Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Rushlow

Abstract

Akt and the Wnt pathway, two cascades that regulate GSK-3, have been implicated in schizophrenia and antipsychotic drug action. Although it is known that antipsychotic drugs alleviate psychosis by blocking the dopamine D2 receptor (D2DR) and that metabotropic glutamate receptor 2/3 (mGluR2/3) agonists may improve some of the symptoms of schizophrenia, it is unclear if both classes of drugs exert their effects through Akt, GSK-3 and/or the Wnt pathway or if changes in these pathways are mediated through the D2DR and mGluR2/3 respectively. In addition to antipsychotics, mood stabilizers and antidepressants also target GSK-3, suggesting that there must be something unique in the way GSK-3 is targeted by antipsychotics since neither mood stabilizers nor antidepressants alleviate psychosis. The current study examined whether Akt and the Wnt pathway are regulated by the D2DR and mGluR2/3 and investigated the role of Akt and Dvl-3, a key activator in the Wnt pathway, in regulating GSK-3 in the rat brain. The study also compared the effects of antipsychotic, mood stabilizers and antidepressants on Akt and Wnt pathway proteins to determine if antipsychotics have unique effects on these signalling proteins. Results showed that raclopride (D2DR antagonist) regulated Akt and the Wnt pathway via Dvl-3 and the response was identical to antipsychotic treatment. Administration of the mGluR2/3 agonist, LY379268 also targeted Akt and the Wnt pathway and induced a similar response as antipsychotics. In addition, repeated amphetamine treatment, an established animal model for the positive symptoms of schizophrenia, quinpirole (D2DR agonist) and LY341495 (mGluR2/3 antagonist) induced similar changes in Akt and Wnt signalling that parallel alterations reported in schizophrenia. Furthermore, systemic inhibition of GSK-3 was able to attenuate the increase in locomotion induced by LY341495, a behavioural measure that models the positive symptoms of schizophrenia. The study also showed that clozapine and haloperidol (antipsychotics) induced a common Wnt response that was not mimicked by the mood stabilizers or antidepressants tested but that all neuropsychiatric drugs tested induced changes in Akt. Collectively the data shows that the Wnt pathway is regulated specifically by drugs with antipsychotic properties and may represent a novel target for pharmaceutical intervention.


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