Schizophrenia Research Trends

In: Schizophrenia Research Trends ISBN 13: 978-1-60021-746-3Editor: Konstance V. Almann, pp. 95-114© 2008 Nova Science Publishers, Inc.Chapter IIINMDA RECEPTOR HYPOFUNCTION INSCHIZOPHRENIA: FROM MOUSE TO MANStephen I. Deutsch ∗ , 1,2 John Mastropaolo, 1 Barbara L. Schwartz, 1,2Richard B. Rosse, 1,2 and Brooke Gaskins 11 Mental Health Service Line, Department of Veterans Affairs Medical CenterNW, Washington, DC2 Department of Psychiatry, Georgetown University School of Medicine,Washington, DCABSTRACTGlutamate is one of the most abundant neurotransmitters in the brain; it may beresponsible for mediating synaptic neurotransmission at 40 percent or more of the brain’ssynapses. The glutamatergic signal is recognized by both metabotropic and ion channelreceptors. The N-methyl-D-aspartic acid (NMDA) receptor is an example of a glutamategatedion channel receptor; the binding of glutamate to this receptor increases thelikelihood that its channel will transiently assume an open-configuration, allowing theinflux of calcium ions. Importantly, there are allosteric modulatory sites, including anobligatory co-agonist site that recognizes glycine, on the NMDA receptor complex thatinfluence glutamate’s ability to promote calcium ion conductance. Abnormalities ofNMDA receptor-mediated neurotransmission are implicated in a variety of majorneuropsychiatric disorders, especially schizophrenia. Specifically, NMDA receptorhypofunction (NRH) is implicated in the pathophysiology of schizophrenia because ofthe ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis. PCP is anoncompetitive NMDA receptor antagonist that binds to a hydrophobic site within thechannel; it is referred to as an open-channel blocker. Descriptively, the PCP-model ofschizophrenia is the best pharmacological model of this disorder with symptoms manifestin all of the relevant domains of psychopathology, including positive (e.g.,∗ Corresponding Author: Stephen I. Deutsch, M.D., Ph.D. Associate Chief of Staff for Mental Health Department ofVeterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422; 202 745 8156 (Office); 202 7458169 (Fax); E-Mail Address: Stephen.Deutsch@med.va.gov