Translational psychiatryOct 6, 2025

Psychedelic drugs activate specific brain cells in the thinking and decision area through a serotonin receptor

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 29, 2026

Abstract

Psilocin significantly increased activity in the medial prefrontal cortex (mPFC), where 5-HT receptors are abundant.

Functional magnetic resonance imaging revealed substantial increases in mPFC activity following psilocin administration.
A specific population of 5-HT receptor neurons was identified in the prelimbic/anterior cingulate area of the mPFC.
Both psilocin and a selective 5-HT receptor compound heightened excitability and firing rates in these neurons.
Effects on neuronal activity were found to depend on both 5-HT receptors and Gα signaling pathways.
A non-hallucinogenic psychedelic compound exhibited similar excitatory effects on the identified neurons.

Simplified

Psilocybin, and its active metabolite psilocin, have seen renewed interest due to studies suggesting potential therapeutic utility. 5-Hydroxytryptamine2A receptors (5-HTRs) 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-HTR expression. We identified a population of 5-HTR neurons in the prelimbic/anterior cingulate mPFC. Psilocin and the 5-HTR-selective compound 25-CN-NBOH increased excitability, and stimulated firing across a range of current injections in these neurons that was both 5-HTR and Gαdependent. Similar effects were observed with a novel, non-hallucinogenic psychedelic compound. These findings provide valuable insight into the specific role of 5-HTR-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-HTRs and subsequent intracellular Gαsignaling as therapeutic targets. 2A2A2A2A2A q2A2A q

Key numbers

>120%

Increase in neuronal firing

Observed in most neurons after psilocin application.

3.13

fMRI signal increase in ACC

Statistical significance at p < 0.005.

2.43

fMRI signal increase in PrL

Statistical significance at p < 0.005.

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Funding

Competing interests

Competing interests: The authors declare no competing interests.

PubMed

Psychedelic drugs activate specific brain cells in the thinking and decision area through a serotonin receptor

Abstract

Key numbers

Full Text

Funding

Competing interests

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Abstract

Key numbers

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the psychedelic science brief