Striatal Dopamine Dynamics Upon Manganese Accumulation

<p>STRIATAL DOPAMINE DYNAMICS UPON MANGANESE ACCUMULATION </p> <p>by MADIHA KHALID</p> <p>August 2013</p> <p>Advisor: Dr. Tiffany Mathews</p> <p>Major: Chemistry (Analytical)</p> <p>Degree: Doctor of Philosophy</p> <p>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. </p> <p>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.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2013

Author dc:creator

• Khalid, Madiha

Contributors dc:contributor

• Tiffany A. Mathews

• behavior
• dopamine
• fast scan cyclic voltammetry
• manganese
• microdialysis
• striatum
• Analytical Chemistry
• Neurosciences

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/774

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1773