Cunningham M O, Dhillon A, Wood S J, Jones R S
Department of Physiology, University of Bristol, School of Medical Sciences, UK.
Neuroscience. 2000;95(2):343-51. doi: 10.1016/s0306-4522(99)00468-6.
Although conventional wisdom suggests that the effectiveness of phenytoin as an anticonvulsant is due to blockade of Na+-channels this is unlikely to be it's sole mechanism of action. In the present paper we examined the effects of phenytoin on evoked and spontaneous transmission at excitatory (glutamate) and inhibitory (GABA) synapses, in the rat entorhinal cortex in vitro. Evoked excitatory postsynaptic potentials at glutamate synapses exhibited frequency-dependent enhancement, and phenytoin reduced this enhancement without altering responses evoked at low frequency. In whole-cell patch-clamp recordings the frequency of excitatory postsynaptic currents resulting from the spontaneous release of glutamate was reduced by phenytoin, with no change in amplitude, rise time or decay time. Similar effects were seen on miniature excitatory postsynaptic currents, recorded in the presence of tetrodotoxin. Evoked inhibitory postsynaptic potentials at GABA synapses displayed a frequency-dependent decrease in amplitude. Phenytoin caused a reduction in this decrement without affecting the responses evoked at low frequency. The frequency of spontaneous GABA-mediated inhibitory postsynaptic currents, recorded in whole-cell patch mode, was increased by phenytoin, and this was accompanied by the appearance of much larger amplitude events. The effect of phenytoin on the frequency of inhibitory postsynaptic currents persisted in the presence of tetrodotoxin, but the change in amplitude distribution largely disappeared. These results demonstrate for the first time that phenytoin can cause a simultaneous reduction in synaptic excitation and an increase in inhibition in cortical networks. The shift in balance in favour of inhibition could be a major factor in the anticonvulsant action of phenytoin.
尽管传统观点认为苯妥英作为抗惊厥药的有效性是由于其对钠离子通道的阻断作用，但这可能并非其唯一的作用机制。在本文中，我们研究了苯妥英对体外培养的大鼠内嗅皮质中兴奋性（谷氨酸）和抑制性（γ-氨基丁酸，GABA）突触的诱发和自发传递的影响。谷氨酸突触处诱发的兴奋性突触后电位表现出频率依赖性增强，而苯妥英可降低这种增强作用，同时不改变低频诱发的反应。在全细胞膜片钳记录中，苯妥英可降低由谷氨酸自发释放引起的兴奋性突触后电流的频率，而其幅度、上升时间或衰减时间均无变化。在存在河豚毒素的情况下记录到的微小兴奋性突触后电流也观察到类似的效应。GABA突触处诱发的抑制性突触后电位在幅度上呈现频率依赖性降低。苯妥英可减少这种降低幅度，且不影响低频诱发的反应。在全细胞膜片钳模式下记录到的自发GABA介导的抑制性突触后电流的频率，苯妥英可使其增加，同时伴随着出现幅度大得多的事件。苯妥英对抑制性突触后电流频率的影响在存在河豚毒素时依然存在，但幅度分布的变化基本消失。这些结果首次证明，苯妥英可同时降低皮质网络中的突触兴奋并增加抑制作用。向有利于抑制的平衡转变可能是苯妥英抗惊厥作用的一个主要因素。
