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Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat—a back translational study

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Abstract

Rationale

Selective cognitive impairments, including those of executive function as assessed using the Wisconsin Card Sort Test or intradimensional–extradimensional (ID–ED) tests, are a key feature of schizophrenia but remain inadequately treated by existing therapies. Recently, however, modafinil has been shown to improve attentional set-shifting performance in patients with schizophrenia.

Objective

The present study evaluated the recently described analogous rat ID–ED attentional set-shifting task by investigating the effects of various pharmacological challenges to a phencyclidine (PCP)-induced ED shift impairment, namely, haloperidol, risperidone, sertindole, and modafinil.

Materials and methods

Rats were subjected to a subchronic systemic administration of either saline vehicle or PCP (5 mg/kg i.p. b.i.d. for 7 days) followed by a 7-day washout period. During this period, rats were trained to dig in baited bowls for a food reward and to discriminate based on odor or digging media. In a single test session conducted the day after the washout period (day 8), rats performed a series of discriminations following acute administration of either vehicle, or haloperidol (0.1 mg/kg s.c.), or risperidone (0.2 mg/kg i.p.), or sertindole (1.25 mg/kg p.o.) or modafinil (64 mg/kg p.o.).

Results

The subchronic PCP-induced ED deficit was ameliorated by sertindole and modafinil but not by haloperidol or risperidone.

Conclusions

Overall, these findings further support that the rat ID–ED test in subchronic PCP-treated rats has utility and validity as a preclinical model of the cognitive symptoms of schizophrenia and demonstrates back-translational potential.

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Acknowledgements

The authors wish to extend special thanks to Mr. Christian Spang Pedersen, Ms. Tanja Bruun, and Mr. Claus Nørgaard Johansson for their assistance in running the behavioral intradimensional–extradimensional experiment and in their contribution to the “Materials and methods” section of the manuscript.

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  1. H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Pascal Goetghebeur & Rebecca Dias

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  1. Pascal Goetghebeur
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  2. Rebecca Dias
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Correspondence to Rebecca Dias.

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Goetghebeur, P., Dias, R. Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat—a back translational study. Psychopharmacology 202, 287–293 (2009). https://doi.org/10.1007/s00213-008-1132-9

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  • DOI: https://doi.org/10.1007/s00213-008-1132-9

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