TY - JOUR
T1 - Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation
T2 - Comparison with desipramine
AU - Shah, A. P.
AU - Carreno, F. R.
AU - Wu, H.
AU - Chung, Y. A.
AU - Frazer, A.
N1 - Funding Information:
Dr. A. Frazer has served on advisory boards for Lundbeck, Takeda Pharmaceuticals International, Inc. and Eli Lilly and Co. In the past, Dr. Frazer has received financial compensation as a consultant for Cyberonics Inc. and has also obtained grant support from them for a preclinical study. None of the other authors have any conflicting interests to declare.
Funding Information:
This work was supported by the National Institute of Mental Health grant MH082933 (Alan Frazer). We would like to acknowledge the technical assistance of Marisa DeGuzman, Jonathan Chemello and Mohona Sadhu and thank Drs. David Morilak and Wouter Koek for their guidance with statistical analyses. We would also like to acknowledge that Cyberonics Inc., TX, generously provided the VNS stimulators, dummy stimulators and electrodes as gifts.
Publisher Copyright:
© 2016 IBRO.
PY - 2016/5/13
Y1 - 2016/5/13
N2 - 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.
AB - 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.
KW - Antidepressants
KW - BDNF
KW - Depression
KW - Desipramine
KW - TrkB
KW - Vagal nerve stimulation
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UR - http://www.scopus.com/inward/citedby.url?scp=84960958237&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2016.02.024
DO - 10.1016/j.neuroscience.2016.02.024
M3 - Article
C2 - 26899129
AN - SCOPUS:84960958237
SN - 0306-4522
VL - 322
SP - 273
EP - 286
JO - Neuroscience
JF - Neuroscience
ER -