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, 5H)-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 dose 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.
Borowicz
K K
KK
Department of Pharmacology and Toxicology, Lublin Medical University School, Poland.
Luszczki
J
J
Szadkowski
M
M
Kleinrok
Z
Z
Czuczwar
S J
SJ
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D002998:Clonazepam / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004357:Drug Synergism; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D013045:Species Specificity
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D001569:Benzodiazepines; D002998:Clonazepam; C085266:talampanel; D010433:Pentylenetetrazole