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A Computational Analysis of Dopamine Signaling at the Level of the Varicosity in Rodent Striatum

Rooney, Katherine Elizabeth
http://orcid.org/0000-0003-3665-7162
http://rave.ohiolink.edu/etdc/view?acc_num=osu1444656266

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Dopamine is a modulatory neurotransmitter that signals the saliency of the environmental input and is involved in the learned formation of responses. Dopamine neurons exist in twelve distinct nuclei throughout the brain, including the substantia nigra pars compacta and ventral tegmental area. The dopamine neurons in these two nuclei send projections to the extended striatum and frontal cortex. These dopamine neurons fire intrinsically at about 5 Hz, creating a baseline low nanomolar extracellular dopamine concentration in the striatum that can be measured using microdialysis. This suggests that baseline dopamine is essential for proper brain function. Dysfunction in the dopamine system leads to diseases such as Parkinson’s disease, addiction, schizophrenia and others. Currently, most of what we know about dopamine neurotransmission has been inferred from studies of other neurotransmitter systems. Because dopamine is a modulatory neurotransmitter, it is difficult to study dopamine signaling directly. Greater knowledge of dopamine release, re-uptake and receptor binding is vital in understanding the dopamine system as a whole and would provide valuable data to better treat the disease states associated with dopamine signaling. Herein, I will present research aimed at dissecting the parameters necessary to build a complete computer model of a dopamine varicosity to be used to better understand dopamine signaling. Chapter 1 introduces the extended striatum, the various neurons and inputs present in the striatum, and the dopamine system in this brain region. This chapter will focus on the characteristics of each and how each part of the striatum contributes to its overall function. Next, the chapter will discuss in detail the characteristics of the dopamine system as a whole including dopamine transmission, receptors and transporters involved in signaling and the modulatory function of the neurotransmitter. Chapter 2 presents the findings that dopamine release probability in the striatum is low. A computer simulation of a single dopamine release site was used to determine that less than one vesicle needs to be released per firing event to maintain the reported baseline extracellular concentration. The simulation model was also used to determine the amount of dopamine released to match published data of extracellular dopamine following electrical stimulation in vitro. The model suggests that the dopamine release induced by a single electrical stimulation may be as large as two vesicles. Our findings argue that dopamine release at any one particular varicosity is very low. Chapter 3 presents the findings of a literature review to determine the quantitative details of all aspects in the striatal complex. These details provided evidence that, while the striatum is typically thought of as a dopaminergic area, quantitatively dopamine is a minor system compared to others present in the striatum. While dopamine’s number of varicosities and receptors is lower than other systems, we also determined on which elements the receptors are located. We found that dopamine receptors have a diffuse presence. This suggests that dopamine has the capability to modulate the overall output of the striatum. Chapter 4 presents the findings of a computer simulation of dopamine receptor binding in the vicinity of a single release site under multiple conditions. Baseline, tonic dopamine release results in about half of the dopamine D2 receptors being occupied while no D1 receptors are occupied. A phasic burst of dopamine has little effect on receptor binding overall. A 30% increase in release probability is necessary to occupy a majority of D1 receptors. In this chapter we also explored the effects of a more complex simulation space and found that as the extracellular dopamine concentration increases, the location of D1 receptors becomes an important factor in receptor binding. Chapter 5 presents the findings of a computer simulation of dopamine receptor binding in the vicinity of a single release site in the presence of cocaine or amphetamine. The highest dose of cocaine tested (25 mg/kg) only increased D1 receptor binding 4% and almost saturated the D2 receptors in the model. Modeling of the presence of 2 mg/kg amphetamine led to a 13% increase in D1 receptor binding and fully saturated D2 receptors. Our findings argue that the effects of cocaine are more likely due to D2 receptor activation and some of amphetamine’s effects may be due to D1 receptor activation. Finally, chapter 6 summarizes the findings and significance of this dissertation research as well as provides future perspectives. In summary, this dissertation has: (I) summarized the function and overall organization of the striatal complex and dopamine system, (II) determined that dopamine release probability at any one particular release site is low, (III) determined the quantitative details of the elements within the striatum, (IV) studied dopamine D1 and D2 receptor binding under tonic and phasic firing conditions and (V) characterized receptor binding in the presence of the psychostimulants cocaine and amphetamine.
Lane Wallace (Advisor)
Anthony Young (Committee Member)
Howard Gu (Committee Member)
168 p.
Neurobiology; Pharmacology
Dopamine; Striatum; Rodent; computer model

Recommended Citations

Citations

  • Rooney, K. E. (2015). A Computational Analysis of Dopamine Signaling at the Level of the Varicosity in Rodent Striatum [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1444656266

    APA Style (7th edition)

  • Rooney, Katherine. A Computational Analysis of Dopamine Signaling at the Level of the Varicosity in Rodent Striatum. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1444656266.

    MLA Style (8th edition)

  • Rooney, Katherine. "A Computational Analysis of Dopamine Signaling at the Level of the Varicosity in Rodent Striatum." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1444656266

    Chicago Manual of Style (17th edition)

osu1444656266
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© 2015, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.