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.
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.
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|Johnson, Justin A; Rodeberg, Nathan T; Wightman, R Mark (2016) Failure of Standard Training Sets in the Analysis of Fast-Scan Cyclic Voltammetry Data. ACS Chem Neurosci 7:349-59|
|Kirkpatrick, D C; Walton, L R; Edwards, M A et al. (2016) Quantitative analysis of iontophoretic drug delivery from micropipettes. Analyst 141:1930-8|
|Kirkpatrick, Douglas C; Wightman, R Mark (2016) Evaluation of Drug Concentrations Delivered by Microiontophoresis. Anal Chem 88:6492-9|
|Dankoski, Elyse C; Carroll, Susan; Wightman, Robert Mark (2016) Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release. J Neurochem :|
|Fox, Megan E; Bucher, Elizabeth S; Johnson, Justin A et al. (2016) Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis. ACS Chem Neurosci 7:1681-1689|
|Kirkpatrick, D C; McKinney, C J; Manis, P B et al. (2016) Expanding neurochemical investigations with multi-modal recording: simultaneous fast-scan cyclic voltammetry, iontophoresis, and patch clamp measurements. Analyst 141:4902-11|
|Fox, Megan E; Rodeberg, Nathan T; Wightman, R Mark (2016) Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal. Neuropsychopharmacology :|
|Fox, Megan E; Mikhailova, Maria A; Bass, Caroline E et al. (2016) Cross-hemispheric dopamine projections have functional significance. Proc Natl Acad Sci U S A 113:6985-90|
|Rodeberg, Nathan T; Johnson, Justin A; Cameron, Courtney M et al. (2015) Construction of Training Sets for Valid Calibration of in Vivo Cyclic Voltammetric Data by Principal Component Analysis. Anal Chem 87:11484-91|
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