NMDA and AMPA/kainate receptors are involved in the anticonvulsant activity of riluzole in DBA/2 mice

The anticonvulsant activity of riluzole against sound-induced seizures was studied in the DBA/2 mouse model. Riluzole (0.1-4 mg kg(-1), intraperitonea l (i.p.)) produced dose-dependent effects with ED50 values for the suppress ion of tonic, clonic and wild running phases of 0.72, 1.38 and 2.71 mg kg(- 1), respectively. Riluzole also protected DBA/2 mice from seizures induced by an intracerebroventricular (i.c.v.) injection of N-methyl-D-aspartate (N MDA) with ED50 values of 3.03 and 5.0 mg kg(-1) for tonus and clonus, respe ctively. Pretreatment with glycine, an agonist to the glycine/NMDA receptor s, shifted the dose-response effect of riluzole to the right (ED50 = 6.53 a gainst tonus and 9.34 mg kg(-1) vs, clonus). Similarly, D-serine, an agonis t at the glycine site, shifted the ED50 of riluzole against the tonic compo nent of audiogenic seizures from 0.72 to 1.97, and that against clonus from 1.38 to 2.77 mg kg(-1). Riluzole was also potent to prevent seizures induc ed by administration of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropioni c acid (AMPA), an AMPA/kainate receptor agonist (ED50 = 1.80 and 3.35 mg kg (-1), against tonus and clonus, respectively). Pretreatment with aniracetam , a positive allosteric modulator of AMPA/kainate receptors, shifted the do se-response curve of riluzole to the right (ED50 = 1.78 against tonus and 2 .58 mg kg(-1) vs, clonus). The data indicate that riluzole is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our f indings suggest that the anticonvulsant properties of riluzole depend upon its interaction with neurotransmission mediated by both the glycine/NMDA an d the AMPA/kainate receptor complex. (C) 2000 Elsevier Science B.V. All rig hts reserved.