Dual Modulation of 5-HT_2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers

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-HT_2A receptor (5-HT_2AR) and serotonin transporter (SERT). In vitro, all three compounds displaced [³H]ketanserin from 5-HT_2AR with micromolar affinity; however, only S(+)-AET elicited weak partial agonist activity in calcium mobilization assays, an effect abolished by the 5-HT_2AR 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-HT_2AR 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-HT_2AR 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.