Ketamine and PCP are commonly used as selective NMDA receptor antagonists to model the putative hypoglutamate state of schizophrenia and to test new antipsychotics. Recent findings question the NMDA receptor selectivity of these agents. To examine this further, we measured the affinity of ketamine and PCP for the high-affinity states of the dopamine D(2) and serotonin 5-HT(2) receptor and found that ketamine shows very similar affinity at the NMDA receptor and D(2) sites with a slightly lower affinity for 5-HT(2) (0.5 microM, 0.5 microM and 15 microM respectively), while PCP shows similar affinity for the NMDA and 5-HT(2) sites, with a slightly lower affinity for the D(2) site (2 microM, 5 microM and 37 microM respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [(35)S]GTP-gamma-S binding in CHO-cells expressing D(2) receptors, which was prevented by raclopride, suggesting a partial agonist effect at the D(2) receptor. Thus, ketamine and PCP may not produce a selective hypoglutamate state, but more likely produce a non-selective multi-system neurochemical perturbation via direct and indirect effects. These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia.