Psychedelic compounds directly excite 5-HT 2A Layer 5 Pyramidal Neurons in the Prefrontal Cortex through a 5-HT 2A Gq -mediated activation mechanism
Gavin P. Schmitz, Yi-Ting Chiu, Gabriele M. König, Evi Kostenis, Bryan L. Roth, Melissa A. Herman
bioRxiv (Cold Spring Harbor Laboratory) November 15, 2022 preprint DOI: 10.1101/2022.11.15.516655 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro electrophysiology study |
|---|---|
| Population | Layer 5 pyramidal neurons in the prelimbic prefrontal cortex of C57BL/6J mice (including 5-HT2A-ERT2-Cre crossed with Ai9 tdTomato reporter mice) |
| Intervention | Psilocin |
| Dose | 10 μM |
| Topics | Serotonin |
| Keywords | Infralimbic cortex Prefrontal cortex 5-HT Receptor Agonist Electrophysiology Neurotransmission Biophysics |
| Citations | 15 |
| Key points | Psilocin increases firing in identified 5-HT2A receptor-expressing layer 5 pyramidal neurons in the mouse prelimbic prefrontal cortex, an effect dependent on 5-HT2A receptors and Gαq signaling. |
Abstract
Summary Psilocin, the active compound in Psilocybe sp . mushrooms, is a serotonergic psychedelic that has recently gained renewed interest due to its potential as a therapeutic tool. Despite promising clinical findings, the underlying signaling mechanisms and brain region-specific effects of psilocin and other psychedelic drugs remain unclear. Psilocin, like other psychedelic compounds, is an agonist at many serotonin and other biogenic amine receptors; however, activation of serotonin (5-Hydroxytryptamine, or 5-HT) 2A receptors (5-HT 2A Rs) is understood as the main molecular target for the psychoactive effects in animals and humans. 5-HT 2A Rs are abundantly expressed in the prefrontal cortex (PFC); however, the biochemical actions of psilocin on PFC neurons remain poorly understood. In this study, we used in vitro slice electrophysiology to examine how psilocin acutely alters the activity and electrophysiological properties of layer 5 pyramidal neurons in the mouse PFC. Focal application of psilocin (10 μ M) onto nonspecified Layer 5 Pyramidal neurons in the prelimbic PFC of C57BL/6J mice produced variable effects on firing (increase, decrease, or no change). 5-HT 2A R layer 5 pyramidal neurons in the mouse prelimbic PFC were identified via labeling in a 5-HT2A-ERT2-Cre mouse crossed with an Ai9 tdTomato reporter. Focal application of psilocin increased firing in all identified 5-HT 2A R neurons but did not result in any significant changes in synaptic transmission. Overall, the results demonstrate that psilocin evokes strong firing changes in the PFC that are 5-HT 2A R and G α q dependent, thereby providing valuable insights into the effects of psilocin on a brain region implicated in mediating psychedelic drug actions.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 9
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- Psychedelics as Transformative Therapeutics. American Journal of Psychiatry May 1, 2023
- The Effects of Psychedelics on Neuronal Physiology. Annu Rev Physiol November 6, 2023
- Cellular rules underlying psychedelic control of prefrontal pyramidal neurons bioRxiv (Cold Spring Harbor Laboratory) October 23, 2023
- Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles. Nature Neuroscience June 1, 2025
and 4 more in the library
Cites 35
- 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 30 more in the library