Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons

Title & Introduction

• Paper Title: Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons
• Published In: Journal of Neurochemistry
• Publish date: February 5, 2025
• Authors: Aneta Petrušková, Debarpan Guhathakurta, Enes Yağız Akdaş, Bartomeu Perelló-Amorós, Renato Frischknecht, Eva-Maria Weiss, Tomáš Páleníček, Anna Fejtová
• Objective: To investigate the effects of serotonergic psychedelics on synaptic glutamate release in cortical neurons, with implications for their antidepressant and neuroplasticity-enhancing properties.
• Importance: Understanding how psychedelics modulate glutamate transmission could help explain their rapid-acting antidepressant effects and inform future treatments for psychiatric disorders.

Summary & Takeaways

Key Takeaway: Serotonergic psychedelics (psilocybin, LSD, and DMT) rapidly alter glutamate release and synaptic plasticity, supporting their potential as fast-acting antidepressants.

Practical Application: These findings contribute to the understanding of psychedelic-induced neuroplasticity, informing the development of novel therapeutics for depression, PTSD, and addiction.

Key Background Information

• Context: Classic psychedelics like psilocybin and LSD interact with serotonin (5-HT2A) receptors, triggering profound changes in brain function. Their potential for treating depression and other disorders is linked to their effects on neural plasticity.
• Hypothesis: Psychedelics enhance glutamate signaling, leading to synaptic modifications that underlie their rapid and long-lasting therapeutic effects.

Methodology

• Study Design: In vitro experimental study using cultured rat cortical neurons.
• Participants: Primary rat cortical neuron cultures.
• Intervention/Exposure: Application of psilocybin, LSD, and DMT to measure synaptic vesicle release and glutamate dynamics.
• Controls: Vehicle-treated neurons as baseline controls.
• Duration: Short-term effects assessed over a 30-minute period post-treatment, with additional 24-hour observations.

Key Findings

Primary Outcomes:

• Psilocin and DMT increase evoked glutamate release, suggesting enhanced synaptic excitability.
• LSD and psilocin reduce presynaptic calcium levels, potentially regulating neurotransmission balance.
• Psilocin alters short-term plasticity, leading to a depression of responses to paired stimuli.

Secondary Outcomes:

• Psychedelic effects on synaptic function are transient, with most changes normalizing within 24 hours.
• Different psychedelics have distinct but overlapping impacts on glutamatergic signaling.
• These findings align with previous research linking psychedelics to neuroplasticity and antidepressant effects.

Interpretation & Implications

• Conclusion: Psychedelics rapidly modulate glutamate release, reinforcing their role in neuroplasticity and fast-acting antidepressant mechanisms.
• Implications: Future psychiatric treatments could leverage psychedelics to target glutamatergic pathways for depression and other disorders.
• Limitations: Findings are based on in vitro models, requiring validation in animal and human studies.

Researchers & Publication

• Researchers: Aneta Petrušková, Debarpan Guhathakurta, Enes Yağız Akdaş, Bartomeu Perelló-Amorós, Renato Frischknecht, Eva-Maria Weiss, Tomáš Páleníček, Anna Fejtová
• Publication Name: Journal of Neurochemistry
• Study URL: https://doi.org/10.1111/jnc.70020