Fast-Acting Antidepressants Rapidly Stimulate ERK Signaling and BDNF Release in Primary Neuronal Cultures
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Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu 2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABA A receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 h increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.
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Unlike traditional monoaminergic antidepressants, which gradually increase BDNF expression, ketamine induces a rapid release of BDNF.
“Unlike traditional monoaminergic antidepressants, which gradually increase BDNF expression, ketamine induces a rapid release of BDNF [73].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [73]
The dissociative ketamine is another substance whose antidepressant effects are suggested to result from enhanced BDNF and synaptic plasticity.
“The dissociative ketamine is another substance whose antidepressant effects are suggested to result from enhanced BDNF and synaptic plasticity (107).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [107]
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- Authors
- Lepack, A. E., Bang, E., Lee, B., Dwyer, J. M., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 111
- Pages
- 242-252
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC5075989
- OpenAlex
- W2518741199
- Cited by
- 174
- References
- 42
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 15 · 2023: 20 · 2022: 23 · 2021: 18 · 2020: 20 · 2019: 24 · 2018: 20 · 2017: 13
- FWCI
- 15.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (R37MH45481, R01MH93897)
- State of Connecticut
- Yale University
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- rapid-acting antidepressants, ketamine, LY341495, ERK signaling, BDNF release, mTORC1, p70 S6 kinase, AMPA receptors, activity-dependent plasticity, neuronal morphology, cortical neurons, muscimol, GABAA receptor
- MeSH terms
- Amino Acids, Animals, Antidepressive Agents, Cells, Cultured, Cerebral Cortex, Dendrites, Ketamine, Oligopeptides, Xanthenes, Receptors, AMPA, Brain-Derived Neurotrophic Factor, Receptor, trkB, MAP Kinase Signaling System, Rats, GABAergic Neurons, Primary Cell Culture
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