Neuronal Mechanisms of Epilepsy : An Experimental Study with Kindling

为了阐明癫痫的神经机制，我们用点燃的方法对大脑5-羟色胺(5-HT)进行了神经药理学研究。1993年，我们观察了海马内微量注射5-HTIA受体激动剂(8-OH-DPAT)对癫痫发作的影响，提示5-HTIA受体亚型对海马癫痫发作的产生有抑制作用。我们还检测了具有抗抑郁特性的选择性5-羟色胺再摄取抑制剂(氟西汀和帕罗西汀)的效果，发现全身应用这些化合物可以缩短全身惊厥的持续时间。此外，氟西汀的微量注射研究显示了氟西汀对海马区癫痫发作的抑制作用。1994年，我们研究了氟西汀对海马区癫痫发作的急性和慢性影响。氟西汀单次给药对大鼠海马区惊厥活动无明显影响，而氟西汀10 mg/kg给药后21天给药1周，可显著提高大鼠海马区后放电阈值。在接受5-HTIA受体激动剂吉培酮治疗21天的大鼠中，也观察到了急性氟西汀的抑制作用。在这些实验的基础上，5-羟色胺系统被认为在海马区癫痫活动中起抑制作用。我们的结果表明，长期服用氟西汀的效果与长期服用氟西汀可通过脱敏突触前5-羟色胺受体而促进净5-羟色胺神经传递的证据有关。提示选择性5-羟色胺再摄取抑制剂对癫痫患者的抑郁症状有一定的临床疗效。

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.