NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D-2 and serotonin 5-HT2 receptors - implications for models of schizophrenia

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-HT2 receptor and found that ketamine shows very similar affinity at the NMDA receptor and D-2 sites with a slightly lower affinity for 5-HT2 (0.5 muM, 0.5 muM and 15 muM respectively), while PCP shows similar affinity for the NMDA and 5-HT2 sites, with a slightly lower affinity for the D-2 site (2 muM, 5 muM and 37 muM respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [S-35]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.