Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine

Abstract

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.

Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies

“…In support of this hypothesis, we have found that VNS promotes the rapid storage of new extinction memories in rats (Pena et al 2013; Pena et al 2014; Alvarez-Dieppa et al 2016; Noble et al 2017a), and others have reported evidence that chronic VNS can reduce anxiety in rats (Shah et al 2016) and humans (George et al 2008). This unique combination of effects makes VNS an exciting potential adjuvant to exposure-based therapies.…”

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

“…VNS has emerged as a potential strategy to promote neural plasticity, enhance memory, and reduce conditioned fear when delivered coincidentally with cue presentation during fear extinction [29–31], and chronic VNS has anxiolytic effects [32]. We tested whether VNS, like other cognitive enhancing strategies, would promote generalization of extinction and accelerate extinction to multiple fear-related cues in rats.…”

“…Additionally, VNS administration paired with exposure to conditioned cues accelerates the extinction of conditioned fear and attenuates reinstatement in a rat model of PTSD [31]. VNS could also increase tolerability during exposure-based therapies as chronic administration of VNS reduces anxiety in rats [32–33] and humans [34]. These results suggest that VNS, which is FDA approved for epilepsy and treatment-resistant depression in humans, may be a promising adjunct to exposure-based therapies.…”

Vagal Nerve Stimulation for Treatment-Resistant Depression

“…We have shown that both acute (2 h) and chronic (14 days) VNS activates the TrkB receptor, as shown by its causing phosphorylation at 3 tyrosine residues (Y705, Y816, and Y515) on TrkB [129]. Intraventricular pretreatment with a scavenger compound for TrkB, namely TrkB-Fc, which is a homodimer containing the extracellular ligand-binding domains of TrkB linked to human IgG1, prevented the acute VNS-induced increase in TrkB phosphorylation [130]. This suggests that VNS-induced activation of TrkB requires ligand to bind to it [130].…”

“…Intraventricular pretreatment with a scavenger compound for TrkB, namely TrkB-Fc, which is a homodimer containing the extracellular ligand-binding domains of TrkB linked to human IgG1, prevented the acute VNS-induced increase in TrkB phosphorylation [130]. This suggests that VNS-induced activation of TrkB requires ligand to bind to it [130]. In contrast to the effects of VNS on the phosphorylation of TrkB, acute and chronic antidepressant treatments only cause phosphorylation at Y705 and Y816 b u t n o t a t Y 5 1 5 [ 1 2 9 , 1 3 1 , 1 3 2 ] .…”