ANTICONVULSANT AND ADVERSE-EFFECTS OF MK-801, LY-235959, AND GYKI-52466 IN COMBINATION WITH CA2+ CHANNEL INHIBITORS IN MICE

This study was designed to investigate the influence of the calcium (C a2+) channel inhibitors nicardipine, nifedipine, and flunarizine on th e protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or f lunarizine (10 mg/kg), nifedipine (7.5 and 15 mg/kg) potentiated the p rotective potency of MK-801 (0.05 mg/ kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current st rength in mA producing tonic hind limb extension in 50% of the animals ). The protective activity of LY 235959 and GYKI52466 was reflected by their ED50, values in mg/kg, at which the drugs were expected to prot ect 50% of mice against maximal electroshock-induced tonic extension o f the hind limbs. Nicardipine (3.75-15 mg/kg), nifedipine (0.94-15 mg/ kg), and flunarizine (2.5-10 mg/kg) in a dose-dependent manner markedl y potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 an d 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protect ive action of GYKI 52466 against electroconvulsions. Except with MK-80 1 + flunarizine (motor performance) or GYKI 52 466 + flunarizine (long -term memory), combination of NMDA or non-NMDA receptor antagonists wi th Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (mea sured in the passive avoidance task) as compared with vehicle treatmen t. (C) 1997 Elsevier Science Inc.