Date of Award

2016

Document Type

Open Access Thesis

Department

Biomedical Science

Sub-Department

School of Medicine

First Advisor

Pavel I. Ortinski

Abstract

Dopamine is critical for processing of reward and addictive behaviors brought about by drugs of abuse. Scientific investigation of drugs of abuse and their effects on CNS function has traditionally been directed at understanding the role of neurons. However, astrocytes, which constitute approximately half of all human brain cells, play a dynamic role in many essential nervous system functions, including neurotransmission, ion homeostasis, and immune defense. Dopamine effects on astrocytes have been historically understudied, yet research indicates that astrocytes express dopamine receptors and are sensitive to dopaminergic activity. Importantly, astrocytes, comprise a morphologically heterogeneous population of cells, and a distinction between polygonal protoplasmic and stellated fibrous astrocytes in various CNS regions has long been acknowledged. However, the molecular and functional implications of this heterogeneity are largely unknown. Using an in vitro model of elevated extracellular dopamine exposure, our evidence reveals a fast and dramatic dopamine-induced switch from a protoplasmic to a fibrous-like morphology in cultures of rat hippocampal astrocytes. A one hour exposure to dopamine (75μM) produced an average of 4.5 more processes per astrocyte accompanied by a significant decrease in GFAP-positive area. Treatment with dopamine receptor antagonists prior to dopamine exposure significantly blunted dopamine effects on astrocyte morphology. Importantly, brief one hour treatment with dopamine was found to upregulate mRNA for ST8SiaI (a marker of fibrous/type 2 astrocytes), and downregulate mRNA for Ran2 (a marker of protoplasmic cells/type 1 astrocytes). Quantitative RT-PCR analysis revealed a dopamine-induced upregulation of DRD1, DRD2, and DRD3 mRNA. Together these findings support the hypothesis that excess extracellular dopamine, through action on an astrocyte-bound dopamine receptor, induces alterations in astrocytic morphology and molecular profile. Functional implications of such changes in drug abuse, a condition associated with elevated dopamine signaling, remain to be examined

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