The establishment of animal model for negative syndrome of schizophrenia and its pharmacological annlication

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This research is fundamental studies for establishing animal model for negative syndrome of schizophrenia, using DELTA^9-tetrahydrocannabinol (THC) and phencyclidine (PCP) which produce similar behavioral changes of negative syndrome in schizophrenic patients.1.The effect of repeated administration of THC at a dose of 10 mg/kg (once a day for 4 days) 24 hr after administration on delayd matching-to-sample (DMTS) performance in rats using a 3-lever operant apparatus was examined. Although DMTS performance was not changed on the 1st day, it was impaired on the 2nd day. The impairment was potentiated in dependence of repeated administration. After withdrawal of THC,the impairment of DMTS performance gradually disappeared readministration of 10 mg/kg THC resulted in marked impairment of DMTS performance at 24 hr after administration ; behavioral sensitization developed. Furthermore, the suppressive state of lever-pressing induced by repeated THC administration may be a useful animal model … More for amotivational syndrome, similar to negative syndrome in schizoprenic patients.2.We examined whether administration of THC induces the expression of Fos protein or not in the rat brain. Administration of 10 mg/kg THC produced a significant increase in Fos-immunoreactive cells in the striatum and the nucleus accumbens. However, in the globus pallidus, hippocampus and substantia nigra pars reticula, there were few or no Fos-immunoreactive cells induced by THC.SCH-23390, a selective dopamine D_1 receptor antagonist, but not sulpiride, a selective dopamine D_2 receptor antagonist, produced a significant block of the effects of THC on Fos expression in the striatum and the nucleus accumbens. These findings indicate that THC induces the expression of Fos protein and that this expression is mediated at least by dopamine D_1 receptors.3.Attentional and information processing abnormalities have been noted frequently in schizophrenia. We examined the influence of PCP on attentional performance using a 3-choice serial reaction time task in rats. PCP was found to produce an attention deficit, as indicated by a delayd choice reaction time and a reduced choice accuracy. Sigma antagonists (NE-100, DuP734 and XJ448) blocked the attention deficit elicited by PCP.Judging from these results, it is concluded that this process may be mediated by sigma receptors. Less