Citation

Krupp KT, Yaeger JDW, Ledesma LJ, Withanage MHH, Gale JJ, Howe CB, Allen TJ, Sathyanesan M, Newton SS, Summers CH. Neuropharmacology 2024; ePub(ePub): ePub.

Copyright

(Copyright © 2024, Elsevier Publishing)

DOI

10.1016/j.neuropharm.2024.109949

PMID

38636726

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-HT(2A) 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 (TNF(α)) 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 (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects but also concomitantly to reduce the plasma and limbic brain levels of the inflammatory cytokine TNF(α).

Language: en

Keywords

anxiety; defeat; depression; fear conditioning; freezing; hypocretin; locomotion; neuroinflammation; psychedelic; PTSD; resilience; Stress-Alternatives Model; susceptibility