THE MECHANISM OF ACTION AND PHARMACOLOGICAL SPECIFICITY OF THE ANTICONVULSANT NMDA ANTAGONIST MK-801 - A VOLTAGE CLAMP STUDY ON NEURONAL CELLS IN CULTURE
THE MECHANISM OF ACTION AND PHARMACOLOGICAL SPECIFICITY OF THE ANTICONVULSANT NMDA ANTAGONIST MK-801 - A VOLTAGE CLAMP STUDY ON NEURONAL CELLS IN CULTURE
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DOI：
10.1111/j.1476-5381.1989.tb11841.x
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发表时间：
1989-02-01
影响因子：
7.3
通讯作者：
LAMBERT, JJ
中科院分区：
文献类型：
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作者：
HALLIWELL, RF;PETERS, JA;LAMBERT, JJ
抗焦虑、抗惊厥和神经保护剂MK-801的一些可能的分子作用机制已在对大鼠海马和皮质神经元、牛肾上腺髓质嗜铬细胞和N1 E-115神经母细胞瘤细胞进行的“全细胞”电压钳记录中进行了研究。从大鼠海马和皮层神经元记录的响应于局部应用的N-甲基-D-天冬氨酸（NMDA）的跨膜电流被MK-801（0.1-3.0 μ M）拮抗。 阻断是使用依赖性的，受跨膜电位的影响很小。MK-801（3 μ M）对红藻氨酸盐（100 μ M）诱发的电流没有影响。当洗脱期间将细胞膜电位钳制在-60 mV时，MK-801对NMDA诱导电流的拮抗作用仅缓慢且不完全逆转。在洗脱期间，在+40 mV而不是-60 mV下延长NMDA的应用，显著加速从阻滞的恢复。与MK-801相反，氯胺酮（10 μ M）以电压依赖性方式阻断NMDA诱导的电流。阻断随着膜超极化而增加，并且在洗脱后完全可逆。MK-801（1-10 μ M）产生电压和浓度依赖性的膜电流阻断，所述膜电流由从牛嗜铬细胞回收的离子导入应用的乙酰胆碱（ACh）引起。该阻滞在洗脱后很容易逆转。γ-嗜铬细胞的氨基丁酸A（GABAA）受体介导的氯电流不受MK-801（1-100 μ M）的影响。相反，地西泮（1 μ M）增强了这种电流。MK-801（100 μ M）对GABA在海马神经元上诱发的电流没有影响。MK-801（10 μ M）对从N1 E-115神经母细胞瘤细胞记录的响应于离子电泳施加的5-羟色胺（5-HT）的膜电流几乎没有影响。这种电流被5-HT 3受体拮抗剂GR 38032 F（1 nM）以及高浓度（100 μ M）的MN-801拮抗。嗜铬细胞的电压激活的、河豚毒素敏感的钠电流不受10 μ M MK-801的影响。然而，在相对高的浓度（100 μ M）下，MK-801将这种电流的幅度降低到对照的约77%。本文还讨论了MK-801的中枢作用与本研究结果的相关性。
Some possible molecular mechanisms of action of the anxiolytic, anticonvulsant and neuroprotective agent MK-801 have been examined in ''whole-cell'' voltage clamp recordings performed on rat hippocampal and cortical neurones, bovine adrenomedullary chromaffin cells and N1E-115 neuroblastoma cells maintained in cell culture. Transmembrane currents recorded from rat hippocampal and cortical neurones in response to locally applied N-methyl-D-aspartate (NMDA) were antagonized by MK-801 (0.1-3.0 .mu.M). Blockade was use-dependent, and little influenced by transmembrane potential. MK-801 (3 .mu.M) had no effect on currents evoked by kainate (100 .mu.M). The antagonism of NMDA-induced currents by MK-801 was only slowly and incompletely reversed when the cell membrane potential was clamped at -60 mV during washout. Prolonged applications of NMDA at +40, but not -60 mV during washout, markedly accelerated recovery from block. In contrast to MK-801, ketamine (10 .mu.M) blocked NMDA-induced currents in a voltage-dependent manner. Blockade increased with membrane hyperpolarization and was completely reversible upon washout. MK-801 (1-10 .mu.M) produced a voltage- and concentration-dependent block of membrane currents elicited by ionophoretically applied acetylcholine (ACh) recovered from bovine chromaffin cells. The block was readily reversible upon washout. .gamma.-Aminobutyric acidA (GABAA) receptor-mediated chloride currents of chromaffin cells were unaffected by MK-801 (1-100 .mu.M). In contrast, such currents were potentiated by diazepam (1 .mu.M). MK-801 (100 .mu.M) had no effect on currents evoked by GABA on hippocampal neurones. MK-801 (10 .mu.M) had little effect on membrane currents recorded from N1E-115 neuroblastoma cells in response to ionophoretically applied 5-hydroxytryptamine (5-HT). Such currents were antagonized by the 5-HT3 receptor antagonist GR 38032F (1 nM) also by MN-801 at high concentration (100 .mu.M). Voltage-activated, tetrodotoxin-sensitive, sodium currents of chromaffin cells were unaffected by 10 .mu.M MK-801. However, at a relatively high concentration (100 .mu.M), MK-801 reduced the amplitude of such currents to approximately 77% of control. The relevance of the present results to the central actions of MK-801 is discussed.