Development and usefulness of aging model rat with epileptic seizures.

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Spontaneously epileptic rat (SER) is a genetically defined double mutant (zi/zi, tm/tm) obtained by mating the tremor heterozygous rat with the zitter homozygous rat, and exhibits both absence-like and tonic seizures without external stimuli or when mildly stimulated by tapping and sound. Computer analysis using quantitative autoradiographic technique revealed that the amount of the specific binding of (^3H)QNB to muscarinic cholinergic (mACh) receptors in the striatum of SER was more than that of control animals. However, the specific bindings to GABA_A and phencyclidine receptors of SER were not different from those of controls. These results suggested that hyperfunction of mACh receptors was involved in the appearance of seizures of SER. When a single stimulus was applied to the mossy fibers, there was repetitive firing and a depolarization shift in the hippocampal CA3 pyramidal neurons of the mature SER, in which seizures had fully developed. However, in young SER and littermates, which did not show any seizures, only a single spike was elicited with each single stimulation of the mossy fibers. These results indicated that CA3 pyramidal neurons of the SER became abnormally excitable in conjunction with the development of seizures. In the SER, a novel throtropin-releasing hormone (TRH) related analog, CNK-602A, suppressed absence-like and tonic seizures in a dose-dependent manner, and the inhibitory effects of the drug on both seizures were antagonized by pretreatment with haloperidol. CNK-602A increased the release of dopamine in the brain. The antiepileptic effects of CNK-602A were more potent and lasted longer than those of TRH. Furthermore, we showed that L-arginine was a physiological precursor for the formation of nitric oxide in the large cerebral arteries.