The effect of vagus nerve stimulation on CSF monoamines and the PTZ seizure threshold in dogs.

Abstract

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. 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. 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 1h 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. 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. 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.