Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression
Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato, Pek Yee Lum, Brent Louie, Gavin Song, Adam L. Halberstadt, Gerald Billac, Charles D. Nichols
ACS Pharmacology & Translational Science January 25, 2024 DOI: 10.1021/acsptsci.3c00297 via OpenAlex
Summary
Two psychedelic compounds, (R)-DOI and (R)-DOTFM, both activate the serotonin 2A receptor with comparable in vitro activity and behavioral potency, yet only (R)-DOI prevents inflammation and airway hyperresponsiveness in a mouse model of asthma. The compounds produce distinct differences in protein expression and inflammatory-related gene expression in lung tissue. The anti-inflammatory effects of certain psychedelics involve suppression of arginase 1 expression, revealing key mechanistic components of their anti-inflammatory action.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice with ovalbumin-induced asthma |
| Topics | Serotonin |
| Keywords | Functional selectivity Agonist 5-HT Receptor Inflammation |
| Citations | 18 |
| Key finding | (R)-DOI, but not (R)-DOTFM, prevents inflammation and elevated airway hyperresponsiveness in an acute murine asthma model, with distinct differences in protein and gene expression in pulmonary tissues. |
Abstract
Functional selectivity in the context of serotonin 2A (5-HT 2A ) receptor agonists is often described as differences psychedelic compounds have in the activation of Gq vs β-arrestin signaling in the brain and how that may relate to inducing psychoactive and hallucinatory properties with respect to each other. However, the presence of 5-HT 2A receptors throughout the body in several cell types, including endothelial, endocrine, and immune-related tissues, suggests that functional selectivity may exist in the periphery as well. Here, we examine functional selectivity between two 5-HT 2A receptor agonists of the phenylalkylamine class: ( R )-2,5-dimethoxy-4-iodoamphetamine [( R )-DOI] and ( R )-2,5-dimethoxy-4-trifluoromethylamphetamine [( R )-DOTFM]. Despite comparable in vitro activity at the 5-HT 2A receptor as well as similar behavioral potency, ( R )-DOTFM does not exhibit an ability to prevent inflammation or elevated airway hyperresponsiveness (AHR) in an acute murine ovalbumin-induced asthma model as does ( R )-DOI. Furthermore, there are distinct differences between protein expression and inflammatory-related gene expression in pulmonary tissues between the two compounds. Using ( R )-DOI and ( R )-DOTFM as tools, we further elucidated the anti-inflammatory mechanisms underlying the powerful anti-inflammatory effects of certain psychedelics and identified key mechanistic components of the anti-inflammatory effects of psychedelics, including suppression of arginase 1 expression.