Antipsychotic Actions in Models of NMDA Hypofunction

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DESCRIPTION (provided by applicant): Clinical studies have demonstrated that NMDA receptor antagonists induce positive, negative and cognitive schizophrenic-like symptoms in healthy subjects and precipitate psychotic reactions in patients with schizophrenia. These data, and the resulting NMDA receptor hypofunction hypothesis of schizophrenia, provide a compelling rationale for characterizing neurobiological correlates in models of reduced NMDA receptor function. The present proposal will assess behavioral and brain metabolic phenotypes in a genetic model of reduced NMDA receptor function-the NMDA R1 (NR1) subunit deficient mouse. The NR1 subunit is a component of all NMDA receptors and reduced expression of this subunit will therefore result in a chronic state of NMDA receptor hypofunction. It is hypothesized that the behavioral and brain metabolic phenotypes associated with the NR1 deficient mouse model will mimic certain phenotypes observed in schizophrenic patients. Specifically, it is hypothesized that the NR1 deficient mice will exhibit reduced brain metabolism in prefrontal and limbic regions, and exhibit alterations in sensory processing (prepulse inhibition and startle habituation). If these hypotheses are correct, the mouse models could represent an approach to explore potential preventative strategies for schizophrenia. The proposed work also will test the hypothesis that administration of typical and atypical antipsychotic drugs will have different effects on the alterations in behavior and regional brain metabolic activity observed in the genetic model of reduced NMDA receptor function In addition to the heuristic value of the work for understanding differential effects of typical and atypical antipsychotic drugs, the proposed autoradiographic studies are analogous to human PET studies of brain metabolism and blood flow, and therefore offer an important potential translational opportunity to relate results found in rodents to humans. The proposed work will not only contribute to the understanding of neurobiological actions of atypical antipsychotic drugs, but also will provide paradigms in which novel pharmacological strategies could be explored for the treatment of schizophrenia. In addition, characterizing neurobiological actions of antipsychotic drugs in the genetic model of NMDA receptor hypofunction could help delineate neurochemical dysfunction in these models, and by inference, potential pathophysiological processes in schizophrenia.