Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice

Abstract

This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice. ω-Conotoxin MVIIC (0.1, 0.3 μg ICV/mouse) and ω-agatoxin IVA (0.1, 0.3, 1 μg ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED50 values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04-0.36) μg ICV and 0.09 (0.05-0.15) μg ICV, respectively and against tonic seizures 0.07 (0.03-0.16) μg ICV and 0.08 (0.04-0.13) μg ICV, respectively). The N-type calcium channel antagonists ω-conotoxin GVIA and ω-conotoxin MVIIA were also tested in this model. ω-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 μg ICV prevented tonic seizures in 60% of the animals; 10 μg ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas ω-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 μg ICV. Both ω-conotoxin GVIA and ω-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 μg ICV, whereas ω-conotoxin MVIIC and ω-agatoxin IVA did not produce shaking at any of the doses examined. Finally, α-conotoxin GI (0.01-1 μg ICV) and α-conotoxin SI (0.3-30 μg ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of ω-conotoxin MVIIC and ω-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.