Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine
Open accessAbstract
Background Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine.Methods Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine.Results We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B-extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF-tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels.Conclusions The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.
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The association with BPRS positive symptoms was comparable in effect size, but did not reach statistical significance in this sample of 14 subjects.
“The association with the Brief Psychiatric Rating Scale (BPRS) positive symptoms was comparable in effect size, but did not reach statistical significance in this sample of 14 subjects [54,55].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [55]
The Results section reports scopolamine responses in mice, and Methods and Materials describes animal behavioral tests and statistical analyses; neither addresses BPRS positive symptoms. Searches for BPRS, a 14-subject sample, and the stated nonsignificant association found no supporting passage in our copy. No page numbers were provided for these passages. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe blockade of NV-5138 antidepressant actions was observed in both Val/Met and Met/Met knockin mice.
“This was observed in both Val/ Met and Met/Met knockin mice, similar to complete blockade of the antidepressant actions of ketamine and scopolamine in Met/ Met mice, and partial or complete block, respectively, in Val/Met mice (37, 38).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [38]
Ketamine and scopolamine antidepressant actions are completely blocked in Met/Met mice and partially or completely blocked in Val/Met mice.
“This was observed in both Val/ Met and Met/Met knockin mice, similar to complete blockade of the antidepressant actions of ketamine and scopolamine in Met/ Met mice, and partial or complete block, respectively, in Val/Met mice (37, 38).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [38]
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- Authors
- Ghosal, S., Bang, E., Yue, W., Hare, B. D., Lepack, A. E., Girgenti, M. J., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 83
- Issue
- 1
- Pages
- 29-37
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5705490
- OpenAlex
- W2663388482
- Cited by
- 111
- References
- 46
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 10 · 2021: 12 · 2020: 17 · 2019: 21 · 2018: 21 · 2017: 2
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH093897, R37MH045481, R01MH045481, R01MH105910)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- scopolamine, brain-derived neurotrophic factor, rapid antidepressant effects, depression, medial prefrontal cortex, tropomyosin receptor kinase B, ERK signaling, AMPA receptors, voltage-gated calcium channels, verapamil, antimuscarinic agents, BDNF release, genetic polymorphism
- MeSH terms
- Animals, Antidepressive Agents, Brain, Cells, Cultured, Depressive Disorder, Disease Models, Animal, gamma-Aminobutyric Acid, Male, Mice, Transgenic, Motor Activity, Neurons, Scopolamine, Synaptosomes, Time Factors, Verapamil, Rats, Sprague-Dawley, Brain-Derived Neurotrophic Factor, Calcium Channels, L-Type, Receptor, trkB, Receptor, Muscarinic M1, Extracellular Signal-Regulated MAP Kinases
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