Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice.
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.
Long
Katrice D
KD
Mental Health Service Line, Department of Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Mastropaolo
John
J
Rosse
Richard B
RB
Deutsch
Stephen I
SI
D000818:Animals; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004597:Electroshock / Q000009:adverse effects*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D012694:Serine / Q000008:administration & dosage*
D018696:Neuroprotective Agents; D012694:Serine; D016291:Dizocilpine Maleate