This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phencyclidine (PCP) is a non-competitive antagonist of the NMDA glutamate receptor. It produces transient psychosis in normal individuals and exacerbates psychosis in schizophrenics. When administered to rodents, PCP elicits stereotyped behaviors including unrelenting head swaying, digit gnawing and social withdrawal, that are representative of negative signs of schizophrenia in humans. Recent findings have implicated a role for glutamate receptors in schizophrenia. The studies in this project will examine the hypothesis that reduced NMDA receptor function leads to unregulated excitation, disinhibition, and ultimately to neuronal degeneration that contribute to the abnormal cognitive and behavioral manifestations characteristic of schizophrenia. Reduced NMDA receptor function during schizophrenia guides two main hypotheses proposed in this research: (1) that glutamate receptor dysfunction in schizophrenia is dependent on alterations in NMDA receptor subunit composition in the frontal cortex;and (2) that atypical neuroleptics reduce symptoms of schizophrenia through cellular mechanisms that either restore NMDA receptor function or circumvent NMDA dysfunction. Specifically, we will examine whether NR1 subunits of the NMDA receptor are reduced at synaptic sites in frontal cortex of PCP-treated rats compared to control and atypical neuroleptic-treated animals. We will also determine the subunit composition of NMDA receptors at synaptic sites in frontal cortex of PCP-treated rats compared to controls and neuroleptic-treated animals, as well as examine alterations in other proteins within the postsynaptic density (PSD). The primary objective of our research is to contribute to a fundamental understanding of schizophrenia and it?s underlying physiological mechanisms.
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