Mechanism of inhibition by ethanol of NMDA and AMPA receptor channel functions in cultured rat cortical neurons

The effect and mode of action of ethanol on N-methyl-D-aspartate (NMDA) and alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor s of rat cortical neurons in primary culture were compared by means of the patch-clamp technique. The maxima of the concentration-response curves for both NMDA and AMPA were markedly depressed by ethanol without an apparent s hift of the curves to the right. Ethanol inhibited the effects of NMDA and AMPA concentration-dependently and equally well. Excitatory amino acid (EAA ) currents were depressed to the largest extent when ethanol was continuous ly superfused during and between agonist applications only. There was no in hibition by ethanol, when its superfusion was between two agonist applicati ons. According to expectations, the analysis of the ratios of plateau to pe ak currents failed to suggest a use-dependent blockade by ethanol. In addit ion, comparison of the voltage-current curves of NMDA and AMPA in the absen ce and presence of ethanol indicated a voltage-independent effect and no ch ange in the reversal potential of the two agonists. Finally, the measuremen t of activation and deactivation time constants for the ethanol-induced inh ibition of NMDA and AMPA responses confirms the failure of ethanol to cause an open-channel block. In conclusion, these findings as a whole indicate t hat ethanol inhibits NMDA and AMPA currents by a noncompetitive mechanism. The mode of action appears to be similar for both NMDA and AMPA; under the conditions of the present study, a selective interference with structural m otifs of the NMDA receptor is unlikely.