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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice with ovalbumin-induced asthma |
| Topics | Serotonin |
| Keywords | Functional selectivity Agonist 5-HT Receptor Inflammation Context archaeology Pharmacology Arginase Immunology Biochemistry Arginine Amino acid |
| Citations | 18 |
| Key findings | (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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 16
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies Progress in Neuro-Psychopharmacology and Biological Psychiatry September 7, 2024
- Psychedelics, entactogens and psychoplastogens for depression and related disorders British Journal of Pharmacology June 15, 2025
- Are we hallucinating or can psychedelic drugs modulate the immune system to control inflammation? British Journal of Pharmacology July 28, 2025
- Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective. Acta Neuropsychiatrica July 25, 2025
and 11 more in the library
Cites 9
- Psychedelics as Medicines: An Emerging New Paradigm Clinical Pharmacology & Therapeutics November 4, 2016
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- Psychedelics as anti-inflammatory agents International Review of Psychiatry July 4, 2018
- Psychedelic Drugs in Biomedicine TIPS - Trends in Pharmacological Sciences September 22, 2017
- The History of Psychedelics in Psychiatry Pharmacopsychiatry December 7, 2020
and 4 more in the library