¹Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

²Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

Correspondence to: S Kapur, MD, PhD, Centre for Addiction and Mental Health, Clarke Site, 250 College Street, Toronto, Ontario, Canada M5R 1T8. E-mail: skapur@camhpet.on.ca

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 D₂ and serotonin 5-HT₂ receptor and found that ketamine shows very similar affinity at the NMDA receptor and D₂ sites with a slightly lower affinity for 5-HT₂ (0.5 M, 0.5 M and 15 M respectively), while PCP shows similar affinity for the NMDA and 5-HT₂ sites, with a slightly lower affinity for the D₂ site (2 M, 5 M and 37 M respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [³⁵S]GTP--S binding in CHO-cells expressing D₂ receptors, which was prevented by raclopride, suggesting a partial agonist effect at the D₂ 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.

Molecular Psychiatry (2002) 7, 837-844. doi:10.1038/sj.mp.4001093

schizophrenia; dopamine; glutamate; PCP; ketamine; serotonin