EXCITATORY AMINO-ACID ANTAGONISTS PROTECT MICE AGAINST SEIZURES INDUCED BY BICUCULLINE

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the γ-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-((±)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-d-aspartate (NMDA) antagonists. γ-d-Glutamylaminomethylsulphonate (γ-d-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), γ-d-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus. The seizures induced by s.c. injection of BIC in the dose of 3.2 mg/kg (approximately CD97) were blocked by pretreatment (i.p.) with the NMDA antagonists MK-801 (ED50 0.075 mg/kg for clonus and 0.044 mg/kg for tonus), CPP (7.743 mg/kg for clonus and 0.032 mg/kg for tonus) and CGS 19755 (> 10 mg/kg for clonus and 3.01 mg/kg for tonus). GABAA agonist MSC had no effect on clonus (> 2.5 mg/kg) and prevented mice from tonus with an ED50 of 1.77 mg/kg. These results suggest an important role of excitation mediated by dicarboxylic amino acids in the pathogenesis of seizures triggered by bicuculline in mice. © 1990.