Year

2016

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Aripiprazole is a unique antipsychotic drug with favourable therapeutic effects and improved extrapyramidal side-effects. Its partial agonism for the dopamine D2 receptors (D2R) is considered to contribute to the clinical effects of aripiprazole. However, how aripiprazole regulates D2R-mediated cellular signalling pathways, as well as their downstream substrates, is not clear. Therefore, this thesis investigated the cellular mechanisms of aripiprazole on these signalling pathways and regulators in an animal model, by comparing aripiprazole with a D2R antagonist – haloperidol and a D2R partial agonist – bifeprunox.

The study in Chapter 3 investigated the acute effects of aripiprazole (a single injection) on the D2R downstream cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and protein kinase B (Akt)-glycogen synthase kinase 3 beta (GSK3β) signalling pathways. Aripiprazole affected PKA-C expression similarly to haloperidol, but not bifeprunox, in the caudate putamen (CPu) and ventral tegmental area (VTA). In addition, aripiprazole increased phosphorylation of GSK3β in the prefrontal cortex (PFC), nucleus accumbens (NAc), CPu and substantia nigra (SN). Haloperidol also increased phosph-GSK3β in the NAc. These results suggest acute administration of aripiprazole affected the cAMP-PKA and Akt-GSK3β signalling pathways differentially from haloperidol and bifeprunox in various brain areas. It also indicated that its relatively low intrinsic activity for D2Rs might contribute to the effects of aripiprazole.

The study in Chapter 4 continued to examine the effects of 1-week aripiprazole treatment by oral administration. In addition to PKA signalling, γ-aminobutyric acid (GABA)A receptors and cAMP-responsive element-binding protein (CREB) were examined. The data have shown that 1-week administration of aripiprazole elevated PKA activity by increasing the phosphorylation levels of PKA in the NAc. Aripiprazole also increased the expression of the GABAA (β-1) receptor and CREB in the NAc. Furthermore, haloperidol elevated PKA activity in both the NAc and CPu, while haloperidol increased GABAA (β-1) receptor expression and CREB1 expression (not significantly) in the NAc. These findings suggest that aripiprazole might exert its clinical effects via the regulation of GABAA receptors and CREB1 in the NAc, possibly via the D2R-mediated PKA signalling pathway.

In the study in Chapter 5, the effects of 1-week administration of aripiprazole on the Akt-GSK3β and Dvl-GSK3β-β-catenin signalling pathways were examined. The results demonstrated that aripiprazole increased GSK3β phosphorylation in the PFC, NAc and CPu, while haloperidol and bifeprunox had such effects only in the NAc and CPu, respectively. Additionally, both aripiprazole and haloperidol increased the expression of Dvl-3 and β-catenin in the NAc. The studies in Chapters 4 and 5 suggest that upregulation of GABAA (β-1) receptors and CREB1 in the NAc, and GSK3β phosphorylation in the PFC and NAc may be involved in the clinical effects of aripiprazole; they further indicate that the relatively low intrinsic activity for D2Rs might be associated with the actions of aripiprazole.

In the clinic, in order to control symptoms of schizophrenia, patients usually experience chronic antipsychotic treatment. The chronic effects of aripiprazole on the GSK3β- dependent signalling pathways, GABAA receptor and CREB1 are unknown. Therefore, the effects of 10-week administration of aripiprazole on these cellular signalling pathways and regulators were examined in Chapter 6. Administration of both aripiprazole and bifeprunox activated the Akt-GSK3β signalling in the PFC. In the NAc, chronic administration of all three drugs increased Akt-GSK3β signalling; while both aripiprazole and haloperidol up-regulated Dvl-3, β-catenin and GABAA receptors, as well as CREB1 activity. This study has confirmed the involvement of Dvl-GSK3β-β- catenin, GABAA receptors and CREB1 activity in the long-term actions of aripiprazole.

In brief, this thesis provided in vivo evidence that aripiprazole was able to activate the PKA, Akt-GSK3β and Dvl-GSK3β-β-catenin signalling pathways, and also up-regulate GABAA receptor expression, as well as CREB1 activity. Moreover, by comparing aripiprazole with haloperidol and bifeprunox, particularly their effects in the NAc, these studies further suggest that a relatively low intrinsic activity for D2Rs might be the key factor for aripiprazole to exert its unique clinical effects, and for other potential D2R partial agonists to achieve meaningful therapeutic effects.

FoR codes (2008)

1109 NEUROSCIENCES, 1115 PHARMACOLOGY AND PHARMACEUTICAL SCIENCES

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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.