SINGLE-CHANNEL AND WHOLE-CELL ANALYSIS OF ETHANOL INHIBITION OF NMDA-ACTIVATED CURRENTS IN CULTURED MOUSE CORTICAL AND HIPPOCAMPAL-NEURONS

The effects of 0.1 to 500 mM ethanol on NMDA-activated currents were s tudied in primary cultures of mouse cortical and hippocampal neurons. In whole-cell recordings the IC(50)s for inhibition of NMDA-activated currents by ethanol were 129 mM +/- 20 mM in hippocampal neurons and 1 26 +/- 18 mM in cortical neurons. In single-channel recordings from ex cised outside-out patches of cortical neurons, ethanol inhibited total charge per minute with an IC50 of 174 +/- 23 mM, which was not signif icantly different from the IC(50)s for inhibition of whole-cell curren t. The reduction in mean open channel lifetime by ethanol was fit by t he logistic equation with an apparent IC50 of 340 +/- 28 mM. Analysis of single-channel data indicated that ethanol inhibition of NMDA curre nts did not involve substantial changes in fast closed state kinetics, changes in open channel conductance, or block of the open channel. At the whole-cell IC50 of ethanol, mean open channel lifetime would decr ease by 28% and frequency of opening would decline by 31% to account f or the reduction in current. Single-channel data were consistent with ethanol being an allosteric modulator of gating which reduces agonist efficacy.