Dynamics of hippocampal acetylcholine release during lithium-pilocarpine-induced status epilepticus in rats
Dynamics of hippocampal acetylcholine release during lithium-pilocarpine-induced status epilepticus in rats
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DOI：
10.1111/jnc.12787
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发表时间：
2014-10-01
影响因子：
4.7
通讯作者：
Klein, Jochen
中科院分区：
文献类型：
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作者：
Hillert, Markus H.;Imran, Imran;Klein, Jochen
锂-匹鲁卡品模型是一种类似人类癫痫持续状态的癫痫大鼠模型。在这里，我们报告的变化，乙酰胆碱（ACh）释放在海马癫痫持续状态之前，期间和之后的微透析监测在未麻醉大鼠。给药毛果芸香碱（30 mg/kg s.c.）氯化锂（127 mg/kg i. p.）导致海马ACh释放大量增加六倍，与强直性癫痫发作的发展平行。当通过给予地西泮（10 mg/kg i. p.）或氯胺酮（75 mg/kg i. p.），ACh水平恢复正常。在此过程中，细胞外谷氨酸浓度保持不变。给予阿托品（1 mg/kg i. p.）毛果芸香碱注射后2小时，ACh进一步增加，但不影响癫痫发作，而注射美加明（5 mg/kg腹腔注射）降低乙酰胆碱水平和延迟发作。局部注射河豚毒素（1 M局部）或半胆碱（10 M局部）强烈减少ACh释放，并对癫痫发作有延迟作用。给药葡萄糖或肌醇（每种250 mg/kg i. p.）没有明显的后果。在平行实验中，锂-匹罗卡品诱导的癫痫持续状态也增强了纹状体ACh的释放，海马ACh水平同样增加时，癫痫持续状态由红藻氨酸（30 mg/kg i. p.）。两者合计，我们的研究结果表明，癫痫持续状态模型中的癫痫发作的发展是伴随着大量增加的细胞外乙酰胆碱，但不是谷氨酸，水平。减少癫痫发作活动的治疗也可靠地降低细胞外ACh水平。
The lithium-pilocarpine model is a rat model of epilepsy that mimics status epilepticus in humans. Here, we report changes of acetylcholine (ACh) release in the hippocampus before, during and after status epilepticus as monitored by microdialysis in unanesthetized rats. Administration of pilocarpine (30mg/kg s.c.) to rats pretreated with lithium chloride (127mg/kg i.p.) caused a massive, six-fold increase of hippocampal ACh release, paralleling the development of tonic seizures. When seizures were stopped by administration of diazepam (10mg/kg i.p.) or ketamine (75mg/kg i.p.), ACh levels returned to normal. Extracellular concentrations of glutamate remained unchanged during this procedure. Administration of atropine (1mg/kg i.p.) 2h after pilocarpine caused a further increase of ACh but did not affect seizures, whereas injection of mecamylamine (5mg/kg i.p.) reduced ACh levels and seizures in a delayed fashion. Local infusion of tetrodotoxin, 1M locally) or hemicholinium (10M locally) strongly reduced ACh release and had delayed effects on seizures. Administration of glucose or inositol (250mg/kg each i.p.) had no visible consequences. In parallel experiments, lithium-pilocarpine-induced status epilepticus also enhanced striatal ACh release, and hippocampal ACh levels equally increased when status epilepticus was induced by kainate (30mg/kg i.p.). Taken together, our results demonstrate that seizure development in status epilepticus models is accompanied by massive increases of extracellular ACh, but not glutamate, levels. Treatments that reduce seizure activity also reliably reduce extracellular ACh levels.