Abstracts

Rationale: Vagus nerve stimulation (VNS) is an effective adjunctive treatment for refractory epilepsy. Altered neuronal activity in the locus coeruleus, resulting in increased release of noradrenalin in the hippocampus has been advanced as a possible mechanism of action of VNS in temporal lobe epilepsy. The aim of this study was to determine the effect of VNS on hippocampal EC noradrenalin concentration, and to clarify the involvement of noradrenalin in the anticonvulsant mechanism of action of VNS. Methods: Male Wistar rats were implanted with a stimulation electrode around the left vagus nerve. Depth EEG electrodes and a microdialysis probe were stereotactically implanted in the left hippocampus. One week later, limbic seizures were evoked in all all animals by intrahippocampal administration of pilocarpine via the microdialysis probe. Two hours prior to pilocarpine administration, one of the following treatments was initiated (i) no stimulation, (ii) VNS (intensity 1 mA, frequency 30Hz, pulse width 250s, 7s on / 18s off), or (iii) VNS and concomittant intrahippocampal administration via the microdialysis probe of the selective α2 noradrenergic receptor antagonist SKF-86466. Behavioural changes indicative of seizure activity were scored. Hippocampal and cortical EEG and hippocampal extracellular noradrenalin concentration were monitored. Results: VNS produced a rapid and sustained elevation of hippocampal extracellular noradrenalin concentration (150 ± 12% of baseline), and significantly attentuated the behavioral and electrographic changes indicative of pilocarpine-induced limbic seizures. Blockade of hippocampal α2 noradrenergic receptors using SKF-86466 reversed the anticonvulsant effect of VNS. Conclusions: Increased hippocampal extracellular noradrenalin concentration contributes to the anticonvulsant activity of VNS in the focal pilocarpine model for temporal lobe seizures. This effect is at least partly mediated via hippocampal α2 noradrenergic receptors.