Integrated 5-HT2A-TrkB and G protein signaling in serotonergic psychedelic responses

AI Summary

Serotonergic psychedelics recruit an integrated 5-HT2A and TrkB signalling network yielding distinct structural, transcriptional and metabolic neuroplastic outputs.
TrkB silencing abolishes dendritogenesis induced by psychedelics, ketamine and TrkB agonists; 5-HT2A silencing selectively impairs psychedelic-induced plasticity.
Gq/11 and Gi/o protein coupling differentially modulate ligand- and endpoint-specific neuroplastic, transcriptional and lactate metabolic responses.

AI Summary

TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses.

Serotonergic psychedelics further induced a 5-HT2A receptor dependent lactate response that was generally sensitive to disruption of either Gq/11 or Gi/o protein coupling.

Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signalling 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 signalling basis of psychedelic action.

Basic summary

Mol Psychiatry. 2026 Jul 16. doi: 10.1038/s41380-026-03746-6. Online ahead of print.

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 signalling 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 signalling 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 signalling basis of psychedelic action.

PMID:42463904 | DOI:10.1038/s41380-026-03746-6

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