Abstract

Dopamine is thought of as the reward molecule of the brain, and while it does deal with reward, it is also associated with motivation and crucial for controlled movement. There are two main dopaminergic systems in the brain, the nigrostriatal system, which originates in the substantia nigra compacta and projects dopamine into the dorsal striatum; and the mesolimbic system, which originates in the ventral tegmental area and projects dopamine into the nucleus accumbens. While the mesolimbic dopamine system deals with motivation and reward, the nigrostriatal pathway underlies movement. Microglia are the immune cells of the brain and are incredibly dynamic. Chapter 1 introduces the nigrostriatal and mesolimbic dopamine systems, as well as microglia and the anti-parasitic drug ivermectin that also has allosteric modulating effects on nicotinic receptors and to the P2X4 receptor. Chapter 2 explains how ivermectin has dopaminergic effects in the dorsal striatum through the cholinergic system, independent of purinergic P2X4 receptors. Ivermectin also was able to increase dopamine release past L-Dopa alone, showing a potential avenue for treatment for Parkinson’s Disorder that should be studied further. Chapter 3 explores microglia in the context of dopamine release, and how they are activated by reactive oxygen species (ROS) and other activators, that also are affecting dopamine and ATP release. Chapter 4 looks at microglia activation in the context of both acute and repeated exposure to methamphetamine, showing that acute activation of microglia by methamphetamine is through ROS, and that after repeated exposure microglia have changed levels of activation and responsivity. Chapter 5 discusses the ramifications of these findings, as well as the limitations and future directions of these studies. Altogether these studies look at dopaminergic systems and how these systems are modulated by the anti-parasitic drug ivermectin and by immune activation through changes in microglia ramification and motility. These studies elucidate how immune activation affects dopaminergic systems and how dopaminergic systems results in immune activation.

Degree

PhD

College and Department

Life Sciences; Neuroscience

Rights

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