Abstracts

Rationale: Vagus nerve stimulation (VNS) is an adjunctive treatment for patients with refractory epilepsy. Drawbacks of this treatment are the lack of responder identification and knowledge of the mechanism of action. The aim of this study is to unravel the potential mechanism of action by screening of the VNS-induced changes in hippocampal neurotransmitters in relation to the limbic seizure suppressing action of this treatment in the intrahippocampal pilocarpine model. Methods: Rats were stereotactically implanted with a guide cannula and a bipolar electrode in the hippocampus and a stimulation cuff-electrode around the left vagus nerve. VNS was performed in all rats using the following stimulation parameters: 30 Hz, 1 mA, 250 sec, 7 sec ON-18 sec OFF. This was combined with intracerebral microdialysis to measure hippocampal noradrenalin, dopamine, serotonin and GABA concentrations and to evoke limbic seizures by intrahippocampal administration of pilocarpine. Clinical and electrographic seizure activity was identified using video-EEG monitoring. In this way the effect of VNS on hippocampal neurotransmitter levels and pilocarpine-induced seizure activity was assessed. In a second set of experiments the importance of the VNS-induced noradrenergic stimulation to its seizure-suppressive effect was evaluated by co-administration of SKF 86466, a noradrenergic ?2-receptor antagonist. Results: VNS significantly increased the latency between the start of the pilocarpine infusion and the onset of epileptiform discharges. It also significantly attenuated duration of pilocarpine-induced seizures and reduced clinical seizure severity. Neurochemically, VNS significantly increased extracellular hippocampal noradrenalin levels. A highly significant positive correlation was found between the noradrenergic and seizure-suppressive effects of VNS. Selective blockade of noradrenergic ?2-receptors completely reverted the seizure-suppressive effects of VNS in the intrahippocampal pilocarpine model. Conclusions: VNS has seizure-suppressing effects in the intrahippocampal pilocarpine model for limbic seizures as a result of an increase in hippocampal noradrenalin concentration induced by VNS. Increased noradrenalin concentration is a promising biomarker for the evaluation of anti-seizure effects of VNS.