NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of
schizophrenia because of the ability of
phencyclidine (PCP), a noncompetitive
NMDA receptor antagonist, to precipitate a schizophreniform
psychosis. The possible role that NRH plays in the pathophysiology of
schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example,
MK-801 (
dizocilpine), a noncompetitive
NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of
MK-801 is significantly reduced following stress. We showed that an exogenously administered
glycine prodrug (i.e.,
milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-
Serine may serve as an endogenous agonist for the obligatory
glycine co-agonist site on the
NMDA receptor complex. Orally administered d-
serine has been studied clinically as an adjuvant therapeutic intervention in
schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-
serine as a viable therapeutic intervention for
schizophrenia and, possibly, other disorders.