Determining the Role of Spontaneous Adenosine as a Neuromodulator using Fast Scan Cyclic Voltammetry
Borgus, Jason, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Venton, Jill, AS-Chemistry, University of Virginia
Adenosine is an important signaling molecule in the central nervous system that modulates neurotransmitter release and can provide neuroprotective effects. Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique used with carbon fiber microelectrodes and is the primary method of measuring spontaneous adenosine release. Previous research has focused on the mechanisms of formation and release for spontaneous transient adenosine in males only. This thesis will investigate adenosine’s role as a neuromodulator and its variation in males and females using FSCV to measure these events in vivo.
Adenosine is introduced in Chapter 1, covering formation and release, metabolism, receptor interactions, and function in the central nervous system. The techniques used to measure adenosine are also briefly covered with the main focus being on FSCV, due to its rapid time scale. Data analysis innovations are discussed for the processing of both adenosine and dopamine data. There is also extensive review of the state of current adenosine research on rapid adenosine signaling, sex differences, adenosine/dopamine interactions, as well as predictions of where the field is heading.
Chapter 2 investigates sex differences in spontaneous transient adenosine in the prefrontal cortex, caudate-putamen, and hippocampus as well as during the four stages of estrous. These sex differences are characterized for the first time in vivo in the magnitude and frequency of transients, showing that not only are these differences present, but that they are heterogenous by brain region. When stage of estrous is examined, there is an increase in adenosine transient concentration during proestrus stage when progesterone and estradiol are elevated.
Chapters 3 and 4 investigates adenosine/dopamine signaling and characterized how these systems interact in real time. Chapter 3 describes simultaneous coincident release of adenosine and dopamine in the caudate-putamen. Dopamine release is determined to coincide with adenosine release 86% of the time, suggesting a common origin for about 1/3 of spontaneous adenosine transients. It is also observed that A2A receptors play a large role in regulating this release by measuring these events in global A1 and A2A receptor knockout mice. Chapter 4 examines dopamine’s ability to affect spontaneous adenosine release through the use of cocaine and haloperidol, drugs that restrict the uptake of dopamine and antagonize D2 receptors, respectively. Increased dopamine activity from these drugs causes a 20% reduction in the frequency of spontaneous dopamine transients, which is contrary to the expected effect.
Overall, this thesis highlights the need for a wider range of studies into sex differences in adenosine signaling and expands knowledge of adenosine/dopamine interactions in the caudate. In understanding these differences, better and more effective therapeutic treatments may be developed for diseases that currently have no good treatment options.
PHD (Doctor of Philosophy)
Electrochemistry, Adenosine, Neurochemistry