Kapur J, Lothman E W
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Epilepsy Res. 1990 Mar;5(2):103-11. doi: 10.1016/0920-1211(90)90025-q.
Previously we have shown that delivery of rapidly recurring hippocampal seizures (RRHS) to awake rats causes a rapid kindling and that RRHS in urethane-anesthetized rats leads to a progressive lengthening of afterdischarges and diminution of paired pulse inhibition. The present experiments examined the relationship between the changes in afterdischarge durations and inhibition. Pre-treatment before RRHS with the non-competitive NMDA receptor antagonists MK-801 and ketamine blocked afterdischarge lengthening. MK-801 also prevented RRHS-induced changes in paired pulse inhibition. For pharmacodynamic and pharmacokinetic reasons the ability of ketamine to counteract RRHS-induced changes of paired pulse inhibition was not examined. MK-801 also blocked the rightward shift of stimulus intensity vs. population spike curves which RRHS caused. We suggest that RRHS leads to an enduring diminution of GABAergic inhibition and that this accounts, at least in part, for the lengthening of afterdischarges seen with recurrent hippocampal seizures. In addition, NMDA receptor activation appears to play a role in this decrease of the potency of GABAergic inhibition. However, mechanisms which are not dependent on NMDA receptor activation also play a critical role in hippocampal epileptogenesis.
此前我们已经表明，向清醒大鼠传递快速反复出现的海马癫痫发作（RRHS）会导致快速点燃，而在乌拉坦麻醉的大鼠中RRHS会导致放电后时程逐渐延长以及双脉冲抑制减弱。本实验研究了放电后时程变化与抑制之间的关系。在RRHS之前用非竞争性NMDA受体拮抗剂MK-801和氯胺酮进行预处理可阻止放电后时程延长。MK-801还可防止RRHS诱导的双脉冲抑制变化。出于药效学和药代动力学原因，未研究氯胺酮对抗RRHS诱导的双脉冲抑制变化的能力。MK-801还可阻止RRHS引起的刺激强度与群体峰电位曲线的右移。我们认为RRHS会导致GABA能抑制的持久减弱，这至少部分解释了复发性海马癫痫发作时放电后时程的延长。此外，NMDA受体激活似乎在这种GABA能抑制效力降低中起作用。然而，不依赖于NMDA受体激活的机制在海马癫痫发生中也起关键作用。
