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Dissertation
Extracellular dopamine concentration control: computational model of feedback control
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2006
DOI:
https://doi.org/10.17918/etd-1160
Abstract
Dopamine is one of the central neurotransmitters; its homeostatic concentration is highly maintained through release, uptake, and feedback. The dopamine release is mediated both presynaptic and postsynaptic mechanisms. The extracellular dopamine concentration is regulated presynaptically by the dopamine transporter and dopamine autoreceptors. The postsynaptic control is mediated by postsynaptic dopamine receptors. Dopamine is the subject of a numerous experimental studies. As a result, a great deal of experimental data describing the components of dopamine system has been collected. This experimental data provides an excellent foundation for theoretical study to model complex dopamine system. The integration of a published experimental data in one theoretical model would be a valuable tool to describe the dopamine system and generate better understanding of the complex process of the dopamine concentration control. The object of this thesis was to develop a computational system describing the behavior of the complex extracellular dopamine concentration control system. There are two principal processes of the dopamine concentration control: uptake and negative feedback. The novelty of the presented modeling work is that it integrates the dopamine concentration control by uptake and negative feedback in a single computational model. The proposed model was used to evaluate the contribution of kinetic and feedback mechanisms to maintain low basal dopamine concentration; test the extracellular dopamine concentration outcomes under conditions of increased/decreased dopamine release; and predict changes in extracellular dopamine concentration under conditions equivalent to the presence of dopamine agonist/antagonists in the experimental dopamine system. Mathematical modeling was based on published pharmacokinetic parameters for dopamine uptake and receptor binding in rat striatum, and the computational data generated by thesis developed models. The mathematical modeling results showed that the computational extracellular dopamine concentration outcomes were consistent with the experimentally observed responses for the dopamine system. It was demonstrated computationally that both uptake by DAT and negative feedback mediated by receptors are necessary components to maintain a low extracellular dopamine concentration under basal conditions. The mathematical modeling showed the critical role of negative feedback to control stable extracellular dopamine concentration under conditions of increased/decreased dopamine release. The model generated results predicting extracellular dopamine concentration change under conditions equivalent to the presence of dopamine agonist/antagonist were in a good accordance with published experimental data. In addition to the mathematical modeling, programming, and computational analysis, the value of this work is demonstrated through its ability to illustrate how integration of published experimental and model simulated data provides an excellent foundation for computational theoretical research.
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Details
- Title
- Extracellular dopamine concentration control
- Creators
- Elena Koshkina - DU
- Contributors
- Leonid Hrebien (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Dana and David Dornsife School of Public Health; Epidemiology and Biostatistics; Drexel University
- Other Identifier
- 1160; 991014632581904721