Project Summary

David A. Baker, Ph.D., (Young Investigator 2006) of Marquette University, aims to use an animal model of schizophrenia to study the mechanism of certain cognitive defects and their reversal. The model involves giving rats phencyclidine (PCP), which blocks NMDA glutamate receptors and produces a schizophrenia-like state and cognitive defects in the animals (and in healthy humans). Recently, the PCP rat model revealed that group 2/3 metabotropic glutamate receptor (2/3 mGluRs) stimulation can reverse PCP-induced cognitive deficits. In healthy rats, stimulation of these glutamate receptors is controlled by cystine-glutamate antiporters. Besides regulating glutamate receptors, these antiporters help brain cells survive by regulating the synthesis of the antioxidant glutathione. Interestingly, patients with schizophrenia exhibit reduced glutathione levels, implying that the activity of the antiporters may be altered. The studies in the present proposal will extend earlier NARSAD-funded work showing that increasing cystine-glutamate exchange via administration of the cysteine prodrug N-acetylcysteine (Nac) blocks the cognitive deficits produced by PCP. The present proposal will examine whether an Nac-induced blockade of the behavioral and neurochemical effects is due to increasing cystine-glutamate exchange in the prefrontal cortex, and if it involves increasing glutathione levels or stimulating group 2/3 mGluRs. Findings could lead to new schizophrenia drug targets.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDER\Schizophrenia

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