Interactions of dextromethorphan with the N-methyl-D-aspartate receptor-channel complex: single channel recordings.

The actions of dextromethorphan (DXM) on the 50 pS conductance state of the N-methyl-D-aspartate (NMDA) receptor-operated channel were studied using outside-out patches obtained from cultured rat hippocampal pyramidal neurons. DXM (5-50 microM) had no effect on the amplitudes of unitary currents but caused concentration-dependent reductions in channel mean open times and the frequency of channel openings. Channel open probability was reduced in a concentration-dependent manner by DXM and was one-half of the control value at a DXM concentration of 6 microM, with the patch potential held at -60 mV. An IC50 value of 4 microM was obtained for the reduction by DXM of NMDA-evoked rises in [Ca2+]i in cultured rat hippocampal pyramidal neurons loaded with Fura-2. The results were consistent with drug block of the open NMDA channel with an onward (blocking) rate constant of 7.7 x 10(6) M-1.s-1 (at -60 mV). The estimated unblocking rate constant was about 10 s-1, a value considerably higher compared to the off-rate constant found for dizocilpine block of the NMDA channel.