A principal hypothesis of the present Conte Center application is that NMDA hypofunction may be a primary mechanism of dysfunction in schizophrenia, and may well lead to secondary dysregulation of dopaminergic neurotransmission in key brain regions such as prefrontal cortex and striatum. This Project will evaluate the degree to which persistent NMDA dysfunction in non-human primates, induced by subchronic phencyclidine (PCP) treatment, leads to increased frontal D1 receptor density and increased subcortical DA response to amphetamine as observed in patients with schizophrenia (see preliminary data of Projects by Abi-Dargham and Laruelle). In addition, this Project will examine whether subchronic treatment leads to persistent neurophysiological deficits similar to those observed in schizophrenia (e.g., impaired auditory N 1 generation, impaired P50 gating, impaired PPI) and whether these changes can be prevented by the glutamate co-agonist D-serine. In preliminary studies, acute PCP administration has been found to produce schizophrenia-like neurophysiological deficits in monkeys. Subchronic PCP treatment has been found to induce schizophrenia like dysregulation of striatal DA release in rodents. In monkeys, PCP is well tolerated during subchronic administration and produces behavioral changes highly reminiscent of schizophrenia. This study will examine whether such behavioral changes are accompanied by specific neurochemical and neurophysiological markers of schizophrenia. PCP-treated monkeys (n = 5), saline-treated controls (n = 5) and PCP/D-serine-treated animals (n= 5) will be scanned at Columbia, before and during treatment, to measure D1 receptors with 1C]NNC 112 and amphetamine-induced dopamine release with [18F]fallypride. The hypotheses are that subchronic PCP treatment will lead to 1) increased [l ]C]NNC 112 binding potential (BP) in the prefrontal cortex (PFC}; 2) increased amphetamine-induced dopamine release in the striatum; 3) neurophysiological deficits. By treating one of the groups with D-serine, we will also evaluate the biological effectiveness of this treatment to prevent the emergence of these abnormalities. In parallel with the D-serine treatment of patients in Project by Abi-Dargham, this experiment will further elucidate the potential of NMDA augmentation strategies in schizophrenia.
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