Shah A P, Carreno F R, Wu H, Chung Y A, Frazer A
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, TX, USA.
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, TX, USA.
Neuroscience. 2016 May 13;322:273-86. doi: 10.1016/j.neuroscience.2016.02.024. Epub 2016 Feb 16.
A current hypothesis regarding the mechanism of antidepressant (AD) action suggests the involvement of brain-derived neurotrophic factor (BDNF). Consistent with this hypothesis, the receptor for BDNF (and neurotrophin 4/5 (NT-4/5)), Tropomyosin-related kinase B (TrkB), is activated in rodents by treatment with classical AD drugs. Vagal nerve stimulation (VNS), a therapy for treatment resistant depression (TRD), 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 using its inhibitor, K252a. Anxiolytic-like and AD-like effects were analyzed using the novelty suppressed feeding test (NSFT) and forced swim test (FST), respectively. K252a blocked the anxiolytic-like effect of chronic VNS treatment and the AD-like effect of acute VNS treatment. By contrast, blocking TrkB did not prevent either the anxiolytic-like or AD-like effect of chronic treatment with desipramine (DMI), a selective noradrenergic reuptake inhibitor; it did, however, block the acute effect of DMI in the FST. To examine whether the activation of TrkB caused by either VNS or DMI 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 AD drug and a stimulation therapy as well as its role in acute versus chronic effects of DMI.
目前关于抗抑郁药（AD）作用机制的一种假说认为，脑源性神经营养因子（BDNF）参与其中。与该假说一致的是，BDNF（以及神经营养因子4/5（NT-4/5））的受体——原肌球蛋白相关激酶B（TrkB），在啮齿动物中可被经典AD药物激活。迷走神经刺激（VNS）是一种治疗难治性抑郁症（TRD）的方法，它在啮齿动物中也能激活TrkB。然而，该受体在VNS治疗效果中的作用尚不清楚。在本研究中，使用TrkB抑制剂K252a在大鼠中研究了TrkB在VNS作用中的参与情况。分别使用新奇抑制摄食试验（NSFT）和强迫游泳试验（FST）分析了抗焦虑样和抗抑郁样作用。K252a阻断了慢性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并不能预防去甲丙咪嗪（DMI，一种选择性去甲肾上腺素再摄取抑制剂）慢性治疗的抗焦虑样或抗抑郁样作用；然而，它确实阻断了DMI在FST中的急性作用。为了研究由VNS或DMI引起的TrkB激活是否依赖配体，使用了TrkB-Fc，一种TrkB配体的分子清除剂。脑室内注射TrkB-Fc阻断了两种治疗诱导的TrkB急性激活，表明治疗诱导的该受体激活是依赖配体的。行为学结果突出了TrkB在AD药物慢性作用和刺激疗法中的参与差异，以及它在DMI急性和慢性作用中的作用。
