Periodic transmeningeal muscimol maintains its antiepileptic efficacy over three weeks without inducing tolerance, in rats

Abstract

Periodic transmeningeal administration of muscimol into the neocortical epileptogenic zone via a subdurally implanted device has been proposed for the treatment of intractable focal neocortical epilepsy. It is unknown whether such muscimol applications induce tolerance. The purpose of this study was to determine whether daily transmeningeal (epidural) muscimol applications into the rat parietal cortex induce tolerance to the antiepileptic effect of this drug. Rats were chronically implanted with an epidural cup and adjacent epidural EEG electrodes over the right parietal cortex. After recovery 1.0 mM muscimol was delivered into the implanted cortical area through the cup while the animal behaved freely, once per day for 4 consecutive days in each week, with each delivery followed within 3 min by the delivery of a seizure-inducing concentration of acetylcholine (Ach) into the same area. The study lasted for 3 weeks. In each week, one day was used to test the epileptogenicity of the examined cortical site by replacing muscimol with saline prior to Ach delivery. The duration of Ach-induced EEG seizures was measured in each experimental session to assess the antiepileptic efficacy of muscimol, while the rat's behavior was also monitored. The daily epidural muscimol pretreatments prevented Ach-induced EEG and behavioral seizures in all rats. This antiepileptic action did not diminish over time and was maintained throughout the 3-week test period. When muscimol was replaced with saline, the subsequent Ach administrations induced EEG and behavioral seizures. These results suggest that periodic transmeningeal administrations of a relatively low concentration of muscimol into the neocortex over three weeks do not induce tolerance to the localized antiepileptic effects of this drug.