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PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

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Abstract

Rationale

N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness.

Objectives

To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences.

Results

Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice.

Conclusions

Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.

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Acknowledgments

This work has received support from the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (13INT4 intramural project), and the Innovative Medicine 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). We thank Emilio Regli, Patricia Sariñana, and Miguel Angel López-Venegas, as well as Leticia Campa, Mireia Galofré, Noemí Jurado, and Verónica Paz for technical support.

Conflict of interest

Francesc Artigas has received consulting and educational honoraria from Lundbeck, and he is PI of a grant from Lundbeck. He is also member of the scientific advisory board of Neurolixis. The rest of authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neurochemistry and Neuropharmacology, CSIC-Institut d’Investigacions Biomèdiques de Barcelona (IIBB), IIBB. Rosselló 161, 6th floor, 08036, Barcelona, Spain

    Anna Castañé, Noemí Santana & Francesc Artigas

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain

    Anna Castañé, Noemí Santana & Francesc Artigas

  3. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Anna Castañé, Noemí Santana & Francesc Artigas

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  1. Anna Castañé
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Correspondence to Anna Castañé.

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Castañé, A., Santana, N. & Artigas, F. PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacology 232, 4085–4097 (2015). https://doi.org/10.1007/s00213-015-3946-6

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