Vagal Nerve Stimulation and Antidepressants: c-Fos deltaFosB and Activation of T

迷走神经刺激和抗抑郁药：c-Fos deltaFosB 和 T 激活

• 批准号: 8071549
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-04 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071549
• 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; Desipramine; Devices; Electrodes; Epilepsy; FDA approved; FOS gene; Frequencies; Gene Expression; Goals; Heart Rate; Hour; Immediate-Early Genes; Immunohistochemistry; Major Depressive Disorder; Manufacturer Name; Measures; Mental Depression; Monitor; Nerve; Neuraxis; Neuromodulator; Neurons; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Norepinephrine; Nucleus solitarius; 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; 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

DESCRIPTION (provided by applicant): 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 relevant for its antidepressant effect. We completed recently some preliminary studies in which VNS was administered either acutely or chronically to 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 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, 21-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. Immunohistochemistry will be used to measure c-Fos, FosB, Egr-1, and phosphorylated TrkB. Quantitative autoradiography will be used to measure 21- 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.

描述（由申请人提供）：近 30% 的重度抑郁症患者患有难治性慢性病。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，很少有临床前研究探讨 VNS 可能与其抗抑郁作用相关的核心作用。我们最近完成了一些初步研究，其中使用临床相关的刺激参数对大鼠进行急性或长期的 V​​NS 给药。观察到功能性神经解剖学和行为效应。该提案的目标是扩展和放大这些观察结果，以便更全面地评估 VNS 在大脑中产生的效应以及这种效应背后的机制。我们的总体假设是，VNS 通过激活大脑中的多种神经递质/神经调节系统，特别是血清素或去甲肾上腺素和/或含有神经元的脑源性神经营养因子（通过 TrkB 受体的磷酸化）来产生有益的临床效果。为了测试这些想法，我们将：（1）首先优化刺激参数，使用急性和慢性（3周）VNS，确定其在 FST 中产生的行为效应，并将其效应与选择性去甲肾上腺素能再摄取抑制剂地昔帕明产生的效应进行比较，以及选择性5-羟色胺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、FosB、Egr-1的影响， TrkB、21-肾上腺素受体和体细胞树突 5-HT 自身受体敏感性的激活，并将结果与​​长期使用地昔帕明或舍曲林治疗引起的结果进行比较，以及（3）测试去甲肾上腺素和血清素在慢性 VNS 的抗抑郁样作用中的作用，地昔帕明和舍曲林。免疫组织化学将用于测量 c-Fos、FosB、Egr-1 和磷酸化 TrkB。定量放射自显影将用于测量21-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的指标。这些结果可以提供有关 VNS 对中枢神经系统影响的重要新信息，这对于抑郁症的治疗很重要。