Pharmacological Application of Spontaneously Epileptic Rat(SER).

Abstract

The spontaneously epileptic rat (SER) is a double mutant (zi/zi, tm/tm) obtained by mating zitter homozygote (zi/zi) with tremor heterozygote (tm/ + ) . This animal exhibits both tonic convulsion and absence-like seizures characterized by a sudden appearance of 5-7 Hz spikes and wave complex in cortical and hippocampal EEG. This study was performed to elucidate the usefulness of SER in evaluating of acute and long-term effects of antiepileptic drugs. Moreover, activities of the central inhibitory system and abnormal excitability of neurons related to the epileptic seizures were investigated. (1) From recordings of implanted electrode in cerebral cortex and hippocampus, phenytoin and carbamazepine (agents for tonic-clonic grand mal seizure) inhibited tonic convulsion without affecting absence-like seizures, whereas trimethadione and ethosuximide (agents effective for absence seizure, petit mal epilepsy) suppressed absence-like seizures without any effects on tonic convulsion. Both seizures were inhibited by phenobarbital, valproate and diazepam, agents which are effective for grand and petit mal epilepsy. This antiepileptic profile suggests that tonic and absence-like seizures in SER correspond to human grand and petit mal seizures. Therefore, SER is a useful model for evaluating the acute effects of novel antiepileptics. (2) The group of SER, which were orally administered with 1 % phenobarbital-containing pellet displayed a marked increase in body weight and longer a life span than the control group with a plasma concentration of 35-50 μg/ml. Similar to the futile results of chronic administration of phenobarbital in human absence epilepsy, absence-like seizures in SER were not affected by this drug, although tonic convulsion was inhibited. Long-term effects of valproate (1 and 5 %) were similar to those of phenobarbital except for its efficacy on absence-like seizures. Therefore, SER is also useful for the evaluation of long-term effects of antiepileptics. (3) Both tonic and absence-like seizures in SER were inhibited by TRH and its analog, CNK-602A, and dopamine agonists, methamphetamine and apomorphine. These results suggest that dopaminergic pathways act as an inhibitory system on the seizure-producing mechanism. Further, SER can be used for investigations of the central inhibitory system involved in the regulation of seizures. (4) In hippocampal slice preparations, a single stimulus given to the mossy fiber induced a longlasting depolarization shift with repetitive firings in CA3 field pyramidal neurons of the SER but not zitter or wistar rats. This abnormal excitation of the neurons were completely blocked by verapamil, a calcium channel blocker. These findings suggest that abnormal calcium channel activities in the CA3 pyramidal neurons are involved in the seizures of SER. Thus, SER is a useful animal model for investigating abnormalities related to epileptic seizures.