Neuronal Mechanisms of Epilepsy : An Experimental Study with Kindling

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In order to clarify the neuronal mechanisms of epilepsy, we conducted neuropharmacological research on brain serotonin (5-HT) using hippocampal kindling, an experimental model of temporal lobe epilepsy.In 1993, we examined the effects of intra-hippocampal microinjection of a 5-HTIA receptor agonist (8-OH-DPAT) on hippocampal kindled seizures and suggested that the 5-HTIA receptor subtype has an inhibitory action against the generation of hippocampal seizure activity. We also examined the effects of selective 5-HT reuptake inhibitors with antideperssant properties (fluoxetine and paroxetine) , and found that the systemic administration of these compounds shortened the duration of generalized convulsion. In addition, the microinjection study of fluoxetine showed the antiepileptic action of fluoxetine against hippocampal seizure generation.In 1994, we examined acute and chronic effects of fluoxetine upon hippocampal seizures. Its single administration did not affect hippocampal seizure activity, whereas fluoxetine at a dose of 10 mg/kg significantly elevated the hippocampal afterdischarge threshold when administered 1 week after its daily treatment for 21 days. The inhibitory effect of acute fluoxetine was also observed in rats receiving a 21-day treatment of gepirone, a 5-HTIA receptor agonist.Based on these experiment, the 5-HT system is suggested to play an inhibitory role in hippocampal seizure activity. Our results indicate that the effect of long-term fluoxetine administration relate to the well-demonstrated evidence that fluoxetine, upon its long-term administration, can facilitate net 5-HT neurotransmission through desensitization of presynaptic 5-HT autoreceptors. It is also auggested that slective 5-HT reuptake inhibitors prossess clinical efficacy on depressive symptoms in patients with seizure disorder.