Comparative Studies On The Neuropharmacological Effects Of Clozapine, Olanzapine And Haloperidol

The antipsychotic drugs are divided into typical and atypical ones. The typical antipsychotic drugs, such as haloperidol, have shown efficacy in treating the positive symptoms of schizophrenia, but can also result in extrapyramidal side effects (EPS) , which has imposed limitations on their clinical use. Clozapine is the first atypical antipsychotic drug. It has shown better therapeutic action and much lower induction of EPS than the typical ones. However, administration of clozapine is associated with a serious side effect, agranulocytosis. Olanzapine is a new atypical antipsychotic drug. It closely resembles clozapine in terms of its chemical structure and pharmacological profiles, and does not induce agranulocytosis. Further study on its pharmacological characteristics will be beneficial for its more effective and safer application in clinical setting. Thus, in the present paper comparative studies were performed between olanzapine and representative typical and atypical drugs, haloperidol and clozapine on their neuropharmacological effects by using different methods, including brain microdialysis, behavioral experiments and cell culture.The effects of clozapine, olanzapine and haloperidol on ethanol-induced striatal ascorbic acid (AA) release in mice were compared by using microdialysis coupled to high performance liquid chromatography with electrochemical detection. Ethanol (4.0 g/kg i.p.) significantly stimulated striatal AA release by about 200% of baseline in mice. Clozapine, at the doses of 1 and 3 mg/kg s.c, had no effect on basal AA or ethanol-induced AA release. Clozapine, at the dose of 10 mg/kg s.c, significantly inhibited ethanol-induced AA release without affecting basal AA release, Olanzapine. at the dose of 1 mg/kg s.c, had no effect on basal AA or ethanol-induced AA release. Olanzapine, at the doses of 3 and 10 mg/kg s.c, significantly inhibited ethanol-induced AA release without affecting basal AA release. In contrast, haloperidol, at the doses of 0.1, 0.3 and 1.0 mg/kg s.c, had no effect on either basal or ethanol-induced AA release. The results demonstrated that similar actions were exhibited by clozapine and olanzapine, but not by haloperidol, for the regulation of ethanol-induced AA release in the mouse striatum.Clozapine, at the doses of 1 and 3 mg/kg s.c., had no effect on basal AA or ethanol-induced AA release in mouse prefrontal cortex. Clozapine, at the dose of 10 mg/kg s.c., significantly inhibited ethanol-induced AA release in mouse prefrontal cortex without affecting basal AA release. Olanzapine, at the dose of 1 mg/kg, s.c., had no effect on basal AA or ethanol-induced AA release in mouse prefrontal cortex. Olanzapine, at the doses of 3 and 10 mg/kg s.c., significantly inhibited ethanol-induced AA release in mouse prefrontal cortex without affecting basal AA release. In contrast, haloperidol, at the doses of 0.1, 0.3 and 1.0 mg/kg s.c., had no effect on either basal or ethanol-induced AA release in mouse prefrontal cortex.Behavior experiments were used to evaluate the effects of clozapine, olanzapine and haloperidol on learning and memory in mice. The step-through test showed that, clozapine (1 mg/kg) impaired memory acquisition process, while did not affect the consolidation or retrieval process. Haloperidol (0.01 and 0.1 mg/kg) impaired memory consolidation process, while did not affect the acquisition or retrieval process. Olanzapine (0.01-0.1 mg/kg) did not affect the memory acquisition, consolidation or retrieval process. The results of the Morris water maze showed that, clozapine (1 mg/kg) impaired acquisition process of spatial memory on the 1st, 3rd, 4th and 5th day. Haloperidol(0.1 mg/kg)impaired acquisition process of spatial memory on the 5th day. Olanzapine (0.1 mg/kg) improved acquisition process of spatial memory on the 3rd and 5th day. Clozapine (3-30 mg/kg) and olanzapine (0.3-3 mg/kg) did not affect the consolidation process of spatial memory while haloperidol (1 mg/kg) impaired it. The above results suggested that clozapine and haloperidol impaired learning and memory, function, while olanzapine did not or even improved it. were compared. It was found that both clozapine and haloperidol reduced the cell viability in a time- and dose-dependent manner. The cytotoxicity of clozapine and haloperidol were shown to be of apoptosis-induction as demonstrated in AO/EB staining and DNA fragmentation analysis. Unlike clozapine and haloperidol, olanzapine had no effect on the viability of N9 cells. Clozapine and haloperidol did not affect NO production induced by LPS in N9 cells, while olanzapine significantly inhibited it. These results suggested that olanzapine showed different effect from clozapine and haloperidol on N9 cells, implying a new therapeutic mechanism and potential new indications in clinical applications.In conclusion, the results of brain microdialysis demonstrated that clozapine and olanzapine, the two atypical antipsychotic drugs, shared the common property. The results of behavioral experiments suggested that olanzapine may be superior to clozapine and haloperidol in the psychiatric treatment. In cell culture experiments, it was found that olanzapine showed different effect from clozapine and haloperidol on N9 cells.