Dual Modulation of 5-HT2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers.
Justin M Silverman, Michael Fiorillo, Jason Younkin, Charles B Jones, Jessica L Maltman, Isaac Herszenhorn, Anaceli Artigas, Jennifer T Wolstenholme, Małgorzata Dukat, Javier González-Maeso
ACS chemical neuroscience December 17, 2025 Peer reviewed DOI: 10.1021/acschemneuro.5c00468 via PubMed
Summary
α-Ethyltryptamine (AET) and its isomers interact with the serotonin 5-HT2A receptor and serotonin transporter, influencing behavior in mice. While all forms of AET triggered a dose-dependent head-twitch response, only S(+)-AET showed partial agonist activity at the receptor. The head-twitch response was blocked by a specific antagonist, confirming the receptor's role. Notably, fluoxetine pretreatment inhibited the response to AET but not to the classical psychedelic DOI, suggesting a unique mechanism involving both direct receptor activation and serotonergic release.
Study at a glance
| Population | mice |
|---|---|
| Key finding | AET's behavioral effects involve dual mechanisms of direct 5-HT2AR activation and indirect serotonergic potentiation via SERT. |
Abstract
α-Ethyltryptamine (AET), a synthetic tryptamine formerly used as an antidepressant, has resurfaced as a compound of interest due to its structural and functional overlap with serotonergic psychedelics and entactogens. Here, we characterized the pharmacological properties of racemic AET and its optical isomers, R(-)-AET and S(+)-AET, focusing on their interactions with the serotonin (or 5-hydroxytryptamine) 5-HT2A receptor (5-HT2AR) and serotonin transporter (SERT). In vitro, all three compounds displaced [3H]ketanserin from 5-HT2AR with micromolar affinity; however, only S(+)-AET elicited weak partial agonist activity in calcium mobilization assays, an effect abolished by the 5-HT2AR antagonist volinanserin. In vivo, all forms of AET induced a dose-dependent effect on the head-twitch response (HTR) in mice, which was completely blocked by volinanserin, confirming the 5-HT2AR involvement. Notably, pretreatment with fluoxetine abolished AET-induced HTR without affecting responses to the classical psychedelic DOI, implicating SERT-mediated serotonin release in AET's mechanism of action. These findings indicate that AET's behavioral effects rely on a dual mechanism involving both direct 5-HT2AR activation and indirect serotonergic potentiation via SERT. This dual pharmacology distinguishes AET from classical psychedelics and places it within a unique niche alongside MDMA-like serotonergic agents, highlighting the therapeutic and neuropsychiatric potential of AET isomers for modulating mood and cognition.