Ethanol inhibition of N-methyl-D-aspartate-activated current in mouse hippocampal neurones: whole-cell patch-clamp analysis

Abstract

1. The action of ethanol on N-methyl-D-aspartate (NMDA)-activated ion current was studied in mouse hippocampal neurones in culture using whole-cell patch-clamp recording.

2. Ethanol inhibited NMDA-activated current in a voltage-independent manner, and did not alter the reversal potential of NMDA-activated current.

3. Concentration–response analysis of NMDA- and glycine-activated current revealed that ethanol decreased the maximal response to both agonists without affecting their EC₅₀ values.

4. The polyamine spermine (1 μM) increased amplitude of NMDA-activated current but did not alter the percentage inhibition of ethanol.

5. Compared to an extracellular pH of 7.0, pH 6.0 decreased and pH 8.0 increased the amplitude of NMDA-activated current, but these changes in pH did not significantly alter the percentage inhibition by ethanol.

6. The sulphydryl reducing agent dithiothreitol (2 mM) increased the amplitude of NMDA-activated current, but did not affect the percentage inhibition by ethanol.

7. Mg²⁺ (10, 100, 500 μM), Zn²⁺ (5, 20 μM) or ketamine (2, 10 μM) decreased the amplitude of NMDA-activated current, but did not affect the percentage inhibition by ethanol.

8. The observations are consistent with ethanol inhibiting the function of NMDA receptors by a non-competitive mechanism that does not involve several modulatory sites on the NMDA receptor–ionophore complex.

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