Integrated 5-HT2A–TrkB and G protein signaling in serotonergic psychedelic responses
- 1Instituto de Parasitología y Biomedicina “López-Neyra” (IPBLN-CSIC), E-18016 Granada, Spain.
- 2Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
- 3Biomedical Sciences Graduate Program, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
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-HT2A 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 Gq/11 or Gi/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-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.
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BibTeX
@article{taddeitardon2026integrated,
title = {{Integrated 5-HT2A–TrkB and G protein signaling in serotonergic psychedelic responses}},
author = {Marco Taddei-Tardón and Lidia Medina-Rodríguez and Jessica L. Maltman and Sarah Hudson and Sritanvi Potukanuma and Javier Hidalgo Jiménez and Sandra M. Martín-Guerrero and Javier González-Maeso and Juan F. López-Giménez},
journal = {Molecular psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03746-6},
url = {https://europepmc.org/article/PMC/PMC13718869},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Integrated 5-HT2A–TrkB and G protein signaling in serotonergic psychedelic responses
AU - Marco Taddei-Tardón
AU - Lidia Medina-Rodríguez
AU - Jessica L. Maltman
AU - Sarah Hudson
AU - Sritanvi Potukanuma
AU - Javier Hidalgo Jiménez
AU - Sandra M. Martín-Guerrero
AU - Javier González-Maeso
AU - Juan F. López-Giménez
PY - 2026
DA - 2026/07/16
JO - Molecular psychiatry
DO - 10.1038/s41380-026-03746-6
UR - https://europepmc.org/article/PMC/PMC13718869
AB - 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-HT2A 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 Gq/11 or Gi/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-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.
SN - 1359-4184
SN - 1476-5578
ER -