Influence of LY 300164, an antagonist of AMPA/kainate receptors, on the anticonvulsant activity of clonazepam

LY 300164 [7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine], an antagonist of AMPA/kainate receptors, at 5 mg/kg exerted a significant anticonvulsant effect, as regards seizure and afterdischarge durations in amygdala-kindled seizures in rats. At lower doses, LY 300164 did not exert anticonvulsant activity. Clonazepam alone (0.003-0.1 mg/kg) significantly diminished seizure severity, seizure and afterdischarge durations. Coadministration of LY 300164 (2 mg/kg) with clonazepam (0.001 mg/kg) resulted in the significant anticonvulsant activity. Seizure severity score, seizure and afterdischarge durations were reduced from 5 to 4, from 32.6 s to 12.3 s, and 42.7 s to 23.2 s. LY 300164 (2 mg/kg), clonazepam (0.001-0.1 mg/kg) and the combination of clonazepam (0.001 mg/kg) with LY 300164 (2 mg/kg) did not affect long-term memory evaluated in the passive avoidance task in rats. LY 300164 (at the subprotective close of 2 mg/kg) significantly potentiated the anticonvulsant action of clonazepam against maximal electroshock but not against pentylenetetrazol-induced convulsions in mice. The results indicate that blockade of glutamate-mediated events at AMPA/kainate receptors may differently affect the protection offered by clonazepam, which seems dependent upon the model of experimental seizures. (C) 1999 Elsevier Science B.V. All rights reserved.