Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions.

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (-)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT(2) receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT(2) receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.