Phencyclidine-induced Cognitive Impairments

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DESCRIPTION (provided by applicant): Despite major advances in treatment of schizophrenia, cognitive impairments are, in fact, the, most important determination of functional outcome. Rates of patient recovery in areas of social and vocational function remain at levels similar to those seen in the 1930s in spite of more effective antipsychotic drugs, thus, cognitive deficits are a major limiting factor, in recovery from schizophrenia, but little is known about the etiology of these deficits. It is important to develop a preclinical model to elucidate the molecular basis of these deficits and to screen drugs capable of treating these deficits. One approach for investigating the molecular correlates of behavior and drug action is the use of gene-targeted-knockout and transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological agents do not exist. Because these mutations are only available in mice, it is necessary to first develop preclinical assays using mice in order to use these techniques. The current proposal is an important first step in this process. C57BL/6-mice will be subchronically administered phencyclidine, which produces schizophrenia-like cognitive deficits in chronic abusers. The mice will be evaluated in a spatial memory task, and, changes in the expression of glutamate NMDA, NR1, and NR2 subunits will be assessed. The ability of the atypical antipsychotic olanzapine to attenuate PCP's behavioral effects and PCP's effects on expression of NMDA receptors in frontal cortex and hippocampus will then be assessed.