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The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia

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Abstract

Rationale

Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-d-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals.

Objectives

The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks.

Methods

Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination.

Results

Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation.

Conclusions

The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

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Financial disclosure

SJ and HS declare being employees of Orion Corp. Orion Pharma. JT, GK and TS declare being employees of Janssen Pharmaceuticals. NP and LL declare being employees of Lundbeck. TB, MH and RW declare being employees of F. Hoffmann-La Roche Ltd. The research and collaboration leading to the results and review has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013).

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  1. CNS Research, Research and Development, Orion Pharma, Orion Corporation, Tengstrominkatu 8, P.O. Box 425, 20101, Turku, Finland

    Sanna K. Janhunen & Heta Svärd

  2. Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    John Talpos, Gaurav Kumar & Thomas Steckler

  3. Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Niels Plath, Linda Lerdrup & Trine Ruby

  4. Neuroscience, Ophthalmology and Rare Diseases, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Marie Haman, Roger Wyler & Theresa M. Ballard

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Janhunen, S.K., Svärd, H., Talpos, J. et al. The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia. Psychopharmacology 232, 4059–4083 (2015). https://doi.org/10.1007/s00213-015-3954-6

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