Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Neuropharmacology. 2012 Feb;62(2):807-14. doi: 10.1016/j.neuropharm.2011.09.006. Epub 2011 Sep 17.
Ethosuximide is the drug of choice for treating generalized absence seizures, but its mechanism of action is still a matter of debate. It has long been thought to act by disrupting a thalamic focus via blockade of T-type channels and, thus, generation of spike-wave activity in thalamocortical pathways. However, there is now good evidence that generalized absence seizures may be initiated at a cortical focus and that ethosuximide may target this focus. In the present study we have looked at the effect ethosuximide on glutamate and GABA release at synapses in the rat entorhinal cortex in vitro, using two experimental approaches. Whole-cell patch-clamp studies revealed an increase in spontaneous GABA release by ethosuximide concurrent with no change in glutamate release. This was reflected in studies that estimated global background inhibition and excitation from intracellularly recorded membrane potential fluctuations, where there was a substantial rise in the ratio of network inhibition to excitation, and a concurrent decrease in excitability of neurones embedded in this network. These studies suggest that, in addition to well-characterised effects on ion channels, ethosuximide may directly elevate synaptic inhibition in the cortex and that this could contribute to its anti-absence effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
乙琥胺是治疗全身性失神发作的首选药物，但它的作用机制仍存在争议。长期以来，人们一直认为它通过阻断 T 型通道来干扰丘脑焦点，从而在丘脑皮质通路中产生棘波活动。然而，现在有充分的证据表明全身性失神发作可能起源于皮质焦点，而乙琥胺可能针对这个焦点。在本研究中，我们使用两种实验方法研究了乙琥胺对体外大鼠内嗅皮层突触中谷氨酸和 GABA 释放的影响。全细胞膜片钳研究显示，乙琥胺增加了自发性 GABA 释放，而谷氨酸释放没有变化。这反映在从细胞内记录的膜电位波动中估计全局背景抑制和兴奋的研究中，其中网络抑制与兴奋的比率显著升高，嵌入该网络的神经元兴奋性同时降低。这些研究表明，除了对离子通道的特征性影响外，乙琥胺还可能直接增加皮质中的突触抑制，这可能有助于其抗失神作用。本文是题为“创伤后应激障碍”的特刊的一部分。
