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 (Ca2+) channel inhibitors nicardipine, nifedipine, and flunarizine on the protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI 52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or flunarizine (10 mg/kg) nifedipine (7.5 and 15 mg/kg) potentiated the protective potency of MK-801 (0.05 mg/kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current strength in mA producing tonic hind limb extension in 50% of the animals). The protective activity of LY 235959 and GYKI 52466 was reflected by their ED50 values in mg/kg, at which the drugs were expected to protect 50% of mice against maximal electroshock-induced tonic extension of 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 markedly potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 and 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protective action of GYKI 52466 against electroconvulsions. Except with MK-801 + flunarizine (motor performance) or GYKI 52466 + flunarizine (long-term memory), combination of NMDA or non-NMDA receptor antagonists with Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (measured in the passive avoidance task) as compared with vehicle treatment.
Gasior
M
M
Department of Pharmacology, Medical University School, Lublin, Poland. mgasior@irp.nih.nida.gov
Borowicz
K
K
Kleinrok
Z
Z
Starownik
R
R
Czuczwar
S J
SJ
D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology* / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000633:toxicity; D004347:Drug Interactions; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000633:toxicity; D005444:Flunarizine / Q000494:pharmacology / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology / Q000633:toxicity; D009543:Nifedipine / Q000494:pharmacology / Q000633:toxicity; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; C061950:GYKI 52466; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; C088643:LY 235959; D009529:Nicardipine; D009543:Nifedipine; D005444:Flunarizine