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A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia

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Abstract

Rationale

The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects.

Objective

We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH).

Results

Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the “freezing” of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals’ attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto–mesolimbic–basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies.

Conclusions

The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed.

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Notes

  1. The task described in this manuscript was recently selected by the CNTRICS initiative (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) for development for assessing the domain “control of attention” (http://cntrics.ucdavis.edu/meetings.shtml).

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Acknowledgments

The authors’ research that is reviewed in this paper was supported by PHS Grants MH063114, NS37026, MH080426, MH073600, and KO2 MH01072. Vicente Martinez is now at the University of Washington, Dept. of Psychiatry and Behavioral Sciences.

Disclosure of biomedical financial interests and potential conflicts of interests

Dr. Martin Sarter has received honoraria for speaking at Abbott Laboratories and Pfizer, Inc. He conducted a research that has been supported by grants from Abbott Laboratories and Pfizer Pharmaceuticals and served as a consultant for Sonexa Therapeutics Inc. in 2007.

Dr. Vicente Martinez indicated that he has no conflict of interest.

Dr. Rouba Kozak is employed by Pfizer, Inc.

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  1. Department of Psychology, University of Michigan, 530 Church Street, 4032 East Hall, Ann Arbor, MI, 48109-8862, USA

    Martin Sarter & Vicente Martinez

  2. CNS Biology, Pfizer, Inc., Groton, CT, USA

    Rouba Kozak

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  1. Martin Sarter
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Correspondence to Martin Sarter.

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Sarter, M., Martinez, V. & Kozak, R. A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia. Psychopharmacology 202, 237–258 (2009). https://doi.org/10.1007/s00213-008-1216-6

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