PMID- 28751069 OWN - NLM STAT- MEDLINE DCOM- 20180709 LR - 20220318 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 83 IP - 1 DP - 2018 Jan 1 TI - Activity-Dependent Brain-Derived Neurotrophic Factor Release Is Required for the Rapid Antidepressant Actions of Scopolamine. PG - 29-37 LID - S0006-3223(17)31716-X [pii] LID - 10.1016/j.biopsych.2017.06.017 [doi] AB - 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. CI - Copyright (c) 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Ghosal, Sriparna AU - Ghosal S AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Bang, Eunyoung AU - Bang E AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Yue, Wenzhu AU - Yue W AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Hare, Brendan D AU - Hare BD AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Lepack, Ashley E AU - Lepack AE AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Girgenti, Matthew J AU - Girgenti MJ AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. FAU - Duman, Ronald S AU - Duman RS AD - Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: ronald.duman@yale.edu. LA - eng GR - R01 MH045481/MH/NIMH NIH HHS/United States GR - R01 MH093897/MH/NIMH NIH HHS/United States GR - R01 MH105910/MH/NIMH NIH HHS/United States GR - R37 MH045481/MH/NIMH NIH HHS/United States PT - Journal Article DEP - 20170623 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Calcium Channels, L-Type) RN - 0 (Receptor, Muscarinic M1) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - CJ0O37KU29 (Verapamil) RN - DL48G20X8X (Scopolamine) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Antidepressive Agents/*pharmacology MH - Brain/drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Calcium Channels, L-Type/metabolism MH - Cells, Cultured MH - Depressive Disorder/*drug therapy/*metabolism/pathology MH - Disease Models, Animal MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Male MH - Mice, Transgenic MH - Motor Activity/drug effects MH - Neurons/drug effects/metabolism/pathology MH - Rats, Sprague-Dawley MH - Receptor, Muscarinic M1/antagonists & inhibitors/metabolism MH - Receptor, trkB/metabolism MH - Scopolamine/*pharmacology MH - Synaptosomes/drug effects/metabolism MH - Time Factors MH - Verapamil/pharmacology MH - gamma-Aminobutyric Acid/metabolism PMC - PMC5705490 MID - NIHMS887452 OTO - NOTNLM OT - Depression OT - Muscarinic receptor OT - Prefrontal cortex OT - TrkB receptor OT - Voltage-dependent calcium channel OT - mTORC1 COIS- Conflict of Interest and Disclosures: R.S.D. has received consulting fees from Taisho, Johnson & Johnson, and Naurex, and grant support from Taisho, Johnson & Johnson, Naurex, Allergan, Navitor, Lundbeck, and Lilly. SG, EB, WY, BH, AEL, MJG, report no biomedical financial interests or potential conflicts of interest. None of the above-listed companies or funding agencies have had any influence on the content of this article. EDAT- 2017/07/29 06:00 MHDA- 2018/07/10 06:00 PMCR- 2019/01/01 CRDT- 2017/07/29 06:00 PHST- 2017/01/27 00:00 [received] PHST- 2017/06/09 00:00 [revised] PHST- 2017/06/12 00:00 [accepted] PHST- 2017/07/29 06:00 [pubmed] PHST- 2018/07/10 06:00 [medline] PHST- 2017/07/29 06:00 [entrez] PHST- 2019/01/01 00:00 [pmc-release] AID - S0006-3223(17)31716-X [pii] AID - 10.1016/j.biopsych.2017.06.017 [doi] PST - ppublish SO - Biol Psychiatry. 2018 Jan 1;83(1):29-37. doi: 10.1016/j.biopsych.2017.06.017. Epub 2017 Jun 23.