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

This study investigates the molecular mechanisms linking the acute effects of serotonergic psychedelics to their long-term neuroplastic outcomes. Specifically, it examines the functional interplay between the 5-HT2A receptor and the TrkB receptor (the primary receptor for BDNF) in driving structural and functional neuronal plasticity.

The researchers developed a neural stem cell-derived in vitro model capable of differentiating into neurons and glia. Using this system, they implemented inducible shRNA-mediated silencing to selectively knock down 5-HT2A or TrkB receptors. They tested a diverse panel of tryptamines, phenethylamines, and ergolines—including both psychedelic and non-psychedelic analogues—alongside ketamine and TrkB agonists. Endpoints included dendritogenesis (Sholl analysis), synaptogenesis (rabies virus-based tracing), immediate-early gene expression (c-Fos, Egr-2), and metabolic lactate production. Pharmacological uncoupling of Gq/11 and Gi/o proteins was used to dissect the downstream signaling requirements.

The study reveals that both 5-HT2A and TrkB receptors are essential for the neuroplastic effects of serotonergic psychedelics. While TrkB silencing completely abolished dendritogenic responses to all tested compounds, 5-HT2A silencing selectively impaired psychedelic-induced plasticity and attenuated TrkB-dependent responses, suggesting a functional interaction between these two systems. Furthermore, the researchers found that hallucinogenic serotonergic psychedelics induce a specific metabolic signature—increased lactate production—that is dependent on 5-HT2A receptor expression and G protein signaling. The data indicate that morphological and functional plasticity (synaptogenesis) are distinct processes that do not always correlate, and that Gq/11 and Gi/o pathways contribute differentially to these outcomes depending on the specific ligand.