Dantrolene, a Calcium-Induced Calcium Release Inhibitor, Prevents the Acquisition of Amygdaloid Kindling in Rats, a Model of Experimental Epilepsy

Abstract

Kindling phenomenon (an experimental model of acquired epilepsy) and long-term potentiation (LTP) have many features in common. LTP is associated with an increase in intracellular Ca²⁺ concentration where intracellular Ca²⁺ stores play an important role. Dantrolene has an inhibitory action against Ca²⁺ release from intracellular Ca²⁺ stores. This substance has been reported to inhibit the induction of LTP. We investigated whether or not the development of kindling would be inhibited by dantrolene. We first determined at the right amygdala afterdischarge threshold (ADT) that is the minimal electric current necessary to evoke afterdischarge. For investigating the effects of dantrolene on the development of kindling, rats were stimulated once daily at the right amygdala with a current, 10% larger than ADT, one hour after either dantrolene or vehicle had been injected intraperitoneally. We observed daily the progress of both intensities of behavioral seizures (stages of seizures) and the duration of afterdischarge. Dantrolene significantly delayed both the progression of kindling stages and the elongation of afterdischarge duration at a dose of 10 mg/kg or 20 mg/kg, as compared with control vehicle. To investigate the effects of dantrolene on seizures in already kindled rats, we determined generalized seizure threshold (GST) that is the minimum electric current necessary to evoke generalized seizures in fully kindled rats. Rats were stimulated at a current, 10% larger than GST, one hour after treated with the drug or vehicle. Dantrolene showed no anticonvulsant action against either the stages of seizures or afterdischarge durations in fully kindled rats. Therefore, the inhibitory effect of dantrolene on the acquisition of kindling was not attributed to an anticonvulsant action. These results suggest that the prevention of kindling acquisition is associated with an inhibitory action of dantrolene on calcium-induced calcium release from intracellular Ca²⁺ stores.