The cognitive deficits that occur in schizophrenia are arguably the most debilitating of the symptoms, and the most resistant to pharmacological treatment. While the atypical antipsychotic drug (APD), clozapine, is one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, it's mechanism of action is not fully understood, and this has hindered development of other agents that are more effective than clozapine and lack its dangerous side effects. In man, repeated use of phencyclidine (PCP) can often induce an enduring schizophrenic-like syndrome. In the monkey, we have found that subchronic exposure to PCP induces a decrease in dopamine function in the prefrontal cortex (PFC) which persists for more than a month, and demonstrates neurochemical and anatomical specificity. This PCP- induced PFC dopamine deficiency correlates with cognitive impairments in the monkey, which resemble those occurring in schizophrenia. Furthermore, these cognitive deficits are partially ameliorated by administration of clozapine. PCP also causes a decrease in the number of spine synapses and density of dendritic spines in layer V of rat PFC. Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the mechanisms responsible for the neurobiological changes induced by repeated PCP administration on the anatomical integrity, neurotransmitter regulation and behavioral functions associated with the PFC. In addition, the mechanisms involved in the pharmacological reversal of the cognitive deficits produced by subchronic exposure to PCP will be evaluated. The research plan will address the following: Does dopamine play a critical role in the PCP induced decrease in dendritic spine density and spine synapse loss observed in the PFC of rodents? Can these anatomical changes be reversed by atypical APDs? Is the loss in the number of spine synapses and decrease in spine density and the dopamine modulation of this effect observed in the rat conserved in monkeys? Can the PCP and MPTP induced loss of dendritic spine synapses in the PFC and the ensuing cognitive deficits be reversed by chronic administration of atypical APDs? What receptors are essential for clozapine's ability to normalize dopamine turnover in the PFC of PCP treated monkeys? Do atypical APDs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkeys attenuate the cognitive impairments? The generation of critical neurochemical, anatomical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant to the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical, anatomical and behavioral deficits in this potential animal model, and hopefully in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-A (90))
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Winsky, Lois M
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Yale University
Schools of Medicine
New Haven
United States
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Elsworth, John D; Groman, Stephanie M; Jentsch, James D et al. (2014) Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex. Int J Neuropsychopharmacol 18:
Elsworth, John D; Roth, Robert H (2013) Pregnancy, a risky time: keep calm, clean, and carry on! Biol Psychiatry 74:478-9
Elsworth, John D; Leranth, Csaba; Redmond Jr, D Eugene et al. (2013) Loss of asymmetric spine synapses in prefrontal cortex of motor-asymptomatic, dopamine-depleted, cognitively impaired MPTP-treated monkeys. Int J Neuropsychopharmacol 16:905-12
Miller, Brooke H; Zeier, Zane; Xi, Li et al. (2012) MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc Natl Acad Sci U S A 109:3125-30
Elsworth, John D; Groman, Stephanie M; Jentsch, J David et al. (2012) Asenapine effects on cognitive and monoamine dysfunction elicited by subchronic phencyclidine administration. Neuropharmacology 62:1442-52
Abizaid, A; Mineur, Y S; Roth, R H et al. (2011) Reduced locomotor responses to cocaine in ghrelin-deficient mice. Neuroscience 192:500-6
Elsworth, John D; Hajszan, Tibor; Leranth, Csaba et al. (2011) Loss of asymmetric spine synapses in dorsolateral prefrontal cortex of cognitively impaired phencyclidine-treated monkeys. Int J Neuropsychopharmacol 14:1411-5
Elsworth, John D; Morrow, Bret A; Hajszan, Tibor et al. (2011) Phencyclidine-induced loss of asymmetric spine synapses in rodent prefrontal cortex is reversed by acute and chronic treatment with olanzapine. Neuropsychopharmacology 36:2054-61
Jentsch, J David; Sanchez, Diana; Elsworth, John D et al. (2008) Clonidine and guanfacine attenuate phencyclidine-induced dopamine overflow in rat prefrontal cortex: mediating influence of the alpha-2A adrenoceptor subtype. Brain Res 1246:41-6
Elsworth, John D; Jentsch, J David; Morrow, Bret A et al. (2008) Clozapine normalizes prefrontal cortex dopamine transmission in monkeys subchronically exposed to phencyclidine. Neuropsychopharmacology 33:491-6

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