Hung-Wei Kan1, Wei-Hao Peng1,2, Cheng-Chun Wu3, Deng-Wu Wang3,4, Ming Tatt Lee5, Yung-Kuo Lee6, Tian-Huei Chu6, Yu-Cheng Ho7. 1. School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, 82445, Taiwan, Republic of China. 2. School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, Republic of China. 3. School of Medicine, College of Medicine, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445, Taiwan, Republic of China. 4. Department of Psychiatry, E-Da Hospital, Kaohsiung City, 82445, Taiwan, Republic of China. 5. Faculty of Pharmaceutical Sciences, UCSI University, 56000, Cheras, Kuala Lumpur, Malaysia. 6. Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City, 80284, Taiwan, Republic of China. 7. School of Medicine, College of Medicine, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445, Taiwan, Republic of China. r96443003@ntu.edu.tw.
Abstract
RATIONALE: Clinical reports reveal that scopolamine, an acetylcholine muscarinic receptor antagonist, exerts rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic effects have not been fully identified. OBJECTIVES: The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG). METHODS: We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG. RESULTS: The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects. CONCLUSIONS: Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.
RATIONALE: Clinical reports reveal that scopolamine, an acetylcholine muscarinic receptor antagonist, exerts rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic effects have not been fully identified. OBJECTIVES: The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG). METHODS: We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG. RESULTS: The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects. CONCLUSIONS: Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.
Authors: Kenichi Fukumoto; Manoela V Fogaça; Rong-Jian Liu; Catharine Duman; Taro Kato; Xiao-Yuan Li; Ronald S Duman Journal: Proc Natl Acad Sci U S A Date: 2018-12-17 Impact factor: 11.205
Authors: Jay C Fournier; Robert J DeRubeis; Steven D Hollon; Sona Dimidjian; Jay D Amsterdam; Richard C Shelton; Jan Fawcett Journal: JAMA Date: 2010-01-06 Impact factor: 56.272