Locus Coeruleus Lesions Suppress the Seizure‐Attenuating Effects of Vagus Nerve Stimulation

Purpose: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug‐resistant epilepsy, the therapeutic mechanism of action of VNS‐induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. Methods: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6‐hydroxydopamine (6‐OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS‐induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. Results: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS‐induced seizure suppression was attenuated. Conclusions: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS‐induced seizure suppression.