Neuropsychopharmacological study on an animal model for negative symptom of schizophrenia induced by repeated phencyclidine treatment

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h af ter the final injection compared with saline treatment. The enhancing effec t of PCP on the immobility persisted for 21 d after the withdrawal of the d rug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin -S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effec ts may be mediated via serotonin-S2 receptors. In contrast with atypical an tipsychotics, typical antipsychotics, antidepressants and anxiolytics had n o effect. No functional changes in post-synaptic serotonin-S2 receptors wer e observed in PCP-treated mice following the forced swimming test. Serotoni n utilization in the prefrontal cortex was increased, but dopamine utilizat ion was decreased in PCP-treated mice showing the enhancement of immobility . The enhancing effect of PCP was significantly attenuated by D-cycloserine , an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) recept or ionophore complex. Decreases of NMDA receptor function or of the cortica l glutamate and glycine levels were observed in PCP-treated mice showing th e enhancement of immobility. These results suggest that the enhancing effec t of PCP on immobility is mediated by the imbalance of the cortical seroton ergic, dopaminergic and glutamatergic systems and could be used as an anima l model for negative symptoms of schizophrenia.