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Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia—sub-chronic and early postnatal PCP treatment in attentional set-shifting

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Abstract

Rationale

Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present.

Objective

The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional–extradimensional (ID–ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models.

Methods

Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56–95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5–40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally).

Results

The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516.

Conclusion

Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID–ED attentional set-shifting task.

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Acknowledgments

Funding from H. Lundbeck A/S, the Faculty of Health Sciences, University of Copenhagen, and the Graduate School of In Vivo Pharmacology, University of Copenhagen supported this research. The authors specifically thank Mr. Pascal Goetghebeur, Mrs. Tanja Bruun, and Mr. Christian S. Pedersen for help and training in the attentional set-shifting task procedure. Additionally, Mr. Anders Sylvest is thanked for his help in preparing the animals for the final test.

Ethical standards

All animal procedures were carried out in compliance with the European Commission Directive 86/609/EEC and with Danish law regulating experiments on animals.

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Authors and Affiliations

  1. Department of In Vivo Neurobiology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Brian Villumsen Broberg & Christina Kurre Olsen

  2. Department of Discovery ADME, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Dorrit Bjerg Larsen

  3. Department of Psychopharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Rebecca Dias

  4. Center for Neuropsychiatric Schizophrenia Research, Faculty of Health Sciences, Psychiatric Center Glostrup, University of Copenhagen, Glostrup, Denmark

    Brian Villumsen Broberg & Birte Yding Glenthøj

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  1. Brian Villumsen Broberg
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Correspondence to Brian Villumsen Broberg.

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Broberg, B.V., Glenthøj, B.Y., Dias, R. et al. Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia—sub-chronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology 206, 631–640 (2009). https://doi.org/10.1007/s00213-009-1540-5

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