Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons
Aneta Petrušková, Debarpan Guhathakurta, Enes Yağız Akdaş, Renato Frischknecht, Tomáš Páleníček, Anna Fejtová, Bartomeu Perelló‐amorós, Eva‐maria Weiss
Journal of Neurochemistry February 28, 2025 DOI: 10.1111/jnc.70020 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Primary rat cortical neurons |
| Interventions | Psilocybin LSD DMT |
| Duration | 3–30 min after application, with effects no longer present 24 h after treatment |
| Topics | Serotonin |
| Keywords | Cortical neurons Glutamate receptor |
| Citations | 8 |
| Key findings | Serotonergic psychedelics rapidly and transiently reduce synaptic vesicle fusion and modulate glutamate release and presynaptic calcium levels in a drug-specific manner. |
Abstract
ABSTRACT The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end‐of‐life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3–30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short‐term plasticity leading to a depression of responses to paired stimuli. The rapid and drug‐specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics. image
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 8
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- Psychedelics for treatment of negative symptoms and depressive symptoms in schizophrenia spectrum disorder: A narrative review Schizophrenia Research March 13, 2026
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
- Psychedelics and autism spectrum disorder: Mechanistic insights, translational evidence and ethical challenges Journal of Psychiatric Research June 23, 2026
- Trip killers: Addressing a critical knowledge gap in psychedelic research. Journal of Psychopharmacology May 1, 2026
and 3 more in the library
Cites 39
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- 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 34 more in the library