Integrated 5-HT 2A –TrkB and G protein signaling in serotonergic psychedelic responses
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman, Sarah Hudson, Sritanvi Potukanuma, Javier Hidalgo Jiménez, Sandra M. Martin-Guerrero, Javier González-Maeso, Juan F López-Giménez
bioRxiv (Cold Spring Harbor Laboratory) March 23, 2026 preprint DOI: 10.64898/2026.03.19.712961 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study |
|---|---|
| Population | Neural stem cell-derived in vitro model differentiating into neuronal and glial lineages |
| Interventions | phenethylamines ketamine TrkB agonists |
| Topics | Neuroplasticity Serotonin |
| Keywords | Phenethylamines Gene silencing G protein-coupled receptor Signal transduction Cell biology P-chloroamphetamine |
| Key points | Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives dendritogenesis, synaptogenesis, gene expression, and lactate production, with ligand-specific differences and dependence on both Gq/11 and Gi/o protein pathways. |
Abstract
Abstract Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT 2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses. Most serotonergic compounds also increased synaptogenesis and induced c-Fos and Egr-2 expression, although ligand-specific differences were evident, particularly for psilocin and the phenethylamines DOI and Ariadne. Uncoupling of G q/11 or G i/o protein-dependent signaling differentially modified neuroplastic and transcriptional responses, indicating a ligand and endpoint dependent contribution of both pathways. Serotonergic psychedelics further induced a 5-HT 2A receptor dependent lactate response that was generally sensitive to disruption of either G q/11 or G i/o protein coupling. Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT 2A -TrkB signaling network with distinct structural, transcriptional and metabolic outputs, and establish this neural stem cell-derived system as a valuable platform for screening and dissecting the signaling basis of psychedelic action.
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 |