Amphetamine-Induced Toxicity in Astrocytes and its Implications in the Pathogenesis of Psychiatric Disorders
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Amphetamine-type stimulants (ATS), such as amphetamine (AMPH) and methamphetamine (METH), cause long-term toxic effects on the dopaminergic neurons in the brain leading to the development of several psychiatric disorders. The mechanisms underlying ATS neurotoxicity are unclear, but oxidative stress has been implicated. Most studies on ATS have focused on neurons. However, in recent years, the role of glial cells, particularly astrocytes, in ATS pathogenesis has received considerable focus. Yet, little work has been done to study gene expression changes in ATS-treated astrocytes as a part of the ATS neurotoxicity cascade. Therefore, these studies aimed to examine the contribution of gene expression in astrocytes to ATS toxicity and to identify novel gene targets for treating ATS-induced psychiatric disorders. In the first chapter, we studied the effects of repeated METH exposure on astrocyte transcriptome using microarray. METH induced differential expression of 1,819 genes in astrocytes. Furthermore, METH significantly dysregulated biological pathways, molecular functions, cellular components, and transcriptional regulators involved in the cell cycle, DNA replication and repair, apoptosis, and phagocytosis. These results suggested that METH-induced gene expression changes play a critical role in METH-induced cell cycle arrest, defective DNA repair, and increased apoptosis. In the second chapter, we investigated the effect of METH treatment on the expression of integrins in astrocytes and the involvement of integrins in METH-induced apoptosis. We found that METH significantly decreased the expression of 10 integrin subunits expressed in astrocytes and that integrin subunit β1 is involved in METH-induced apoptosis in astrocytes. In the third chapter, we utilized a population-level study to determine the prevalence of psychiatric disorders in METH-abusing individuals using the Cerner Health Facts database. Our results showed a significantly higher prevalence of anxiety, depression, bipolar disorder, psychosis, and schizophrenia among METH-abusing individuals compared to the general population. We then identified common gene expression signatures by comparing gene expression changes from our microarray data and independent microarray datasets from patients with anxiety, depression, and schizophrenia retrieved from the gene expression omnibus (GEO) database. In conclusion, we demonstrated that ATS-induced gene expression alterations are involved in developing neurotoxicity and psychiatric disorders in ATS-abusing users.
Table of Contents
General introduction -- Transcriptome analysis of methamphetamine-treated astrocytes -- Evaluation of the effect of amphetamine on the expression of integrins and cell death in astrocytes -- Prevalence of psychiatric disorders in meth-abusing individuals and identification of novel gene targets in meth-associated psychiatric disorders -- Future directions
Ph.D. (Doctor of Philosophy)