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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Abstract
1 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. 2 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 μm). Blockade was use-dependent, and little influenced by transmembrane potential. MK-801 (3 μm) had no effect on currents evoked by kainate (100 μm). 3 The antagonism of NMDA-induced currents by MK-801 was only slowly and incompletely reversed when the cell membrane potential was clamped at −60mV during washout. Prolonged applications of NMDA at +40, but not −60 mV during washout, markedly accelerated recovery from block. 4 In contrast to MK-801, ketamine (10 μm) blocked NMDA-induced currents in a voltage-dependent manner. Blockade increased with membrane hyperpolarization and was completely reversible upon washout. 5 MK-801 (1–10 μm) produced a voltage- and concentration-dependent block of membrane currents elicited by ionophoretically applied acetylcholine (ACh) recorded from bovine chromaffin cells. The block was readily reversible upon washout. 6 γ-Aminobutyric acidA (GABAA) receptor-mediated chloride currents of chromaffin cells were unaffected by MK-801 (1–100 μm). In contrast, such currents were potentiated by diazepam (1 μm). MK-801 (100 μm m) had no effect on currents evoked by GABA on hippocampal neurones. 7 MK-801 (10 μm) 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) and also by MK-801 at high concentration (100 μm). 8 Voltage-activated, tetrodotoxin-sensitive, sodium currents of chromaffin cells were unaffected by 10 μm MK-801. However, at a relatively high concentration (100 μm), MK-801 reduced the amplitude of such currents to approximately 77% of control. 9 The relevance of the present results to the central actions of MK-801 is discussed.