Year

2010

Degree Name

Master of Science - Research

Department

School of Health Sciences

Abstract

Schizophrenia is a devastating mental disorder influencing functions of the central nervous system. Olanzapine, an atypical antipsychotic drug, is extremely efficient in treating both the positive and negative symptoms, as well as the cognitive deficits of schizophrenia. However, it induces some serious side effects, such as body weight gain/obesity, hormonal dysfunction and other metabolic disorders. Since the antagonistic affinities to histamine H1 receptors of antipsychotic drugs are thought to be one of the main indicators of antipsychotic-induced weight gain/obesity, it is proposed that a histamine H1 receptor agonist may have potential to reduce antipsychotic-induced weight gain side effects.

This project aimed to investigate whether a combined treatment of betahistine (a histamine H1 receptor agonist and H3 receptor antagonist) with olanzapine could improve the body weight/obesity side effects induced by olanzapine in a rat model. Forty-nine female Sprague Dawley rats were divided into four groups and fed orally with olanzapine (3 mg/kg/day) and/or betahistine (8 mg/kg/day), or vehicle for two weeks. Body weight, food intake, water intake and locomotor activity were measured. An intra-peritoneal glucose challenge test was conducted. Blood samples were taken for measuring appetite hormones including plasma insulin and PYY. White and brown fat tissue was collected and weighed. Brain tissue was obtained for histamine H1 receptor binding experiments in key regions of the brain involved in food intake and body weight regulation.

Rats treated solely with olanzapine exhibited significant body weight gain and increased food intake. However, sole betahistine treatment had no effect on weight gain and food intake. Co-treatment of olanzapine with betahistine significantly reduced (-33%) weight gain and feeding efficiency compared to sole olanzapine treatment. Olanzapine treatment reduced locomotor activity and increased white fat tissue; however betahistine had no influence on these parameters. These results suggested that co-treatment with betahistine partially improves the body weight gain side effect induced by olanzapine.

The hormone measurements in this project revealed that olanzapine tended to decrease fasting plasma insulin levels, and that co-treatment of olanzapine and betahistine can improve insulin levels. No change was detected in plasma PYY levels.

The H1 receptor binding experiments revealed a tendency for betahistine to increase H1 receptor binding density in the ventromedial hypothalamic nucleus (VMH), and significantly decreased H1 receptor binding density in the dorsal vagal complex (DVC), with no significant effect in the arcuate hypothalamic nucleus (Arc). There was no difference in H1 receptor binding in these nuclei following olanzapine treatment, possibly due to the influence of overnight fasting.

In conclusion, the findings of this project revealed that olanzapine-induced body weight gain could partially be reduced by co-treatment with betahistine, which confirms our hypothesis that use of an H1 receptor agonist can improve antipsychotic-induced weight gain/obesity side effects. These findings have important implications for clinical trials involving the use of betahistine to improve olanzapine-induced weight gain/obesity side effects. Furthermore, the finding of this study may aid in the development of a new treatment strategy 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.