mTOR activation is required for the antidepressant effects of mGluR2/3 blockade
Open accessAbstract
Recent studies demonstrate that ketamine, a fast-acting antidepressant, rapidly activates the mammalian target of rapamycin (mTOR) and increases synaptogenesis in the prefrontal cortex. Because of the side-effect and abuse potential of ketamine we are investigating alternative agents that produce similar effects. Here, we demonstrate that a single dose of LY 341495, an mGluR₂/₃ antagonist, produces ketamine-like biochemical and behavioural actions. LY 341495 administration rapidly (1 h) activates the mTOR pathway (mTOR, p70S6K, 4E-BP1) and subsequently (24 h later) increases levels of synaptic proteins (PSD-95, GluR1 and Synapsin I), similar to the effects of ketamine. Finally, the antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor, rapamycin. The results indicate that the antidepressant actions of LY 341495 are mediated by activation of mTOR and suggest that this and other mGluR₂/₃ antagonists could produce rapid antidepressant effects in depressed patients.
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- Authors
- Dwyer, J. M., Lepack, A. E., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-11-24
- Volume
- 15
- Issue
- 04
- Pages
- 429-434
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC3580765
- OpenAlex
- W2166921819
- Cited by
- 169
- References
- 26
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 11 · 2021: 8 · 2020: 9 · 2019: 18 · 2018: 9 · 2017: 8 · 2016: 19 · 2015: 20 · 2014: 17 · 2013: 15 · 2012: 12
- FWCI
- 10.31
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- H. Lundbeck A/S
- National Institute of Mental Health (MH093897, R01MH093897)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- mTOR signaling, rapid-acting antidepressants, p70S6K, 4E-BP1, synaptic proteins, PSD-95, GluR1, synapsin I, rapamycin, forced swim test, depression
- MeSH terms
- Disks Large Homolog 4 Protein, Amino Acids, Animals, Dose-Response Relationship, Drug, Gene Expression Regulation, Ketamine, Male, Membrane Proteins, Swimming, Synaptosomes, Xanthenes, Signal Transduction, Synapsins, Prefrontal Cortex, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Antagonists, Intracellular Signaling Peptides and Proteins, Rats, TOR Serine-Threonine Kinases
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