Integrated 5-HT 2A –TrkB and G protein signaling in serotonergic psychedelic responses
Marco Taddei-tardon, Lidia Medina-rodríguez, Jessica L. Maltman, Sarah Hudson, Sritanvi Potukanuma, Javier Hidalgo Jiménez, Sandra M. Martin-guerrero, Javier Gonzalez-Maeso, Juan F Lopez-gimenez
bioRxiv (Cold Spring Harbor Laboratory) March 23, 2026 Peer reviewed DOI: 10.64898/2026.03.19.712961 via OpenAlex
Summary
Serotonergic psychedelics activate a network involving the 5-HT 2A and TrkB receptors, leading to various neuroplastic responses such as increased synaptogenesis and changes in gene expression. The study used a neural stem cell-derived model to explore how different psychedelic compounds influence these processes, finding that silencing TrkB affected dendritogenesis and that specific receptor pathways contributed differently to the outcomes. This model can help further investigate the mechanisms of psychedelic action.
Study at a glance
| Design | experimental study |
|---|---|
| Population | neural stem cell-derived in vitro model |
| Key finding | Serotonergic psychedelics activate a signaling network involving 5-HT 2A and TrkB receptors, influencing neuroplasticity and metabolic responses. |
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.