Year

2010

Degree Name

Doctor of Philosophy

Department

School of Health Sciences

Abstract

Currently, the control of schizophrenia symptoms is primarily through pharmacological intervention. However, antipsychotics can cause several side effects, such as extrapyramidal symptoms (EPS) and body weight gain/obesity, which severely affect patient compliance to continue with medication. In addition, due to the effects of antipsychotics on neurotransmission, it is unclear whether central pathological changes observed in post-mortem tissue in schizophrenia are the real pathology of the disease or are a result of the effects of antipsychotic drugs. The aim of this study was to investigate the molecular mechanisms of the pharmacological efficacy and side-effects of antipsychotic drugs. To achieve this aim, this study examined the expression of dopamine D2, histamine H1, serotonin 5HT1A and muscarinic M1 receptors in the rat brain following short-term (1 week) and long-term (12 weeks) treatment with aripiprazole, olanzapine and haloperidol.

Aripiprazole and haloperidol both have a high affinity for dopamine D2 receptors, however aripiprazole has a lower risk of EPS than haloperidol. The aim of Chapter 2 was to understand the mechanism underlying why aripiprazole, unlike haloperidol, has a therapeutic effect but does not induce significant EPS. Results showed that aripiprazole selectively increased D2 receptor mRNA expression and decreased tyrosine hydroxylase mRNA expression (TH; a rate-limiting enzyme for the synthesis of dopamine) in the ventral tegmental area (VTA), but not the substantia nigra (SN). Aripiprazole also decreased dopamine transporter (DAT) binding density in the nucleus accumbens (NAc) and VTA. Consistent with previous findings, haloperidol significantly increased D2 receptor binding density, but decreased DAT binding density in the NAc, CPu and VTA. Olanzapine had less widespread effects on D2 receptor expression and DAT binding density. These results suggest that aripiprazole may control schizophrenia symptoms through a novel mechanism: that is, by selectively reducing dopamine synthesis in the VTA but not SN. This may contribute to the long-term efficacy of aripiprazole in controlling schizophrenia symptoms with reduced EPS.

It has been previously reported that aripiprazole and olanzapine increased dopamine release in the prefrontal cortex via the serotonin 5-HT1A receptor, which may partially explain why these drugs can improve the negative symptoms and cognitive functional deficits associated with schizophrenia. It is interesting that aripiprazole has a high affinity for 5-HT1A receptors, but olanzapine has not. Therefore, the aim of Chapter 3 was to examine whether these antipsychotics affect 5-HT1A receptor expression. The results showed that aripiprazole increased 5-HT1A binding density in the CA1 region of the hippocampus and medial posterodorsal nuclei of the posterior amygdala (MeP), while olanzapine down- regulated the binding density of 5-HT1A receptors in the cingulate cortex. However, these changes were not apparent after 12 weeks of drug treatment. This study suggests that aripiprazole and olanzapine have different effects on the binding density of 5-HT1A receptors. The results indicate that aripiprazole and olanzapine have differential effects on 5-HT1A protein expression, which may contribute to their distinct profiles in improving negative symptoms and cognitive deficits in schizophrenia. However, they may induce adaptation and desensitisation in serotonin 5-HT1A receptor expression after long-term treatment.

Schizophrenia patients exhibit a decrease, or no change, in muscarinc M1 receptor expression in certain brain regions. Olanzapine has a high affinity for the M1 receptor, while aripiprazole and haloperidol have low affinities. The aim of Chapter 4 was to investigate how these antipsychotics affect M1 receptor mRNA expression in regions of the brain that are implicated in the pathology of schizophrenia. This study showed that the three antipsychotics increased M1 receptor mRNA expression in the hippocampus. In addition, increases in M1 receptor mRNA expression were also observed in the SN following treatment with haloperidol and olanzapine, and in the NAc following treatment with aripiprazole. These results suggest that alterations of M1 receptor mRNA expression in schizophrenia are unlikely to be a consequence of drug treatment, and implicate the muscarinic M1 receptor as a contributor to the therapeutic effects of schizophrenia treatments.

The aim of Chapter 5 was to investigate whether the body weight gain/obesity side-effect of olanzapine was produced by regulating histamine H1 receptor expression. To the best of this author’s knowledge, this study is the first to compare H1 receptor expression in the rat brain following short and long-term administration of olanzapine, aripiprazole and haloperidol. Results showed that olanzapine significantly down-regulated H1 receptor mRNA expression and binding density in the ventromedial hypothalamic nucleus (VMH), and H1 receptor mRNA expression in the arcuate hypothalamic nucleus (Arc). Consistent with their low risk of weight gain/obesity side-effect, aripiprazole and haloperidol had no effect on H1 receptor expression in the VMH or Arc. Histamine H1 receptor mRNA expression in the VMH and Arc were negatively correlated to body weight gain and energy efficiency, while H1 receptor mRNA expression in the Arc showed negative correlations to food intake and total fat mass. In addition, there was a negative relationship between H1 receptor binding densities in the VMH and total fat mass and body weight gain. This study suggests that an olanzapine-induced down-regulation of histamine H1 receptor expression in regions of hypothalamus involved in the regulation of food intake (the Arc and VMH) may be a key factor contributing to olanzapine-induced body weight gain/obesity.

In conclusion, this study revealed that the effects of antipsychotics on specific neurotransmitter receptors contribute to the mechanisms of their pharmacological efficacy and side-effects. The binding profiles of antipsychotics for specific receptors cannot completely predict the level of their therapeutic efficacies and side-effects. Furthermore, the changes in expression of some receptors (such as 5- HT1A) by antipsychotic treatment may produce the adaptation and desensitisation after long-term use. These results have also provided significant information which may assist with the development of new antipsychotic drugs.

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