Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Tiffany A. Mathews

Abstract

STRIATAL DOPAMINE DYNAMICS UPON MANGANESE ACCUMULATION

by MADIHA KHALID

August 2013

Advisor: Dr. Tiffany Mathews

Major: Chemistry (Analytical)

Degree: Doctor of Philosophy

Although manganese (Mn) is fundamental for many biological processes, exposure to excess amounts leads to a neurological disorder termed manganism. Due to its symptomatic similarity to Parkinson's disease, as well its preferential accumulation in dopamine rich brain regions, alterations in the dopamine system are implicated in the onset of manganism. In my research, Mn overexposure is mimicked via subcutaneous administration of manganese chloride to C57BL/6 mice over the course of seven days using a protocol that has been shown to result in accumulation of Mn in the basal ganglia. The subsequent short and long term effects of this treatment on striatal dopamine function were evaluated 1, 7, and 21 days after treatment cessation. This work used a variety of complementary analytical methods to take a multifaceted approach in studying the Mn-treated animals. The first study used fast scan cyclic voltammetry, microdialysis, and tissue content analysis to characterize the dopamine system after the sub-acute treatment protocol. Behavioral tests were subsequently used to elucidate any phenotypic differences in the treated mice as compared to controls. Finally, pharmacological studies were conducted to test the hypothesis of intraneuronal dysfunction to explain the changes observed in the first study.

Overall, these findings revealed that the dopamine system in the striatum has lower extracellular levels of dopamine after Mn accumulation due to a functional defect in the release mechanism that is apparent within a week of treatment. Interestingly, most behavioral changes appear to manifest within 24 hours of treatment, when no dopamine change is observed, indicating the involvement of other neurotransmitter systems in the onset of motor deficits following Mn exposure. Finally, by methodically evaluating the quantity and functionality of dopamine vesicles at the axon terminal, we were able to provide evidence against the theory that dopamine release following Mn accumulation is due to an inability of the reserve pool of dopamine to mobilize to the terminal for release.

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