Project 5 evaluates the pharmacologically-produced of schizophrenia in non-human primates. The pharmacological regimens underlying the models are (1) sensitization to amphetamine (AMPH) via chronic, intermittent AMPH exposure, (2) a similar chronic phencyclidine (PCP) exposure, and (3) acute, low-dose PCP administration. There are several reasons to favor these models: Chronic AMPH abuse in humans produces may symptoms of schizophrenia, such as paranoia, hallucinations, and cognitive and social impairments, and schizophrenic patients have augmented responses to AMPH. Likewise, psychotomimetic properties of PCP are well-known, and recurrent administration of PCP can lead to enduring psychotic syndromes. Moreover, each of these treatments has significant effects on dopamine (DA) transmission in prefrontal cortex (PFC). These models will be evaluated in terms of their behavioral, neurochemical, neurophysiological, and neuropharmacological aspects. First, we will measure the behavioral deficits created by these pharmacological regimens, with emphasis on cognitive and working-memory tasks wherein deficits are associated with schizophrenia and/or PFC dysfunction, including the eye tracking disorder of schizophrenia. Next, we will evaluate these 3 models in terms of neuropharmacological responsivity, with emphasis on understanding how D receptor-specific agonists and antagonists ameliorate or exacerbate the monkeys' symptoms and deficits. We will explore PFC for neurophysiological abnormalities underlying the behavioral deficits. Finally, neurochemical consequences of the chronic AMPH and PCP treatments will be fully characterized to test our working hypothesis is that even in the models based on PCP, a non- competitive antagonist for the NMDA subtype of glutamate receptor, the principal behavior deficits could still be principally related to DAergic dysfunction in PFC. A non human primate model for at least some aspects of schizophrenia would be extremely beneficial in understanding this disease and seeking ways to treat it. Moreover, the mechanisms whereby intermittent exposure to AMPH/PCP induce persistent disturbances in brain function may have direct relevance to the etiology of schizophrenia because endogenous neurochemical sensitization, analogous to PCP or AMPH abuse, could be a critical factor leading to the onset of this illness.
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