Integrated 5-HT2A-TrkB and G protein signaling in serotonergic psychedelic responses.
Molecular psychiatry July 16, 2026 Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.