Chronic PCP Primate PFC Dopamine Deficit and Schizophrenia

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DESCRIPTION (provided by applicant): Our work in both rodents and primates has indicated that the biochemical and behavioral effects of withdrawal from repeated phencyclidine (PCP) form a useful model of the cognitive deficits of schizophrenia. PCP exposure imparts a lasting and regionally-specific decrease in dopamine (DA) turnover in the prefrontal cortex (PFC), a decreased number of asymmetric spine synapses on PFC pyramidal neurons, and deficits in performing PFC-dependent cognitive tasks. Together these novel data support our hypothesis that the number of spine synapse on dendrites in the PFC is DA-dependent and may be a morphological substrate of the cognitive deficits induced by sustained reductions in DA neurotransmission in this region. Because cognitive performance and memory processes seem to be coupled with the remodeling of PFC, pyramidal dendritic spine synapses may, at least partly, contribute to observed cognitive dysfunction in our primate PCP model. These PCP-induced changes in DA transmission, dendritic spine morphology and cognition are reminiscent of alterations reported in brains from schizophrenic patients. During juvenile and adolescent periods of development the PFC in primates is still undergoing significant maturation, both morphologically and biochemically. In man, this is the time in development when signs of schizophrenia typically emerge and also is the age at which the vulnerability to the consequences of psychoactive drugs is enhanced. Thus, we are now eager to extend our primate work to examine the effects of PCP treatment in juvenile and adolescent monkeys. We hypothesize that compared to adults, young monkeys will display more pronounced and longer lasting effects of PCP exposure on diminished DA turnover, NMDA receptor hypofunction and reduced asymmetric spine synapse number in the dorsolateral PFC compared with adults. We expect to observe deficits in cognitive performance that parallel the changes in DA turnover and asymmetric spine synapse number. Consistent with evidence from human and animal studies on the role of serotonin in the ventral prefrontal cortex on inhibitory control and impulsivity, in young monkeys we also expect a magnified reduction in serotonin turnover in the lateral orbital cortex and nucleus accumbens shell in a time-course that parallels the cognitive deficit in the reversal learning task. This work will i) identify the pattern of normal synaptic and monoamine development of the non-human primate PFC, which is critical for a better understanding of the many diseases, such as schizophrenia, thought to be related to synaptic maldevelopment, ii) reveal the vulnerability of PFC cognitive circuits to psychotomimetic agents during development, iii) provide insight concerning the relationship between NMDA receptor function and PFC integrity as a function of development, and iv) provide a useful primate developmental model of PFC cognitive deficits in schizophrenia. PUBLIC HEALTH RELEVANCE: The cognitive deficit in schizophrenia is the most treatment resistant sign. Repeated PCP treatment of monkeys is a useful model of schizophrenic cognitive deficits. Due to the increased vulnerability of PFC circuitry to psychoactive drugs during development, and the typical emergence of schizophrenic symptoms in early adulthood, the treatment of juvenile and adolescent monkeys with repeated PCP promises to provide a better and more relevant model of schizophrenic cognitive deficits.