Cellular rules underlying psychedelic control of prefrontal pyramidal neurons
Tyler G. Ekins, Isla A. W. Brooks, Sameer Kailasa, Chloe Rybicki-Kler, Izabela Jedrasiak‐cape, Ethan Donoho, George A. Mashour, Jason C. Rech, Omar J. Ahmed
bioRxiv (Cold Spring Harbor Laboratory) October 23, 2023 preprint DOI: 10.1101/2023.10.20.563334 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Pyramidal neurons |
| Intervention | multiple classes of psychedelics |
| Topics | Serotonin |
| Keywords | Prefrontal cortex Consumer neuroscience Pyramidal cell Self-reference effect Cognitive psychology |
| Citations | 17 |
| Key findings | Psychedelic drugs suppress intrinsic excitability of pyramidal neurons by enhancing potassium M-current channels, independent of serotonin 2A receptor activation. |
Abstract
ABSTRACT Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2 A receptors (5-HT2 A Rs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium “M-current” channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.
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 13
- On the varieties of conscious experiences: Altered Beliefs Under Psychedelics (ALBUS). Neuroscience of Consciousness 2025
- Synthetic surprise as the foundation of the psychedelic experience Neuroscience & Biobehavioral Reviews January 15, 2024
- Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles. Nature Neuroscience June 1, 2025
- Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors Molecular Psychiatry March 1, 2026
- The Selective 5HT2A Receptor Agonist, 25CN-NBOH Exerts Excitatory and Inhibitory Cellular Actions on Mouse Medial Prefrontal Cortical Neurons. Synapse March 1, 2025
and 8 more in the library
Cites 46
- 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
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 41 more in the library