MODEL OF SCHIZOPHRENIA GATING DEFICITS: NMDA EFFECTS

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This proposal seeks to investigate the involvement of the N-methyl-D-aspartate (NMDA) receptor complex in the pathophysiology of schizophrenia. Recent pharmacological, physiological and behavioral studies have indicated that the psychoactive effects of phencyclidine (PCP) are mediated by a component of the NMDA complex. PCP, a drug of abuse, has been noted in several studies to produce a toxic psychosis which in many ways resembles schizophrenia. Our proposed studies will employ the prepulse inhibition (PPI) model of sensorimotor gating in rats to investigate how NMDA receptor perturbation might relate to information processing deficits often noted in schizophrenia. We have found in preliminary studies that PCP produces deficits in PPI similar to those seen in schizophrenic patients and in animals treated with dopamine agonists. Specifically, we intend to isolate the receptor component responsible for PPI deficits through the testing of specific ligands at the three major known components of the NMDA receptor complex: the NMDA site, the PCP site, and the glycine site. Available evidence indicates that activity at NMDA and glycine sites can profoundly influence the effects of PCP, and so manipulation of these sites may reveal the overall mechanism by which this complex regulates sensory gating functions. Rats will be tested in a previously-developed procedure where loud acoustic stimuli are presented either alone or preceded by weaker stimuli. Whole-body startle responses in each condition are recorded and compared. Presentation of the weaker stimulus, or prepulse, typically reduces, or gates, the effects of the main startling event. Antagonists of the NMDA site and glycine site, which in some ways mimic the effects of PCP, will be administered and the resulting effects compared with those of PCP and PCP-like drugs. We will also explore the influence of the sigma opioid receptor in the production of gating deficits. Some sigma opiates have been reported to produce psychosis-like effects in humans, and recent evidence has indicated that many sigma behavioral actions may indeed be mediated at the PCP receptor. We will test psychotomimetic opioids and other drugs which bind to the high- and low-affinity sigma sites in an effort to elucidate the importance of this system in the production of gating deficits by PCP. We hope that these studies will provide a better overall understanding of sensory gating disturbances in schizophrenia and the influences of NMDA function in the genesis of this devastating disease. Such information could lead to the development of new pharmacotherapeutic approaches for schizophreniform psychoses.