Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation

Psilocybin-derived psilocin directly excites 5-HT2A receptor neurons in layer V of the medial prefrontal cortex (mPFC) through 5-HT2A Gq signaling. The study combines fMRI and electrophysiology to pinpoint a 5-HT2A neuron population in the prelimbic/anterior cingulate mPFC. Psilocin increased neuronal excitability and stimulated firing in response to current injections, with effects that depended on both the 5-HT2A receptor and Gαq. A 5-HT2A selective agonist (25-CN-NBOH) produced similar excitability and firing changes, and comparable effects were also reported with a novel non-hallucinogenic psychedelic compound. The findings highlight membrane-bound 5-HT2A receptors and downstream Gαq pathway signaling in mPFC as mechanistic targets potentially relevant to psychedelic-associated plasticity and therapeutic effects.