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Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine.
- Source :
-
Biological psychiatry [Biol Psychiatry] 2018 Jan 01; Vol. 83 (1), pp. 29-37. Date of Electronic Publication: 2017 Jun 23. - Publication Year :
- 2018
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Abstract
- 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.<br />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.<br />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.<br />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.<br /> (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Brain drug effects
Brain metabolism
Brain pathology
Brain-Derived Neurotrophic Factor genetics
Calcium Channels, L-Type metabolism
Cells, Cultured
Depressive Disorder pathology
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases metabolism
Male
Mice, Transgenic
Motor Activity drug effects
Neurons drug effects
Neurons metabolism
Neurons pathology
Rats, Sprague-Dawley
Receptor, Muscarinic M1 antagonists & inhibitors
Receptor, Muscarinic M1 metabolism
Receptor, trkB metabolism
Synaptosomes drug effects
Synaptosomes metabolism
Time Factors
Verapamil pharmacology
gamma-Aminobutyric Acid metabolism
Antidepressive Agents pharmacology
Brain-Derived Neurotrophic Factor metabolism
Depressive Disorder drug therapy
Depressive Disorder metabolism
Scopolamine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 83
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 28751069
- Full Text :
- https://doi.org/10.1016/j.biopsych.2017.06.017