Abstract
To obtain an insight into the possible pharmacotherapy for neuroleptic-resistant symptoms of schizophrenia, we have investigated pharmacological profiles of phencyclidine(PCP)-induced abnormal behavior and c-fos gene expression in the brain using rats because the noncompetitive NMDA receptor blocker PCP elicits schiophreniform psychosis consisting of not only neuroleptic-responsive positive but also neurolepticresistant negative symptoms. Like PCP psychosis, hyperlocomotion, stereotypy and ataxia induced by PCP have been reported to be partially attenuated by neuroleptic drugs in the rat. Intraventricular injection of the D-serine and D-alanine, which are selective agonists for the glycine modulatory site of the NMDA type glutamate receptor, antagonized the ability of PCP to induce abnormal behavior in a stereoselective and a glycine site antagonist-reversible manner. Systemic administration of PCP also resulted in c-fos gene expression, a useful marker of neuronal activity, in various areas of the rat brain in a haloperidol-resistant fashion. In contrast, the neuroleptic drug inhibited the induction of brain c-fos methamphetamine and cocaine that elicit schizophreniform positive symptoms. The distribution patterns of c-fos after PCP were similar to those of a selective NMDA antagonist but different from those of dopamine agonists. The present findings are consistent with the view that disturbed neurotransmission via the NMDA receptor might, at least in part, be involved in the pathophysiology of PCP psychosis and schizophrenia and that PCP-induced behavioral changes and c-fos expression could be appropriate indices for screening a novel class of antipsychotic drugs possessing therapeutic efficacy against neuroleptic-resistant symptoms of these psychotic states.
