Selective depression of N-methyl-D-aspartate-mediated responses by dextrorphan in the hippocampal slice in rat

The effects of dextrorphan (DX) and dextromethorphan (DM) on responses to excitatory amino acids in the CA1 region of the hippocampus of the rat were studied using extracellular and intracellular recording in in vitro slices of brain. Dextrorphan selectively and non-competitively blocked depolarizations evoked by focally-applied N-methyl-D,L-aspartate (NMA), recorded by both extracellular and intracellular techniques. Quisqualate (QUIS) responses and evoked field potentials were not affected by DX. Epileptiform activity elicited in Mg2+-free solution was suppressed by DX. Dextrorphan had no effect on resting membrane potential or input resistance. The antagonism of NMA by DX was dose-dependent with an EC50 of 0.65 microM; DM was also effective but considerably less potent. In the paradigm used in the present study, DX did not produce the clear use-dependent block observed in the presence of MK-801. These data suggest that DX, the metabolite of the widely used antitussive DM, is a potent NMDA antagonist with a potential role as an anticonvulsant and neuroprotective agent.