Serotonergic psychedelics, including tryptamines, phenethylamines, and ergolines, promote structural and transcriptional changes in neurons through an integrated signaling network involving the 5-HT2A receptor and TrkB. Using a neural stem cell-derived model, the study shows that TrkB silencing blocks dendritogenesis induced by psychedelics, ketamine, and TrkB agonists, while 5-HT2A silencing selectively impairs psychedelic-induced plasticity. Most compounds increase synaptogenesis and immediate-early gene expression, though psilocin and the phenethylamines DOI and Ariadne show ligand-specific differences. Lactate production, dependent on 5-HT2A and both Gq/11 and Gi/o protein signaling, also occurs. These results establish a platform for dissecting psychedelic action.
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.