Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine.
Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine.
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DOI：
10.1016/j.neuroscience.2016.02.024
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发表时间：
2016-05-13
期刊：
影响因子：
3.3
通讯作者：
Frazer A
中科院分区：
文献类型：
--
作者：
Shah AP;Carreno FR;Wu H;Chung YA;Frazer A
目前关于抗抑郁作用机制的假设表明脑源性神经营养因子（BDNF）参与其中。与这一假设相一致的是，BDNF（和神经营养蛋白 4/5）的受体原肌球蛋白相关激酶 B (TrkB) 在啮齿类动物中通过经典抗抑郁药物治疗而被激活。迷走神经刺激 (VNS) 是一种治疗难治性抑郁症的疗法，也会激活啮齿类动物的 TrkB。然而，该受体在 VNS 治疗效果中的作用尚不清楚。在当前的研究中，通过使用其抑制剂 K252a 在大鼠中研究了 TrkB 在 VNS 作用中的参与。分别使用新奇抑制进食试验和强迫游泳试验来分析抗焦虑样和抗抑郁样作用。 K252a 阻断慢性 VNS 治疗的抗焦虑样作用和急性 VNS 治疗的抗抑郁样作用。相比之下，阻断 TrkB 并不能阻止地昔帕明（一种选择性去甲肾上腺素能再摄取抑制剂）长期治疗的抗焦虑样或抗抑郁样作用。然而，它确实阻止了地昔帕明在强迫游泳测试中的急性作用。为了检查由 VNS 或地昔帕明引起的 TrkB 激活是否具有配体依赖性，使用了 TrkB-Fc，一种 TrkB 配体的分子清除剂。脑室内注射 TrkB-Fc 可阻断任一治疗诱导的 TrkB 急性激活，表明治疗诱导的该受体激活是配体依赖性的。行为结果强调了 TrkB 在抗抑郁药物和刺激疗法的慢性作用中的参与差异，以及它在地昔帕明的急性与慢性作用中的作用。
A current hypothesis regarding the mechanism of antidepressant action suggests the involvement of brain derived neurotrophic factor (BDNF). Consistent with this hypothesis, the receptor for BDNF (and neurotrophin 4/5), Tropomyosin related kinase B (TrkB), is activated in rodents by treatment with classical antidepressant drugs. Vagal nerve stimulation (VNS), a therapy for treatment resistant depression, also activates TrkB in rodents. However, the role of this receptor in the therapeutic effects of VNS is unclear. In the current study, the involvement of TrkB in the effects of VNS was investigated in rats by using its inhibitor, K252a. Anxiolytic-like and antidepressant-like effects were analyzed using the novelty suppressed feeding test and forced swim test, respectively. K252a blocked the anxiolytic-like effect of chronic VNS treatment and the antidepressant-like effect of acute VNS treatment. By contrast, blocking TrkB did not prevent either the anxiolytic-like or antidepressant-like effect of chronic treatment with desipramine, a selective noradrenergic reuptake inhibitor; it did, however, block the acute effect of desipramine in the forced swim test. To examine whether the activation of TrkB caused by either VNS or desipramine is ligand-dependent, use was made of TrkB-Fc, a molecular scavenger for ligands of TrkB. Intraventricular administration of TrkB-Fc blocked the acute activation of TrkB induced by either treatment, indicating that treatment-induced activation of this receptor is ligand-dependent. The behavioral results highlight differences in the involvement of TrkB in the chronic effects of an antidepressant drug and a stimulation therapy as well as its role in acute versus chronic effects of desipramine.