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

Psilocybin, and its active metabolite psilocin, have seen renewed interest due to studies suggesting potential therapeutic utility. 5-Hydroxytryptamine2A receptors (5-HT2ARs) are primary mediators of the psychoactive effects of psychedelics in animals and humans, but the underlying neurobiological mechanisms remain poorly understood. Functional magnetic resonance imaging identified significant psilocin-induced increases in medial prefrontal cortex (mPFC) activity, a site of enriched 5-HT2AR expression. We identified a population of 5-HT2AR neurons in the prelimbic/anterior cingulate mPFC. Psilocin and the 5-HT2AR-selective compound 25-CN-NBOH increased excitability, and stimulated firing across a range of current injections in these neurons that was both 5-HT2AR and Gαq dependent. Similar effects were observed with a novel, non-hallucinogenic psychedelic compound. These findings provide valuable insight into the specific role of 5-HT2AR-containing neurons in psychedelic-associated plasticity in mPFC regions that are likely implicated in the clinical effects of psychedelics and further identify membrane-bound 5-HT2ARs and subsequent intracellular Gαq signaling as therapeutic targets.