attention to escape routes, and reduced freezing after treatment. These behavioral changes were accompanied by reduced levels of the inflammatory cytokine TNFα in both plasma and limbic brain regions. Stay animals had heightened cytokine gene expression, and both Stay and Escape mice showed elevated TNFα compared to unstressed controls. The findings suggest that (R)-DOI's anxiolytic effects may be linked to its anti-inflammatory properties.

Study at a glance

Abstract

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.