Dextromethorphan and dextrorphan, which reduce excitatory amino acid-induced neurotoxicity, decreased K+ depolarization-evoked 45Ca2+ uptake into brain synaptosomes and cultured neural (PC12) cells. Half-maximal inhibition of synaptosomal 45Ca2+ uptake occurred with 48 microM dextromethorphan or 200 microM dextrorphan, which are similar to concentrations associated with protection from excitotoxicity. The ability to decrease Ca2+ flux through N-type (synaptosomal) and L-type (PC12) voltage-gated Ca2+ channels may therefore contribute to the neuroprotective effects of these compounds.