The Establishment Of Animal Models Of Schizophrenia And Its Drug Role In Screening Platform

Based on the glutamate dysfunction hypothesis for the pathophysiology of schizophrenia, MK801, a noncompetitive antagonist for the NMDA-type of glutamate receptors, was administered to mice by i.p. injection. We observed hyperlocomotion and stereotypy, two behavioral signs indicative of schizophrenic symptoms in human. Aided with automated movement measuring of locomotion and videotaping for off-line scoring of stereotypy, these two schizophrenia-like behaviors are readily evaluated. According to the result of dose-response measurements of serial MK801 dosages in the BALB/c inbred mice, 0.6 mg/kg MK801 was determined as the optimum dosage for these behaviors. Further, the same experiments were performed in another inbred strain C57BL/6 and the outbred stock ICR, and similar results were obtained. These results showed that MK801 induces schizophrenia-like symptoms in both inbred and outbred mice.Risperidone and olanzapine, two clinically used antipsychotic drugs for treating schizophrenia in human, were used in the schizophrenia models using BALB/c and C57/BL/6 mice. The results indicated that risperidone and olanzapine dose-dependently inhibited the MK801-induced schizophrenia-like symptoms in BALB/c and C57/BL/6 mice. Thus, our results indicate that the MK801-induced behaviors may serve as useful mousemodels of schizophrenia.According to the MK801-induced schizophrenia mouse model, we screened anti-schizophrenia drugs from the neuropeptides in the laboratory mouse. From the study of opiate receptor antagonists including GNTI, nor-BNI, CTOP and Naltrexone, we find that GNTI, a κ-opiate receptor antagonist has potent anti-schizophrenia effect in locomotion and stereotypy.In the study of the etiology of schizophrenia, we associate glutamate neuro-path, dopamine neuro-path and opiate receptor path with the schizophrenia in the level of the laboratory mouse for the first time. The result indicates that the dysfunction of glutamate neuro-path, dopamine neuro-path and opiate receptor path can be the causes of schizophrenia.