EXCITATORY AMINO-ACID NEUROTRANSMISSION THROUGH BOTH NMDA AND NON-NMDA RECEPTORS IS INVOLVED IN THE ANTICONVULSANT ACTIVITY OF FELBAMATE IN DBA/2 MICE

The anticonvulsant activity of felbamate against sound-induced seizures was studied in the DBA/2 mouse model. Felbamate (10-300 mg/kg, i.p.) produced dose-dependent effects with ED(50) values for the suppression of tonic, clonic and wild running phases of 23.1, 48.8 and 114.6 mg/kg, respectively. Felbamate also protected DBA/2 mice from N-methyl-D-aspartate (NMDA)-induced seizures with ED(50)values of 12.1 and 29 mg/kg for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of felbamate to the right (ED(50) = 56.8 against tonus and 94.8 mg/kg versus clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED(50) of felbamate against the tonic component of audiogenic seizures from 23.1 to 78.1, and that against clonus from 48.8 to 90.3 mg/kg. Felbamate was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/ kainate receptor agonist (ED(50) = 11.8 and 20.9 mg/kg, against tonus and clonus, respectively). The data indicate that felbamate is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of felbamate depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.