Adenosine is a neuromodulator that regulates neurotransmission and cerebral blood flow but the nature of adenosine signaling in the brain is not well characterized. Most studies have described long-term effects of activation of adenosine receptors or changes in adenosine basal levels. Recently, rapid changes in adenosine have recently been discovered but the function of these transient changes is not known. The long-term goal of this lab is to develop new microelectrode methods to understand the rapid dynamics of neuromodulation in the brain. The objective of this project is to investigate the formation and function of transient adenosine signaling. This research is innovative because it challenges the paradigm that neuromodulation by adenosine is slow and advances technology by employing novel electrochemical sensors that overcome critical instrumentation barriers of slow temporal resolution and low sensitivity. The central hypothesis is that transient adenosine release occurs throughout the brain, is regulated by adenosine receptors, and functions to modulate neurotransmission and blood flow on a rapid time scale. This hypothesis will be tested with three Aims.
In Aim 1, electrically-stimulated adenosine release will be characterized in multiple brain regions. Pharmacological experiments will be performed in brain slices to test the mechanism of adenosine formation and the cellular sources in each region.
In Aim 2, spontaneous adenosine transients will be studied in anesthetized rats. These transients occur without drugs but are more frequent after administration of an A1 receptor antagonist. This study will provide a better understanding of how adenosine receptors regulate transient adenosine release. The goal of Aim 3 is to determine the function of transient adenosine release. The two hypotheses are that adenosine modulates neurotransmission and blood flow. The effect of exogenously applied adenosine on dopamine neurotransmission will be tested in brain slices. In addition, the effect of transient adenosine release on blood flow will be studied n vivo. This research will result in a better understanding of the formation and function of transien adenosine release. Adenosine based therapeutics have been proposed as possible treatments for neurological diseases such as pain, Parkinson disease, Huntington's disease, and drug abuse. New insight into the time course of neuromodulation could lead to better manipulation of transient adenosine changes to mitigate diseases caused by impaired neurotransmission.

Public Health Relevance

The proposed research is relevant to public health because the characterization of the formation and function of adenosine signaling in the brain is ultimately expected to lead to a better understanding of how drugs that act on the adenosine system can be used to treat diseases that result from impaired neurotransmission. Thus, the proposed research is relevant to the NIH's mission to develop fundamental knowledge about the nature of living systems that can be applied to reduce the burdens of illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS076875-01A1
Application #
8387636
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Stewart, Randall R
Project Start
2012-05-15
Project End
2017-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$309,352
Indirect Cost
$90,602
Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Trikantzopoulos, Elefterios; Yang, Cheng; Ganesana, Mallikarjunarao et al. (2016) Novel carbon-fiber microelectrode batch fabrication using a 3D-printed mold and polyimide resin. Analyst 141:5256-60
Yang, Cheng; Denno, Madelaine E; Pyakurel, Poojan et al. (2015) Recent trends in carbon nanomaterial-based electrochemical sensors for biomolecules: A review. Anal Chim Acta 887:17-37
Nguyen, Michael D; Ross, Ashley E; Ryals, Matthew et al. (2015) Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism. Pharmacol Res Perspect 3:e00189
Ross, Ashley E; Venton, B Jill (2015) Adenosine transiently modulates stimulated dopamine release in the caudate-putamen via A1 receptors. J Neurochem 132:51-60
Nguyen, Michael D; Venton, B Jill (2015) Fast-scan Cyclic Voltammetry for the Characterization of Rapid Adenosine Release. Comput Struct Biotechnol J 13:47-54
Zestos, Alexander G; Jacobs, Christopher B; Trikantzopoulos, Elefterios et al. (2014) Polyethylenimine carbon nanotube fiber electrodes for enhanced detection of neurotransmitters. Anal Chem 86:8568-75
Ross, Ashley E; Venton, B Jill (2014) Sawhorse waveform voltammetry for selective detection of adenosine, ATP, and hydrogen peroxide. Anal Chem 86:7486-93
Nguyen, Michael D; Lee, Scott T; Ross, Ashley E et al. (2014) Characterization of spontaneous, transient adenosine release in the caudate-putamen and prefrontal cortex. PLoS One 9:e87165
Ross, Ashley E; Nguyen, Michael D; Privman, Eve et al. (2014) Mechanical stimulation evokes rapid increases in extracellular adenosine concentration in the prefrontal cortex. J Neurochem 130:50-60
Pajski, Megan L; Venton, B Jill (2013) The mechanism of electrically stimulated adenosine release varies by brain region. Purinergic Signal 9:167-74

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