Alteration of [3H]MK‐801 Binding Associated with the JV‐Methyl‐d‐Aspartate Receptor Complex by Acute Ethanol in Rat Cortex and Hippocampus In Vitro

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Abstract
We investigated the effect of ethanol on specific binding of [3H]MK‐801 to the intrachannel phencyclidine (PCP) receptor site, as an index of change in the functional response of the N‐methyl‐d‐Aspartate (NMDA)‐associated ion channel. Saturation binding experiments were performed on synaptic membrane homogenates from adult rat cortex and hippocampus. [3H]MK‐801 binding assays were conducted under conditions of basal, 10 μm glutamate, or 10 μm glutamate + 30 μm d‐serine, with and without 50 or 100 mm ethanol. Association experiments of [3H]MK‐801 binding (5 nm) were conducted under conditions of 0 or 10 μm glutamate, with varying concentrations of glycine (0.01, 0.10, and 10 μm) with and without 100 mm ethanol. Ethanol (50 and 100 mm) significantly decreased the percentage of high‐affinity (open‐channel state) MK‐801 receptors with a concomitant increase in percentage of low‐affinity receptors, but did not change high‐ and low‐affinity constants of the two binding states. An ethanol‐induced increase in the closed‐channel receptor density in basal and activated conditions was suggested by the saturation experiments. Association experiments further explained this finding, in that ethanol (100 mm) significantly decreased fast component (open‐channel) [3H]MK‐801 binding in conditions of glycine (0.01–10 μm) only and activated conditions of glutamate + glycine (0.01–0.10 μm). However, the observed fast and slow kinetic rate constants of [3H]MK‐801 binding, as well as total specific binding (fast + slow components), were not altered. Thus, ethanol seems to act as a noncompetitive antagonist upon the gating mechanism of, and ligand access to, the NMDA‐coupled ion channel. These findings support previous observations of ethanol selectively reducing NMDA‐activated calcium influx, and reducing the frequency and duration of ion channel opening in electrophysiological studies. Similar to previous reports on NMDA‐stimulated calcium influx and [3H]MK‐801 binding, glycine (at the maximal concentration of 10 μm), in the presence of 10 μm glutamate, was found to reverse ethanol inhibition of fast component binding.

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