title: The effect of vagus nerve stimulation on CSF monoamines and the PTZ seizure threshold in dogs.
abstract: BACKGROUND
  Vagus nerve stimulation (VNS) is an established treatment for refractory epilepsy in humans, but the precise mechanism of action (MOA), predictive responsive factors and the optimal stimulation parameters remain to be elucidated.
  
  
  OBJECTIVE
  We aimed to investigate the effect of two rapid cycling VNS paradigms on CSF monoamine levels and the seizure threshold in the canine pentylenetetrazole (PTZ) model.
  
  
  METHODS
  Eight Beagle dogs, implanted with a VNS Therapy(®) System, participated in a cross-over study. Levels of serotonin (5HT), norepinephrine (NE) and dopamine (DA) were quantified in the CSF after 1 h of sham, standard and microburst VNS with a wash-out period of 1 month. One week after the CSF experiment, the PTZ seizure threshold was determined after the same stimulation paradigm. As a positive control, the PTZ seizure threshold was determined after a single oral dose of phenobarbital.
  
  
  RESULTS
  Rapid cycling standard and microburst VNS caused a significant increase of NE levels in the CSF (P = 0.03 and P = 0.02 respectively). No significant changes in 5HT or DA levels were detected. Rapid cycling standard and microburst VNS did not cause significant changes in the PTZ seizure threshold compared to sham.
  
  
  CONCLUSIONS
  VNS induces an increase of NE in the canine brain, which supports previous findings indicating that VNS influences the locus coeruleus-NE (LC/NE) system. Importantly, this study demonstrates that this increase in NE is measurable in the CSF. One hour of VNS did not affect seizure threshold in the canine PTZ model. Therefore, the role of NE in the antiepileptic effect of VNS in dogs remains to be elucidated.
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium. Electronic address: valentine.martle1@gmail.com.
authors.forename: Valentine
authors.initials: V
authors.lastname: Martlé
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, Belgium.
authors.forename: Robrecht
authors.initials: R
authors.lastname: Raedt
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Waelbers
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis & Drug Information Center for Neurosciences C4N, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, Belgium.
authors.forename: Kristl
authors.initials: K
authors.lastname: Vonck
authors.affiliation: Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Boon
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Ham
authors.affiliation: Department of Comparative Physiology and Biometrics, Faculty of Veterinary Medicine, Ghent University, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Duchateau
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Bhatti
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D018592:Cross-Over Studies; D004285:Dogs; D004298:Dopamine / Q000134:cerebrospinal fluid*; D009638:Norepinephrine / Q000134:cerebrospinal fluid*; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D012701:Serotonin / Q000134:cerebrospinal fluid*; D055536:Vagus Nerve Stimulation
chemical_list: D000927:Anticonvulsants; D012701:Serotonin; D004298:Dopamine; D010433:Pentylenetetrazole; D009638:Norepinephrine; D010634:Phenobarbital
keywords: CSF; Canine PTZ model; Norepinephrine; Vagus nerve stimulation