To respond to a constantly changing world, an organism needs adaptive processes to function appropriately. A group of neuronal circuits that form the brain "reward" pathway is activated during goal-directed behaviors. Information processing within this circuit guides the organism to respond optimally for reward acquisition. Dopamine has long been identified as an important neurotransmitter in this pathway, and this concept is given strong support by our own findings using tools that were developed with the support of the existing grant. Similarly, the organism requires an opposing set of circuitry responsive to aversive events and stimuli that predict them. Although the aversive pathways are less well characterized, increased norepinephrine neurotransmission has been implicated in such behaviors, a concept supported by our own research. The involvement of dopamine and norepinephrine in such critical circuits is the central reason that their imbalance has been implicated in a variety of conditions ranging from mental disorders such as schizophrenia and depression to behavioral disorders such as drug abuse and obesity. The goal of the proposed research is to develop tools to evaluate catecholamine neurotransmission within the brain on a subsecond time scale and with submillimeter time resolution. We will use fast-scan cyclic voltammetry at carbon-fiber microelectrodes for measurements of catecholamine release from neurons. We will develop and modify ancillary techniques to reveal the receptor-mediated actions of these substances following their release. This proposal has the following aims. 1. Characterize the spatial and temporal characteristics of iontophoresis. During the previous project period we characterized iontophoresis and revealed that it has a major contribution from electroosmosis. Our approach enables delivery of known amounts of reagents into the extracellular space. A mass-transport based theory of the ejection rate and its spatial distribution is required to understand its effects on nearby receptors. 2. Characterize the spatially distributed chemical and electrical information that arises from neurotransmitter release and the changes in electrical activity that are evoked by its release within the brain. We have developed instrumentation that enables the electrical activity of neurons to be measured simultaneously with measurements of neurotransmitter release. Here we propose to evaluate this electrochemical-electrophysiological system coupled to iontophoresis using a well characterized brain slice preparation. 3. Characterize the effects of dopamine neurotransmission on its target neurons in the nucleus accumbens in response to rewarding stimuli. With the use of the new iontophoresis and electrophysiological approaches that are coupled to our electrochemical techniques for detecting dopamine, we will explore the ways in which dopamine affects the different types of target neurons. 4. Characterize norepinephrine neurotransmission in response to rewarding and aversive stimuli. Our iontophoretic, electrophysiological, and electrochemical approaches will be used to understand this release activity on processing of stimuli.

Public Health Relevance

New approaches employing electrochemical principles will be devised to measure in the brain the dynamic concentrations of catecholamine neurotransmitters. These tools will be used to monitor the roles of dopamine and norepinephrine during reward based behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010900-16
Application #
8670705
Study Section
Special Emphasis Panel (BNVT)
Program Officer
Pilotte, Nancy S
Project Start
1997-04-15
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
16
Fiscal Year
2014
Total Cost
$341,164
Indirect Cost
$111,164
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Hashemi, Parastoo; Walsh, Paul L; Guillot, Thomas S et al. (2011) Chronically Implanted, Nafion-Coated Ag/AgCl Reference Electrodes for Neurochemical Applications. ACS Chem Neurosci 2:658-666
Keithley, Richard B; Wightman, R Mark (2011) Assessing principal component regression prediction of neurochemicals detected with fast-scan cyclic voltammetry. ACS Chem Neurosci 2:514-525

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