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

• Published in: European journal of pharmacology Vol. 380; no. 2; pp. 67 - 72
• Main Authors: Borowicz, Kinga K, Łuszczki, Jarogniew, Szadkowski, Marcin, Kleinrok, Zdzisław, Czuczwar, Stanisław J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.09.1999; Elsevier
• Subjects: AMPA/kainate receptor; Amygdala - drug effects; Amygdala - physiopathology; Amygdala-kindled seizure; Animals; Anticonvulsants - adverse effects; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Ataxia - chemically induced; Avoidance Learning - drug effects; Benzodiazepines - pharmacology; Biological and medical sciences; Clonazepam; Clonazepam - adverse effects; Clonazepam - blood; Clonazepam - pharmacology; Drug Synergism; Electroshock; Electroshock maximal; Excitatory Amino Acid Antagonists - pharmacology; Kindling, Neurologic - drug effects; Kindling, Neurologic - pathology; LY 300164; Male; Medical sciences; Mice; Neuropharmacology; Pentylenetetrazol; Pentylenetetrazole - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, AMPA - antagonists & inhibitors; Seizures - pathology; Seizures - physiopathology; Seizures - prevention & control; Species Specificity; Electroshock maximal; Amygdala-kindled seizure; AMPA/kainate receptor; Clonazepam; LY 300164; Pentylenetetrazol; Drug combination; Rat; Psychotropic; Treatment efficiency; Rodentia; Hypnotic; Anticonvulsant; Kainate receptor; Vertebrata; Chemotherapy; AMPA receptor; Mammalia; Treatment; Tranquillizer; Convulsion; Animal; Benzodiazepine derivatives; Drug interaction; Antagonist; Sedative; Neurological disorder
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00541-5

LY 300164 [7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7 H-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 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.