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

描述（由申请人提供）：几乎30%的重度抑郁症患者患有慢性难治性疾病。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，很少有临床前研究表明VNS的中枢作用可能与其抗抑郁作用有关。我们最近完成了一些初步研究，使用临床相关的刺激参数对大鼠进行急性或慢性迷走神经刺激。观察了功能性神经解剖学和行为学效应。本提案的目标是扩大和扩大这些观察结果，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/神经调节剂系统，特别是5 -羟色胺或去甲肾上腺素和/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）产生有益的临床效果。为了测试这些想法，我们将：(1)初步优化刺激参数，通过确定急性和慢性（3周）VNS在FST中产生的行为效应，并将其与选择性去甲肾上腺素能再摄取抑制剂地西帕明和选择性血清素再摄取抑制剂舍曲林产生的效应进行比较；(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激活、21肾上腺素受体的影响；(3)检测去甲肾上腺素和血清素在慢性VNS、去西帕明和舍曲林抗抑郁样作用中的作用。免疫组织化学将用于测量c-Fos， FosB， Egr-1和磷酸化的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。这一结果可能为VNS对中枢神经系统的影响提供重要的新信息，这对抑郁症的治疗很重要。

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.