Previous work from this laboratory indicated that some antipsychotic drugs possess unique action at N-methyl-D-aspartate (NMDA) receptors. A functional neurochemical assay showed that, at concentrations similar to those found in the cerebrospinal fluid (CSF) of schizophrenics, antipsychotic drugs augment NMDA activity while, at higher concentrations, NMDA activity is suppressed. Using similar analysis, the present paper reports that this pattern of response is also shown by the antipsychotic drugs thioridazine and chlorpromazine. In contrast, promazine, which is structurally similar to chlorpromazine but lacking both D2-effects and antipsychotic potency, had no influence on NMDA receptors. In addition, sulpiride and metoclopramide, drugs with high affinity for D2-dopamine receptors but with weak or no antipsychotic efficacy, also lack effects at the NMDA receptor. Thus, the drugs with clinical efficacy that were tested in the present and previous studies all share unique influence on NMDA receptors. Further work with other antipsychotic agents will be necessary to determine if influence on NMDA receptors contributes to antipsychotic effectiveness.