Year

2021

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Antipsychotic drugs are the mainstay treatment approach for serious mental illnesses such as schizophrenia; however, they are limited in their ability to treat cognitive dysfunction and often cause detrimental side effects. Olanzapine and clozapine are two frequently prescribed antipsychotic drugs with some of the highest risk of causing long-term metabolic dysfunction including weight gain, obesity, type 2 diabetes and cardiovascular disease, problems that can have lifelong consequences and reduce life expectancy. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and antidiabetic drug with anti-obesity and neuroprotective properties; therefore, it may be able to address both metabolic and cognitive dysfunction during olanzapine and clozapine treatment. This thesis employed a female rat model of antipsychotic drug-induced metabolic dysfunction developed in our laboratory to investigate whether chronic liraglutide co-treatment from the commencement of olanzapine and clozapine administration could prevent metabolic side effects and improve cognition. It also investigated the effects of liraglutide co-treatment on central and peripheral markers of metabolism and cognitive function. The findings of Chapter 2 show for the first time that liraglutide co-treatment with olanzapine and clozapine improved aspects of cognition including recognition memory and working memory, prevented weight gain side-effects induced by olanzapine, and prevented hyperglycaemia caused by clozapine. Following on from these metabolic results, Chapter 3 assessed the effect of chronic liraglutide co-treatment with olanzapine and clozapine on key peripheral and neural metabolic signalling markers, including an examination of neurochemical signalling in the hypothalamus and dorsal vagal complex; regions of the brain involved in the central control of metabolism. The main findings of Chapter 3 were an absence of alterations to melanocortinergic, GABAergic, glutamatergic or endocannabinoid markers in the hypothalamus or dorsal vagal complex following chronic olanzapine, clozapine or liraglutide co-treatment with both antipsychotic drugs. Further, peripheral hormones were unaltered by treatment. This lack of change in the presence of significant weight gain suggests the possibility of adaptive mechanisms in this chronic treatment paradigm. Following on from the cognitive findings of Chapter 2, Chapter 4 assessed the neurochemical effects of liraglutide co-treatment with olanzapine and clozapine in the hippocampus and prefrontal cortex, regions of the brain involved in cognitive function. The main findings of Chapter 4 indicate that liraglutide can prevent alterations to cholinergic, GABAergic and endocannabinoid signalling markers in the hippocampus and prefrontal cortex of antipsychotic-treated rats. Collectively, this thesis demonstrates that liraglutide co-treatment can prevent aspects of metabolic and cognitive dysfunction induced by antipsychotic drugs and can prevent abnormalities in the expression of key neurochemicals in brain regions central to cognition. Overall, these findings highlight the possible connection between metabolic and cognitive health and support further investigation into liraglutide and GLP-1 receptor agonists as potential novel therapeutic approaches for the treatment of serious mental illness in individuals at a high risk of experiencing the adverse effects of antipsychotic drugs.

Comments

Thesis by compilation

FoR codes (2008)

1109 NEUROSCIENCES, 1115 PHARMACOLOGY AND PHARMACEUTICAL SCIENCES, 1116 MEDICAL PHYSIOLOGY

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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.