Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation
Gavin P. Schmitz, Yi-Ting Chiu, Mia L. Foglesong, Sarah N. Magee, Martin Mackinnon, Gabriele M. König, Evi Kostenis, Li-Ming Hsu, Yen-Yu I. Shih, Bryan L. Roth, Melissa A. Herman
Translational Psychiatry October 6, 2025 DOI: 10.1038/s41398-025-03611-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Neurons in the prelimbic/anterior cingulate medial prefrontal cortex |
| Interventions | Psilocin 25-CN-NBOH non-hallucinogenic psychedelic compound |
| Topics | Neuroplasticity Serotonin |
| Keywords | Prefrontal cortex Population Intracellular Schizophrenia object-oriented programming Posterior cingulate Cortical neurons Cortex anatomy Inhibitory postsynaptic potential Anterior cingulate cortex Premovement neuronal activity Metabolite Receptor |
| Citations | 13 |
| Key findings | Psilocin and a 5-HT2A receptor-selective compound increase excitability and firing in 5-HT2A receptor-expressing neurons in the mPFC via 5-HT2A receptor and Gα q signaling. |
Abstract
Psilocybin, and its active metabolite psilocin, have seen renewed interest due to studies suggesting potential therapeutic utility. 5-Hydroxytryptamine2A receptors (5-HT 2A Rs) 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-HT 2A R expression. We identified a population of 5-HT 2A R neurons in the prelimbic/anterior cingulate mPFC. Psilocin and the 5-HT 2A R-selective compound 25-CN-NBOH increased excitability, and stimulated firing across a range of current injections in these neurons that was both 5-HT 2A R and Gα q dependent. Similar effects were observed with a novel, non-hallucinogenic psychedelic compound. These findings provide valuable insight into the specific role of 5-HT 2A R-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-HT 2A Rs and subsequent intracellular Gα q signaling as therapeutic targets.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 12
- The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors. Molecular Pharmacology 2026
- Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms Neuropharmacology January 21, 2026
- Psilocybin for Anhedonia in Unipolar and Bipolar Depression: A Systematic Review of Clinical and Preclinical Evidence Journal of Psychiatric Research October 1, 2026
- Psilocybin collapses visual change detection and drives cortical dynamics toward a state of surprise bioRxiv (Cold Spring Harbor Laboratory) August 25, 2026
- Intrinsic excitation-inhibition imbalance in major depressive disorder. Journal of Affective Disorders June 29, 2026
and 7 more in the library
Cites 37
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
and 32 more in the library