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


OBJECTIVE
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.
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), IIBB. Rosselló 161, 6th floor, 08036, Barcelona, Spain. acfnqi@iibb.csic.es.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain. acfnqi@iibb.csic.es.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. acfnqi@iibb.csic.es.
Anna
A
Castañé
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), IIBB. Rosselló 161, 6th floor, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Noemí
N
Santana
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), IIBB. Rosselló 161, 6th floor, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Francesc
F
Artigas
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010622:Phencyclidine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*
D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine; D004298:Dopamine
Behavior; Dopamine; Glutamate; NMDA; Phencyclidine; Reversal learning; Schizophrenia; Serotonin; Working memory; c-fos