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

摘要 几乎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的中枢作用， 因为它有抗抑郁作用我们最近完成了一些VNS管理的初步研究 使用临床相关的刺激参数急性或慢性地对非麻醉大鼠进行。两 观察功能性神经解剖学和行为学影响。该提案的目标是扩大和 为了更全面地评价迷走神经刺激对脑组织的影响， 这种影响的机制。我们的总体假设是VNS产生了有益的临床效果， 如通过大鼠强迫游泳试验（FST）中减少的不动性所测量的，通过激活多个 - 脑中的神经递质/神经调质系统，特别是血清素或去甲肾上腺素和/或脑- 衍生的含有神经营养因子的神经元（通过TrkB受体的磷酸化）。测试这些 想法，我们将：（1）最初优化刺激参数，使用急性和慢性（3周）VNS， 确定它在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，和选择性5-羟色胺再摄取抑制剂， 舍曲林，（2）采用FST中效果最好的慢性VNS方案，测定其对c-Fos的影响， <$FosB、Egr-1、TrkB激活、<$1-肾上腺素受体和体树突5-HT自身受体敏感性， 将结果与地昔帕明或舍曲林长期治疗引起的结果进行比较，以及（3）测试 去甲肾上腺素和5-羟色胺在慢性迷走神经刺激、地昔帕明和舍曲林抗抑郁样作用中的作用 用6-羟基多巴胺或5，7-二羟基色胺损伤大鼠。免疫组织化学将用于 测量c-Fos、p-FosB、Egr-1和磷酸化TrkB。定量放射自显影将用于 测量1-肾上腺素受体。DPAT诱导的纹状体细胞外5-HT的变化将被用作 自身感受器敏感性指数。这些结果可以提供关于中央神经系统的重要的新信息。 迷走神经刺激对神经系统的影响对抑郁症的治疗很重要。项目叙述 大约30%的重度抑郁症患者对标准抗抑郁药治疗有抵抗力。迷走 神经刺激（VNS）最近被批准用于此类难治性患者;它是中等有效的，但它是如何治疗的？ 作品不详。本研究将全面评价迷走神经刺激对大鼠脑的影响， 这种效应的潜在机制，以便提供数据使VNS变得更加有效。

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.