Year

2010

Degree Name

Master of Science - Research

Department

School of Health Sciences

Abstract

Background: The neuregulin-1 (NRG1) gene has been identified as a candidate gene for schizophrenia. NRG1 signals mainly through the ErbB4 receptor. Previous studies have shown that NRG1 and the ErbB4 receptor are dysregulated in the brains of schizophrenia patients. This suggests that the expression of NRG1-ErbB4 could respond to treatment with antipsychotic drugs. This study aimed to investigate the effects of short-term and chronic antipsychotic treatment on the expression of NRG1 isoforms and ErbB4 receptors.

Methods: Female Sprague-Dawley rats were treated orally with three antipsychotic drugs, haloperidol (0.3 mg/kg/day), olanzapine (1.5 mg/kg/day), aripiprazole (2.25 mg/kg/day), or vehicle for either 1 week or 12 weeks. Western blotting was performed to examine the expression levels of three sub-types of NRG1 including type I (105kDa), III (83kDa) and 40 kDa isoform and its ErbB4 receptors in the prefrontal cortex (PFC), the cingulate cortex (CG), the hippocampus, and the hypothalamus.

Results: In the 12-week treatment groups, chronic treatments with aripiprazole and haloperidol significantly decreased the expression of ErbB4 receptors and all three subtypes of NRG1 isoforms in the PFC. NRG1-type I expression was also reduced by longterm treatment with aripiprazole in the CG. In the hypothalamus, 12-week treatment with aripiprazole decreased protein levels of ErbB4 receptors and NRG1-type III and 40 kDa isoforms; and long-term treatment with haloperidol reduced 40 kDa isoform expression. On the other hand, 1-week treatments with these antipsychotics had fewer effects on the expression of NRG1 isoforms and ErbB4 receptors, olanzapine slightly increased the protein level of NRG1-type I and III in the hippocampus, while haloperidol increased the expression of NRG1-type III in the hypothalamus.

Conclusion: Short-term and chronic treatment with typical and atypical antipsychotics have differential effects on regulating the expression of NRG1-ErbB4 in various brain regions, which may contribute to development of new antipsychotic therapeutics for schizophrenia patients.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.