PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments
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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.
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.
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.
Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.
KeywordsBehavior c-fos Dopamine Phencyclidine Glutamate NMDA Serotonin Schizophrenia Reversal learning Working memory
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.
- Franklin K, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego, CaliforniaGoogle Scholar
- McLean SL, Grayson B, Idris NF, Lesage AS, Pemberton DJ, Mackie C, Neill JC (2011) Activation of alpha 7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks inrats: implications for therapy of cognitive dysfunction in schizophrenia. Eur Neuropsychopharmacol 21:333–343CrossRefPubMedGoogle Scholar
- Simon H (1981) Dopaminergic A10 neurons and frontal system. J Physiol 77:81–95Google Scholar