Ramoa A S, Alkondon M, Aracava Y, Irons J, Lunt G G, Deshpande S S, Wonnacott S, Aronstam R S, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
J Pharmacol Exp Ther. 1990 Jul;254(1):71-82.
The effects of MK-801 [( +]-5-methyl-10,11-dihydro-5H-di-benzo[a, d]cyclohepten-5,10-imine) on peripheral and central nicotinic receptors were studied using electrophysiological and biochemical techniques. MK-801 depressed the peak amplitude and accelerated the decay of end-plate currents. The drug (1-10 microM) decreased the frequency of activation of acetylcholine (ACh)-induced single-channel currents in addition to shortening the mean open and burst times of channels activated by either ACh or (+)anatoxin-a (AnTX). MK-801 (10-40 microM) depressed the single potentials and trains of ACh and AnTX-induced potentials in chronically denervated rat soleus muscles. MK-801 blocked the twitch responses (20-100 microM) of both frog sartorius and rat diaphragm muscles evoked by stimulation of their respective nerves. Also this drug (less than 1 microM) decreased the frequency of channels activated by AnTX or ACh in outside-out patch membranes of rat retinal ganglion cells with minimal changes in the channel open time. MK-801 (10-25 microM) depressed (-)nicotine-evoked gamma-amino[2,3-3H]butyric acid release from rat hippocampal synaptosomes; however, it failed to affect the binding of 3Hnicotine to brain membranes and also failed to interfere with the binding of [125I]alpha-bungarotoxin to either frog muscle or Torpedo membranes. On the other hand, MK-801 inhibited the binding of [3H]perhydrohistrionicotoxin to Torpedo membranes and such an effect was more pronounced in the presence of carbamylcholine. Neither AnTX nor any other nicotinic agonist increased the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor ion channel complex. The actions of MK-801 were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors. These results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801.
采用电生理和生化技术研究了MK - 801 [（ + ）-5 - 甲基 - 10,11 - 二氢 - 5H - 二苯并[a, d]环庚烯 - 5,10 - 亚胺]对外周和中枢烟碱受体的影响。MK - 801降低终板电流的峰值幅度并加速其衰减。该药物（1 - 10微摩尔）除了缩短由乙酰胆碱（ACh）或（ + ）anatoxin - a（AnTX）激活的通道的平均开放时间和爆发时间外，还降低了ACh诱导的单通道电流激活频率。MK - 801（10 - 40微摩尔）抑制慢性去神经大鼠比目鱼肌中ACh和AnTX诱导的单电位和电位序列。MK - 801阻断了刺激青蛙缝匠肌和大鼠膈肌各自神经所诱发的抽搐反应（20 - 100微摩尔）。此外，该药物（小于1微摩尔）降低了大鼠视网膜神经节细胞外翻膜片中由AnTX或ACh激活的通道频率，而通道开放时间变化极小。MK - 801（10 - 25微摩尔）抑制（ - ）尼古丁诱发的大鼠海马突触体中γ - 氨基[2,3 - 3H]丁酸释放；然而，它未能影响[3H]（ - ）尼古丁与脑膜的结合，也未能干扰[125I]α - 银环蛇毒素与青蛙肌肉或电鳐膜的结合。另一方面，MK - 801抑制[3H]全氢组胺毒素与电鳐膜的结合，并且在氨甲酰胆碱存在下这种作用更明显。AnTX和任何其他烟碱激动剂均未增加[3H]MK - 801与N - 甲基 - D - 天冬氨酸受体离子通道复合物的结合。MK - 801的作用在与阻断N - 甲基 - D - 天冬氨酸受体所需浓度相当的浓度下就很明显。这些结果表明至少存在三种不同类型的烟碱型AChR，所有这些受体均被MK - 801非竞争性阻断。
