Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Neuroscience. 2010 May 5;167(2):456-74. doi: 10.1016/j.neuroscience.2010.02.021. Epub 2010 Feb 16.
Although most anti-epileptic drugs are considered to have a primary molecular target, it is clear that their actions are unlikely to be limited to effects on a single aspect of inhibitory synaptic transmission, excitatory transmission or voltage-gated ion channels. Systemically administered drugs can obviously simultaneously access all possible targets, so we have attempted to determine the overall effect of diverse agents on the balance between GABAergic inhibition, glutamatergic excitation and cellular excitability in neurones of the rat entorhinal cortex in vitro. We used an approach developed for estimating global background synaptic excitation and inhibition from fluctuations in membrane potential obtained by intracellular recordings. We have previously validated this approach in entorhinal cortical neurones [Greenhill and Jones (2007a) Neuroscience 147:884-892]. Using this approach, we found that, despite their differing pharmacology, the drugs tested (phenytoin, lamotrigine, valproate, gabapentin, felbamate, tiagabine) were unified in their ability to increase the ratio of background GABAergic inhibition to glutamatergic excitation. This could occur as a result of decreased excitation concurrent with increased inhibition (phenytoin, lamotrigine, valproate), a decrease in excitation alone (gabapentin, felbamate), or even with a differential increase in both (tiagabine). Additionally, we found that the effects on global synaptic conductances agreed well with whole cell patch recordings of spontaneous glutamate and GABA release (our previous studies and further data presented here). The consistency with which the synaptic inhibition:excitation ratio was increased by the antiepileptic drugs tested was matched by an ability of all drugs to concurrently reduce intrinsic neuronal excitability. Thus, it seems possible that specific molecular targets among antiepileptic drugs are less important than the ability to increase the inhibition:excitation ratio and reduce overall neuronal and network excitability.
尽管大多数抗癫痫药物被认为具有主要的分子靶点，但它们的作用显然不仅限于对抑制性突触传递、兴奋性传递或电压门控离子通道的单一方面产生影响。全身给予的药物显然可以同时作用于所有可能的靶点，因此我们试图确定不同药物对体外大鼠内嗅皮层神经元中 GABA 能抑制、谷氨酸能兴奋和细胞兴奋性之间平衡的总体影响。我们使用了一种从细胞内记录获得的膜电位波动来估计背景突触兴奋和抑制的方法。我们之前已经在内嗅皮层神经元中验证了这种方法[Greenhill 和 Jones（2007a）神经科学 147:884-892]。使用这种方法，我们发现，尽管它们的药理学不同，但测试的药物（苯妥英、拉莫三嗪、丙戊酸钠、加巴喷丁、氨己烯酸、噻加宾）在增加背景 GABA 能抑制与谷氨酸能兴奋的比值方面具有统一性。这可能是由于兴奋同时伴有抑制减少（苯妥英、拉莫三嗪、丙戊酸钠）、仅兴奋减少（加巴喷丁、氨己烯酸），甚至两者都有差异增加（噻加宾）。此外，我们发现全局突触电导的影响与自发谷氨酸和 GABA 释放的全细胞膜片钳记录非常吻合（我们之前的研究和这里进一步提供的数据）。测试的抗癫痫药物增加突触抑制：兴奋比值的一致性与所有药物同时降低固有神经元兴奋性的能力相匹配。因此，抗癫痫药物的特定分子靶点可能不如增加抑制：兴奋比值和降低整体神经元和网络兴奋性重要。
