Neuronal Mechanisms of Epilepsy : An Experimental Study with Kindling

为了阐明癫痫的神经元机制，我们利用颞叶癫痫的实验模型--海马点燃进行了脑5-羟色胺（5-HT）的神经药理学研究，1993年，我们研究了海马内微量注射5-HTIA受体激动剂的作用，提示5-HTIA受体亚型对海马点燃癫痫发作具有抑制作用。我们还研究了具有抗抑郁特性的选择性5-HT再摄取抑制剂（氟西汀和帕罗西汀）的作用，发现全身给予这些化合物缩短了全身性惊厥的持续时间。1994年，我们研究了氟西汀对海马癫痫发作的急性和慢性作用。其单次给药不影响海马癫痫发作活动，而氟西汀在10 mg/kg剂量下显著升高海马后放电阈值时，每天给药21天后1周给药。用5-HT_（TIA）受体激动剂吉哌隆处理大鼠21天，观察到急性氟西汀的抑制作用，提示5-HT系统在海马癫痫发作中起抑制作用。我们的研究结果表明，氟西汀长期给药的效果与充分证明的证据有关，即氟西汀长期给药后，可通过突触前5-HT自身受体脱敏促进净5-HT神经传递。选择性5-HT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.