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Int J Neuropsychopharmacol. 2014 Oct 31;18(6). pii: pyu048. doi: 10.1093/ijnp/pyu048.

Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex.

Author information

1
Neuropsychopharmacology Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Drs Elsworth, Groman, Redmond, and Roth); Department of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California (Dr Jentsch); Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut (Drs Leranth, Kim, and Diano). john.elsworth@yale.edu.
2
Neuropsychopharmacology Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Drs Elsworth, Groman, Redmond, and Roth); Department of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California (Dr Jentsch); Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut (Drs Leranth, Kim, and Diano).

Abstract

BACKGROUND:

Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits.

METHODS:

The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys.

RESULTS:

One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance.

CONCLUSIONS:

As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia.

KEYWORDS:

brain derived neurotrophic factor; cognition; dopamine; phencyclidine; sex; spine synapse

PMID:
25522392
PMCID:
PMC4438537
DOI:
10.1093/ijnp/pyu048
[Indexed for MEDLINE]
Free PMC Article

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