Molecular Validation of the Acute Phencyclidine Rat Model for Schizophrenia: Identification of Translational Changes in Energy Metabolism and Neurotransmission

Administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine
(PCP) to
rodents is widely used as preclinical model for schizophrenia. Most
studies on this model employ methods investigating behavior and brain
abnormalities. However, little is known about the corresponding peripheral
effects. In this study, we analyzed changes in brain and serum molecular
profiles, together with alterations in behavior after acute PCP treatment
of rats. Furthermore, abnormalities in peripheral protein expression
of first and recent onset antipsychotic free schizophrenia patients
were assessed for comparison with the preclinical model. PCP treatment
induced hyperlocomotion and stereotypic behavior, which have been
related to positive symptoms of schizophrenia. Multiplex immunoassay
profiling of serum revealed molecular abnormalities similar to those
seen in first and recent onset, antipsychotic free schizophrenia patients.
Also, increased insulin levels were detected after administration
of a glucose tolerance test (GTT), consistent with previous studies
showing changes in insulin signaling in patients with schizophrenia.
Finally, schizophrenia-relevant alterations in brain molecules were
found in the hippocampus and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and 1H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia.