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

描述(申请人提供)：近30%的严重抑郁障碍患者患有治疗难治的慢性病。迷走神经刺激(VNS)最近被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的中枢作用，这可能与其抗抑郁作用有关。我们最近完成了一些初步研究，在这些研究中，使用与临床相关的刺激参数，对大鼠急性或慢性地给予VNS。观察功能、神经解剖学和行为学方面的影响。这项建议的目的是扩大和放大这些观察结果，以便更全面地评估VNS在大脑中产生的影响及其潜在的机制。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5-羟色胺或去甲肾上腺素和/或含有脑源性神经营养因子的神经元(通过TrkB受体的磷酸化)而产生有益的临床效应。为了验证这些想法，我们将：(1)初步优化刺激参数，使用急性和慢性(3周)VNS，通过确定它在FST中产生的行为影响，并将其与选择性去甲肾上腺素再摄取抑制剂地昔帕明和选择性5-羟色胺再摄取抑制剂舍曲林产生的效果进行比较；(2)使用在FST中效果最好的慢性VNS方案，测量其对c-Fos、FosB、Egr-1、TrkB、21-肾上腺素受体和生长激素5-羟色胺自身受体敏感性的影响，并与慢性治疗的结果进行比较。(3)检测去甲肾上腺素和5-羟色胺在慢性VNS、地塞帕明和舍曲林抗抑郁药样作用中的作用。免疫组织化学方法检测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-羟色胺的变化将被用作自身受体敏感性的指标。这一结果可能提供有关VNS的中枢神经系统效应的重要新信息，这些信息对抑郁症的治疗非常重要。

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.