Scopolamine Rapidly Increases Mammalian Target of Rapamycin Complex 1 Signaling, Synaptogenesis, and Antidepressant Behavioral Responses
Open accessAbstract
Background Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists.Methods The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors.Results The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist.Conclusions Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents.
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mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.
“These studies indicate that mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [12]
Infusion of rapamycin alone into the mPFC has no effect on these behaviors.
“Previous studies demonstrate that infusion of rapamycin alone into the mPFC has no effect on these behaviors (7, 8, 10, 12).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [12]
Ketamine's actions occur via a burst of glutamate and require AMPA receptor activation.
“While the effects of NV-5138 and ketamine converge on mTORC1 signaling, the actions of ketamine occur via a burst of glutamate and require AMPA receptor activation, based on evidence that pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine as well as other rapid-acting agents (7, 10, 12, 39, 40).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [12]
Pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine and other rapid-acting agents.
“While the effects of NV-5138 and ketamine converge on mTORC1 signaling, the actions of ketamine occur via a burst of glutamate and require AMPA receptor activation, based on evidence that pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine as well as other rapid-acting agents (7, 10, 12, 39, 40).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [12]
Rapid acting antidepressants stimulate mTORC1 signaling in the prefrontal cortex.
“Conversely, rapid acting antidepressants (discussed below) stimulate mTORC1 signaling in the prefrontal cortex52,53.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [53]
Scopolamine acutely stimulates mTORC1 signaling, leading to increased synaptogenesis in the PFC.
“Scopolamine also acutely stimulates mTORC1 signaling, leading to increased synaptogenesis in the PFC53 (Figure 4).”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [53]
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Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test
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Cai, M., Zhu, Y., Shanley, M. R., Morel, C., Ku, S. M., Zhang, H., Shen, Y., Friedman, A. K., & Han, M.-H. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100565 · Cited by 18 · see citing works
- Authors
- Voleti, B., Navarria, A., Liu, R.-J., Banasr, M., Li, N., Terwilliger, R., Sanacora, G., Eid, T., Aghajanian, G., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 74
- Issue
- 10
- Pages
- 742-749
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3773272
- OpenAlex
- W2072298966
- Cited by
- 264
- References
- 40
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 17 · 2021: 24 · 2020: 34 · 2019: 25 · 2018: 33 · 2017: 29 · 2016: 24 · 2015: 21 · 2014: 14 · 2013: 8
- FWCI
- 16.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH 25642, R01MH081211, MH-45481, R01MH093897, R37MH045481, P01MH025642, R01MH045481, R01MH105910)
- 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
- scopolamine, mTORC1 signaling, synaptogenesis, antidepressant effects, rapid-acting antidepressants, antimuscarinic agents, prefrontal cortex, glutamatergic neurotransmission, NMDA receptor, forced swim test, depression
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Antidepressive Agents, Male, Neurons, Scopolamine, Stress, Psychological, Swimming, Synapses, Signal Transduction, Rats, Sprague-Dawley, Prefrontal Cortex, Muscarinic Antagonists, Excitatory Postsynaptic Potentials, Multiprotein Complexes, Dendritic Spines, Rats, TOR Serine-Threonine Kinases
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