Vagal Nerve Stimulation & Antidepressants: c-Fos, deltaFosB and TrkB Activation

迷走神经刺激

基本信息

批准号：
8267085
负责人：
ALAN FRAZER
金额：
$ 33.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-04 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267085
关键词：
Acute Address Adrenergic Receptor Affect Agonist Amygdaloid structure Animals Antidepressive Agents Area Autoreceptors Behavioral Biological Markers Brain Brain region Brain-Derived Neurotrophic Factor Chronic Chronic Disease Corpus striatum structure Data Desipramine Devices Electrodes Epilepsy FDA approved FOS gene Frequencies Gene Expression Goals Heart Rate Hour Immediate-Early Genes Immunohistochemistry Lesion Major Depressive Disorder Manufacturer Name Measures Mental Depression Monitor Nerve Neuraxis Neuromodulator Neurons Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Norepinephrine Nucleus solitarius Oxidopamine Patients Peripheral Phosphorylation Protocols documentation Quantitative Autoradiography Rattus Receptor Activation Refractory Resistance Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT1A Sertraline Staining method Stains Stress Swimming System Telemetry Testing Time Work cingulate cortex clinical effect clinically relevant density dorsal raphe nucleus extracellular indexing inhibitor/antagonist noradrenergic preclinical study receptor sensitivity research study respiratory reuptake vagus nerve stimulation

项目摘要

ABSTRACT Almost 30% of patients with major depressive disorder have a chronic illness that is treatment refractory. Vagus nerve stimulation (VNS) has recently been approved by the FDA for treatment refractory depression. However, there have been few pre-clinical studies addressing the central actions of VNS that may be relevent for its antidepressant effect. We completed recently some preliminary studies in which VNS was administred either acutely or chronically to non-anesthetized rats using clinically-relevant stimulation parameters. Both functional neuroanatomical and behavioral effects were observed. The goal of this proposal is to expand and amplify these observations so as to evaluate more comprehensively effects produced by VNS in brain and the mechanisms underlying such effects. Our overall hypothesis is that VNS produces its beneficial clinical effects, as measured by reduced immobility in the forced swim test (FST) in rats, by activation of multiple neurotransmitter/neuromodulator systems in brain, in particular serotonin or norepinephrine and/or brain- derived neurotrophic factor containing neurons (through phosphorylation of TrkB receptors). To test these ideas, we will: (1) initially optimize stimulation parameters, using both acute and chronic (3 week) VNS by determining behavioral effects it produces in the FST and compare its effects to those produced by the selective noradrenergic reuptake inhibitor, desipramine, and the selective serotonin reuptake inhibitor, sertraline, (2) use the chronic VNS protocol that has the best effect in the FST to measure its effects on c-Fos, ¿FosB, Egr-1, activation of TrkB, ¿1-adrenoceptors, and somatodendritic 5-HT autoreceptor sensitivity and compare results to those caused by chronic treatment with desipramine or sertraline, and (3) test the role of norepinephrine and serotonin in the antidepressant-like effect of chronic VNS, desipramine and sertraline by lesioning rats with either 6-hydroxydopamine or 5,7- dihyroxytryptamine. Immunohistochemistry will be used to measure c-Fos, ¿FosB, Egr-1, and phosphorylated TrkB. Quantitative autoradiography will be used to measure ¿1-adrenoreceptors. DPAT-induced changes in extracellular 5-HT in the striatum will be used as an index of autoreceptor sensitivity. The results could provide important, new information regarding the central nervous system effects of VNS that are important for the treatment of depression. PROJECT NARRATIVE About 30% of patients with major depressive disorder are resistant to standard antidepressant therapy. Vagal nerve stimulation (VNS) was approved recently for such refractory patients; it is moderately effective, but how it works is unknown. Our studies will evaluate comprehensively effects produced by VNS in the brain of rats and the mechanisms underlying such effects, so as to provide data to allow VNS to become even more effective.

抽象的近 30% 的重度抑郁症患者患有难治性慢性疾病。迷走神经刺激（VNS）最近已被 FDA 批准用于治疗难治性抑郁症。然而，很少有临床前研究涉及 VNS 可能相关的核心作用。我们最近完成了一些使用 VNS 的初步研究。使用临床相关的刺激参数对非麻醉大鼠进行急性或慢性刺激。观察到功能性神经解剖学和行为效应。该提案的目标是扩大和扩大。放大这些观察结果，以便更全面地评估 VNS 对大脑和神经系统产生的影响我们的总体假设是 VNS 产生有益的临床效果，通过大鼠强迫游泳测试（FST）中不动性的减少来测量，通过激活多个大脑中的神经递质/神经调节系统，特别是血清素或去甲肾上腺素和/或脑- 含有神经元的衍生神经营养因子（通过 TrkB 受体的磷酸化）来测试这些。想法，我们将：（1）首先使用急性和慢性（3周）VNS优化刺激参数确定它在 FST 中产生的行为效果，并将其效果与 FST 产生的效果进行比较选择性去甲肾上腺素能再摄取抑制剂、地昔帕明和选择性血清素再摄取抑制剂，舍曲林，（2）使用FST中效果最好的慢性VNS方案来测量其对c-Fos的影响， ¿ FosB、Egr-1、TrkB 激活、¿ 1-肾上腺素受体和体细胞树突 5-HT 自身受体敏感性和将结果与长期使用地昔帕明或舍曲林治疗引起的结果进行比较，并且（3）测试去甲肾上腺素和血清素在慢性 VNS、地昔帕明和舍曲林的抗抑郁样作用中的作用将使用 6-羟基多巴胺或 5,7-二羟色胺来缩小大鼠。测量 c-Fos, ¿ FosB、Egr-1 和磷酸化 TrkB 将用于定量放射自显影。措施 1-肾上腺素受体 DPAT 诱导的纹状体细胞外 5-HT 变化将被用作自身受体敏感性指数的结果可以提供有关中枢的重要的新信息。 VNS 对神经系统的影响对于抑郁症的治疗很重要。大约 30% 的重度抑郁症患者对标准的迷走神经治疗有抵抗力。神经刺激（VNS）最近被批准用于此类难治性患者，但它的效果如何？我们的研究将全面评估 VNS 对大鼠大脑的影响。此类效应背后的机制，以便提供数据让 VNS 变得更加有效。