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外2014 (IF 4.138)大鼠中rTMS抗抑郁机制中内源性大麻素系统的作用Hualin Wang YIRD
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Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: The role of the endocannabinoid system Hua-ning Wang a,1, Lei Wang a,b,1, Rui-guo Zhang a,1, Yun-chun Chen a, Ling Liu c, Fang Gao c, Huang Nie d, Wu-gang Hou d, Zheng-wu Peng a,e,**, Qingrong Tan a,* a Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, 17 Changle Road, Xi’an, Shaanxi 710032, China b Xi’an city mental health center, Xi’an, China c Institute of Neuroscience, Fourth Military Medical University, Xi’an 710032, China d Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China e Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi’an 710032, China a r t i c l e i n f o Article history: Received 31 October 2013 Received in revised form 11 December 2013 Accepted 8 January 2014 Keywords: Repetitive transcranial magnetic stimulation Depression Cannabinoid type I receptor Hippocampus a b s t r a c t Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose pref- erence test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal canna- binoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors. 2014 Elsevier Ltd. All rights reserved. 1. Introduction Repetitive transcranial magnetic stimulation (rTMS) is a prom- ising noninvasive treatment for a variety of neuropsychiatric con- ditions; the number of applications continues to increase, with a large number of ongoing clinical trials in a variety of diseases (Devlin and Watkins, 2007; George et al., 2007). One of the first clinical uses of rTMS and its only Food and Drug Administration- approved therapeutic indication is high-frequency stimulation to the left dorsolateral prefrontal cortex for the treatment of medication-resistant depression (O’Reardon et al., 2007; Padberg and George, 2009). However, the underlying mechanisms regarding how rTMS can alter mood are not completely under- stood. Paralleling our limited understanding of the mechanism of rTMS, its therapeutic efficacy, while statistically significant, also remains limited. The basic principle of rTMS is that magnetic pulses enter the brain unimpeded and depolarize neurons in the area under the magnetic coil, and this exerts distant effects in networks connected to the stimulation site (Berlim et al., 2012; Hallett, 2007). By inducing electric currents in brain tissue with a time-varying strong magnetic field, rTMS has the potential to modulate neuronal cir- cuits. There is evidence that rTMS can activate both cortical neurons and more distal cells via transsynaptic connections (Post and Keck, 2001). Regarding the mechanism of depression, there are several * Corresponding author. Tel.: 86 29 84775951; fax: 86 29 83293951. ** Corresponding author. Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, 17 Changle Road, Xi’an, Shaanxi 710032, China. E-mail addresses: pengzhengwu1446@163.com (Z.-w. Peng), tanqingr@fmmu. edu.cn (Q. Tan). 1 These authors are contributed equally to this work. Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2014.01.004 Journal of Psychiatric Research xxx (2014) 1e9 Please cite this article in press as: Wang H-n, et al., Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: The role of the endocannabinoid system, Journal of Psychiatric Research (2014), http://dx.doi.org/10.1016/j.jpsychires.2014.01.004

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