@article{forderhase_kimble_sombers_2023, title={A Student Perspective on the 18th Monitoring Molecules in Neuroscience Meeting in Lyon}, volume={6}, ISSN={["1948-7193"]}, DOI={10.1021/acschemneuro.3c00271}, abstractNote={After being postponed twice due to the global COVID-19 pandemic, approximately 200 scientists gathered in Lyon, France, in late June 2022 for the 18th Biennial Monitoring Molecules in Neuroscience (MMiN) Research Conference. Although there were unprecedented challenges involved with coordinating the 18th MMiN conference, the meeting was a huge success. The meeting provided a wonderful opportunity for young neuroscientists to network and learn about the current state of molecular monitoring in neuroscience research. The topics spanned advancements in well-established analytical techniques to novel method development. Some of the noteworthy techniques expediting our understanding of circuit-level neurochemical function include multiplexed detection of numerous neurochemicals, well-established sensors leveraging enzymes and other biologic components, and the development of diverse, customizable genetically encoded sensors.}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Forderhase, Alexandra G. and Kimble, Laney C. and Sombers, Leslie A.}, year={2023}, month={Jun} }
 @article{de alwis_denison_shah_mccarty_sombers_2023, title={Exploiting Microelectrode Geometry for Comprehensive Detection of Individual Exocytosis Events at Single Cells}, volume={8}, ISSN={["2379-3694"]}, DOI={10.1021/acssensors.3c00884}, abstractNote={Carbon fiber microelectrodes are commonly used for real-time monitoring of individual exocytosis events at single cells. Since the nature of an electrochemical signal is fundamentally governed by mass transport to the electrode surface, microelectrode geometry can be exploited to achieve precise and accurate measurements. Researchers traditionally pair amperometric measurements of exocytosis with a ∼10-μm diameter, disk microelectrode in an "artificial synapse" configuration to directly monitor individual release events from single cells. Exocytosis is triggered, and released molecules diffuse to the "post-synaptic" electrode for oxidation. This results in a series of distinct current spikes corresponding to individual exocytosis events. However, it remains unclear how much of the material escapes detection. In this work, the performance of 10- and 34-μm diameter carbon fiber disk microelectrodes was directly compared in monitoring exocytosis at single chromaffin cells. The 34-μm diameter electrode was more sensitive to catecholamines and enkephalins than its traditional, 10-μm diameter counterpart, and it more effectively covered the entire cell. As such, the larger sensor detected more exocytosis events overall, as well as a larger quantal size, suggesting that the traditional tools underestimate the above measurements. Both sensors reliably measured l-DOPA-evoked changes in quantal size, and both exhibited diffusional loss upon adjustment of cell-electrode spacing. Finite element simulations using COMSOL support the improved collection efficiency observed using the larger sensor. Overall, this work demonstrates how electrode geometry can be exploited for improved detection of exocytosis events by addressing diffusional loss─an often-overlooked source of inaccuracy in single-cell measurements.}, journal={ACS SENSORS}, author={De Alwis, A. Chathuri and Denison, J. Dylan and Shah, Ruby and McCarty, Gregory S. and Sombers, Leslie A.}, year={2023}, month={Aug} }
 @article{mccarty_dunaway_denison_sombers_2022, title={Neurotransmitter Readily Escapes Detection at the Opposing Microelectrode Surface in Typical Amperometric Measurements of Exocytosis at Single Cells}, volume={6}, ISSN={["1520-6882"]}, DOI={10.1021/acs.analchem.2c00060}, abstractNote={For decades, carbon-fiber microelectrodes have been used in amperometric measurements of neurotransmitter release at a wide variety of cell types, providing a tremendous amount of valuable information on the mechanisms involved in dense-core vesicle fusion. The electroactive molecules that are released can be detected at the opposing microelectrode surface, allowing for precise quantification as well as detailed kinetic information on the stages of neurotransmitter release. However, it remains unclear how much of the catecholamine that is released into the artificial synapse escapes detection. This work examines two separate mechanisms by which released neurotransmitter goes undetected in a typical amperometric measurement. First, diffusional loss is assessed by monitoring exocytosis at single bovine chromaffin cells using carbon-fiber microelectrodes fabricated in a recessed (cavity) geometry. This creates a microsampling vial that minimizes diffusional loss of analyte prior to detection. More molecules were detected per exocytotic release event when using a recessed cavity sensor as compared to the conventional configuration. In addition, pharmacological inhibition of the norepinephrine transporter (NET), which serves to remove catecholamine from the extracellular space, increased both the size and the time course of individual amperometric events. Overall, this study characterizes distinct physical and biological mechanisms by which released neurotransmitter escapes detection at the opposing microelectrode surface, while also revealing an important role for the NET in “presynaptic” modulation of neurotransmitter release.}, journal={ANALYTICAL CHEMISTRY}, author={McCarty, Gregory S. and Dunaway, Lars E. and Denison, J. Dylan and Sombers, Leslie A.}, year={2022}, month={Jun} }
 @article{sombers_patisaul_2022, title={Virtual Issue: Neurotoxicology}, volume={13}, ISSN={["1948-7193"]}, DOI={10.1021/acschemneuro.2c00375}, abstractNote={ADVERTISEMENT RETURN TO ISSUEEditorialNEXTVirtual Issue: NeurotoxicologyLeslie A. SombersLeslie A. SombersMore by Leslie A. Sombers and Heather B. PatisaulHeather B. PatisaulMore by Heather B. PatisaulCite this: ACS Chem. Neurosci. 2022, 13, 15, 2238–2239Publication Date (Web):August 3, 2022Publication History Received2 July 2022Published online3 August 2022Published inissue 3 August 2022https://doi.org/10.1021/acschemneuro.2c00375Copyright © Published 2022 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views348Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-AlertsSUBJECTS:Bacteria,Central nervous system,Diseases and disorders,Environmental pollution,Toxicology Get e-Alerts}, number={15}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Sombers, Leslie A. and Patisaul, Heather B.}, year={2022}, month={Aug}, pages={2238–2239} }
 @inbook{meunier_sombers_2021, place={New York}, series={Neuromethods}, title={Fast-Scan for In Vivo Measurements of Neurochemical Dynamics}, ISBN={9781071611456 9781071611463}, ISSN={0893-2336 1940-6045}, url={http://dx.doi.org/10.1007/978-1-0716-1146-3_5}, DOI={10.1007/978-1-0716-1146-3_5}, abstractNote={Background-subtracted fast-scan cyclic voltammetry (FSCV) is an electrochemical method that enables the monitoring of neurochemical dynamics in brain tissue with sub-second resolution. FSCV provides information regarding the magnitude and the time course of neurochemical release and reuptake, with additional qualitative information that can permit analyte identification. When performed in awake animals, this voltammetric approach can provide remarkable information regarding the molecular mechanisms that underlie goal-directed behavior and associative learning. In addition, FSCV can be used to quantify the impact of pharmacological agents on neurotransmitter kinetics. This chapter contains an explicit description of how to make these measurements in animals (rats) as well as critical considerations when interpreting FSCV data.}, booktitle={The Brain Reward System}, publisher={Humana}, author={Meunier, Carl J. and Sombers, Leslie A.}, editor={Fakhoury, M.Editor}, year={2021}, pages={93–123}, collection={Neuromethods} }
 @article{roberts_mitchell_dunaway_mccarty_sombers_2020, title={Carbon-Fiber Nanoelectrodes for Real-Time Discrimination of Vesicle Cargo in the Native Cellular Environment}, volume={14}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/acsnano.9b07318}, DOI={10.1021/acsnano.9b07318}, abstractNote={Carbon-fiber microelectrodes have proven to be an indispensable tool for monitoring exocytosis events using amperometry. When positioned adjacent to a cell, a traditional microdisc electrode is well suited for quantification of discrete exocytotic release events. However, the size of the electrode does not allow for intracellular electrochemical measurements, and the amperometric approach cannot distinguish between the catecholamines that are released. In this work, carbon nanoelectrodes were developed to permit selective electrochemical sampling of nanoscale vesicles in the cell cytosol. Classical voltammetric techniques and electron microscopy were used to characterize the nanoelectrodes, which were ∼5 μm long and sharpened to a nanometer-scale tip that could be wholly inserted into individual neuroendocrine cells. The nanoelectrodes were coupled with fast-scan cyclic voltammetry to distinguish secretory granules containing epinephrine from other catecholamine-containing granules encountered in the native cellular environment. Both vesicle subtypes were encountered in most cells, despite prior demonstration of populations of chromaffin cells that preferentially release one of these catecholamines. There was substantial cell-to-cell variability in relative epinephrine content, and vesicles containing epinephrine generally stored more catecholamine than the other vesicles. The carbon nanoelectrode technology thus enabled analysis of picoliter-scale biological volumes, revealing key differences between chromaffin cells at the level of the dense-core granule.}, number={3}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Roberts, James G. and Mitchell, Edwin C. and Dunaway, Lars E. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2020}, month={Feb}, pages={2917–2926} }
 @article{meunier_denison_mccarty_sombers_2020, title={Interpreting Dynamic Interfacial Changes at Carbon Fiber Microelectrodes Using Electrochemical Impedance Spectroscopy}, volume={36}, ISSN={0743-7463 1520-5827}, url={http://dx.doi.org/10.1021/acs.langmuir.9b03941}, DOI={10.1021/acs.langmuir.9b03941}, abstractNote={Carbon-fiber microelectrodes are instrumental tools in neuroscience used for the electroanalysis of neurochemical dynamics and recordings of neural activity. However, performance is variable and dependent on fabrication strategies, the biological response to implantation, and the physical and chemical composition of the recording environment. This presents an analytical challenge, as electrode performance is difficult to quantitatively assess in situ, especially when electrodes are permanently implanted or cemented in place. We previously reported that electrode impedance directly impacts electrochemical performance for molecular sensing. In this work, we investigate the impacts of individual components of the electrochemical system on impedance. Equivalent circuit models for glass- and silica-insulated carbon-fiber microelectrodes were determined using electrochemical impedance spectroscopy (EIS). The models were validated based on the ability to assign individual circuit elements to physical properties of the electrochemical system. Investigations were performed to evaluate the utility of the models in providing feedback on how changes in ionic strength and carbon fiber material alter impedance properties. Finally, EIS measurements were used to investigate the electrode/solution interface prior to, during, and following implantation in live brain tissue. A significant increase in impedance and decrease in capacitance occur during tissue exposure and persist following implantation. Electrochemical conditioning, which occurs continually during fast-scan cyclic voltammetry recordings, etches and renews the carbon surface, mitigating these effects. Overall, the results establish EIS as a powerful method for characterization of carbon-fiber microelectrodes, providing unprecedented insight into how real-world factors affect the electrode/solution interface.}, number={15}, journal={Langmuir}, publisher={American Chemical Society (ACS)}, author={Meunier, Carl J. and Denison, J. Dylan and McCarty, Gregory S. and Sombers, Leslie A.}, year={2020}, month={Mar}, pages={4214–4223} }
 @article{forderhase_styers_lee_sombers_2020, title={Simultaneous voltammetric detection of glucose and lactate fluctuations in rat striatum evoked by electrical stimulation of the midbrain}, volume={412}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-020-02797-0}, abstractNote={Glucose and lactate provide energy for cellular function in the brain and serve as an important carbon source in the synthesis of a variety of biomolecules. Thus, there is a critical need to quantitatively monitor these molecules in situ on a time scale commensurate with neuronal function. In this work, carbon-fiber microbiosensors were coupled with fast-scan cyclic voltammetry to monitor glucose and lactate fluctuations at a discrete site within rat striatum upon electrical stimulation of the midbrain projection to the region. Systematic variation of stimulation parameters revealed the distinct dynamics by which glucose and lactate responded to the metabolic demand of synaptic function. Immediately upon stimulation, extracellular glucose and lactate availability rapidly increased. If stimulation was sufficiently intense, concentrations then immediately fell below baseline in response to incurred metabolic demand. The dynamics were dependent on stimulation frequency, such that more robust fluctuations were observed when the same number of pulses was delivered at a higher frequency. The rates at which glucose was supplied to, and depleted from, the local recording region were dependent on stimulation intensity, and glucose dynamics led those of lactate in response to the most substantial stimulations. Glucose fluctuated over a larger concentration range than lactate as stimulation duration increased, and glucose fell further from baseline concentrations. These real-time measurements provide an unprecedented direct comparison of glucose and lactate dynamics in response to metabolic demand elicited by neuronal activation.}, number={24}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Forderhase, Alexandra G. and Styers, Hannah C. and Lee, Christie A. and Sombers, Leslie A.}, year={2020}, month={Sep}, pages={6611–6624} }
 @article{meunier_mccarty_sombers_2019, title={Drift Subtraction for Fast-Scan Cyclic Voltammetry Using Double-Waveform Partial-Least-Squares Regression}, volume={91}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/acs.analchem.9b01083}, DOI={10.1021/acs.analchem.9b01083}, abstractNote={Background-subtracted fast-scan cyclic voltammetry (FSCV) provides a method for detecting molecular fluctuations with high spatiotemporal resolution in the brain of awake and behaving animals. The rapid scan rates generate large background currents that are subtracted to reveal changes in analyte concentration. Although these background currents are relatively stable, small changes do occur over time. These changes, referred to as electrochemical drift, result in background-subtraction artifacts that constrain the utility of FSCV, particularly when quantifying chemical changes that gradually occur over long measurement times (minutes). The voltammetric features of electrochemical drift are varied and can span the entire potential window, potentially obscuring the signal from any targeted analyte. We present a straightforward method for extending the duration of a single FSCV recording window. First, we have implemented voltammetric waveforms in pairs that consist of a smaller triangular sweep followed by a conventional voltammetric scan. The initial, abbreviated waveform is used to capture drift information that can serve as a predictor for the contribution of electrochemical drift to the subsequent full voltammetric scan using partial-least-squares regression (PLSR). This double-waveform partial-least-squares regression (DW-PLSR) paradigm permits reliable subtraction of the drift component to the voltammetric data. Here, DW-PLSR is used to improve quantification of adenosine, dopamine, and hydrogen peroxide fluctuations occurring >10 min from the initial background position, both in vitro and in vivo. The results demonstrate that DW-PLSR is a powerful tool for evaluating and interpreting both rapid (seconds) and gradual (minutes) chemical changes captured in FSCV recordings over extended durations.}, number={11}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Meunier, Carl J. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2019}, month={May}, pages={7319–7327} }
 @article{smith_gosrani_lee_mccarty_sombers_2018, title={Carbon-Fiber Microbiosensor for Monitoring Rapid Lactate Fluctuations in Brain Tissue Using Fast-Scan Cyclic Voltammetry}, volume={90}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/acs.analchem.8b03694}, DOI={10.1021/acs.analchem.8b03694}, abstractNote={Recent studies have described a role for lactate in brain energy metabolism and energy formation, challenging the conventional view that glucose is the principle energy source for brain function. To date, lactate dynamics in the brain are largely unknown, limiting insight into function. We addressed this by developing and characterizing a lactate oxidase-modified carbon-fiber microelectrode coupled with fast-scan cyclic voltammetry. This new tool boasts a sensitivity for lactate of 22 ± 1 nA·mM–1 and LOD of 7.0 ± 0.7 μM. The approach has enabled detection of rapid lactate fluctuations with unprecedented spatiotemporal resolution as well as excellent stability, selectivity, and sensitivity. The technology was characterized both in vitro and in vivo at discrete recording sites in rat striatum. We provide evidence that striatal lactate availability increases biphasically in response to electrical stimulation of the dopaminergic midbrain in the anesthetized rat. This new tool for real-time detection of lactate dynamics promises to improve understanding of how lactate availability underscores neuronal function and dysfunction.}, number={21}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Smith, Samantha K. and Gosrani, Saahj P. and Lee, Christie A. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2018}, month={Oct}, pages={12994–12999} }
 @article{calhoun_meunier_lee_mccarty_sombers_2018, title={Characterization of a Multiple-Scan-Rate Voltammetric Waveform for Real-Time Detection of Met-Enkephalin}, volume={10}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/acschemneuro.8b00351}, DOI={10.1021/acschemneuro.8b00351}, abstractNote={Opioid peptides are critically involved in a variety of physiological functions necessary for adaptation and survival, and as such, understanding the precise actions of endogenous opioid peptides will aid in identification of potential therapeutic strategies to treat a variety of disorders. However, few analytical tools are currently available that offer both the sensitivity and spatial resolution required to monitor peptidergic concentration fluctuations in situ on a time scale commensurate with that of neuronal communication. Our group has developed a multiple-scan-rate waveform to enable real-time voltammetric detection of tyrosine containing neuropeptides. Herein, we have evaluated the waveform parameters to increase sensitivity to methionine-enkephalin (M-ENK), an endogenous opioid neuropeptide implicated in pain, stress, and reward circuits. M-ENK dynamics were monitored in adrenal gland tissue, as well as in the dorsal striatum of anesthetized and freely behaving animals. The data reveal cofluctuations of catecholamine and M-ENK in both locations and provide measurements of M-ENK dynamics in the brain with subsecond temporal resolution. Importantly, this work also demonstrates how voltammetric waveforms can be customized to enhance detection of specific target analytes, broadly speaking.}, number={4}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Calhoun, S. E. and Meunier, C. J. and Lee, C. A. and McCarty, G. S. and Sombers, L. A.}, year={2018}, month={Dec}, pages={2022–2032} }
 @article{meunier_mitchell_roberts_toups_mccarty_sombers_2018, title={Electrochemical Selectivity Achieved Using a Double Voltammetric Waveform and Partial Least Squares Regression: Differentiating Endogenous Hydrogen Peroxide Fluctuations from Shifts in pH}, volume={90}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/ACS.ANALCHEM.7B03717}, DOI={10.1021/ACS.ANALCHEM.7B03717}, abstractNote={Hydrogen peroxide (H2O2) is a reactive oxygen species that serves as an important signaling molecule in normal brain function. At the same time, excessive H2O2 concentrations contribute to myriad pathological consequences resulting from oxidative stress. Studies to elucidate the diverse roles that H2O2 plays in complex biological environments have been hindered by the lack of robust methods for probing dynamic H2O2 fluctuations in living systems with molecular specificity. Background-subtracted fast-scan cyclic voltammetry at carbon-fiber microelectrodes provides a method of detecting rapid H2O2 fluctuations with high temporal and spatial resolution in brain tissue. However, H2O2 fluctuations can be masked by local changes in pH (ΔpH), because the voltammograms for these species can have significant peak overlap, hindering quantification. We present a method for removing ΔpH-related contributions from complex voltammetric data. By employing two distinct potential waveforms per scan, one in which H2O2 is electrochemically silent and a second in which both ΔpH and H2O2 are redox active, a clear distinction between H2O2 and ΔpH signals is established. A partial least-squares regression (PLSR) model is used to predict the ΔpH signal and subtract it from the voltammetric data. The model has been validated both in vitro and in vivo using k-fold cross-validation. The data demonstrate that the double waveform PLSR model is a powerful tool that can be used to disambiguate and evaluate naturally occurring H2O2 fluctuations in vivo.}, number={3}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Meunier, Carl J. and Mitchell, Edwin C. and Roberts, James G. and Toups, Jonathan V. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2018}, month={Jan}, pages={1767–1776} }
 @misc{roberts_sombers_2018, title={Fast-Scan Cyclic Voltammetry: Chemical Sensing in the Brain and Beyond}, volume={90}, ISSN={["1520-6882"]}, DOI={10.1021/acs.analchem.7b04732}, abstractNote={In this review we describe the electroanalytical method known as fast-scan cyclic voltammetry (FSCV), how it has advanced over the years, and in what way(s) it is impacting other sciences. To begin, a brief history will be discussed. The various means to enhance chemical selectivity by manipulating the applied potential will be covered. Some limitations of this electroanalytical method will be highlighted to inform and provide clarity to the scientific community. The intent is to seek out effective solutions to the difficult problems associated with the technique, so that the field will continue to flourish. Rounding out the review, the utility and adaptability of this powerful bioanalytical technique will be addressed, as new frontiers of research are established for FSCV outside the scope of the neuroscience community.}, number={1}, journal={ANALYTICAL CHEMISTRY}, author={Roberts, James G. and Sombers, Leslie A.}, year={2018}, month={Jan}, pages={490–504} }
 @article{gómez-a_shnitko_barefoot_brightbill_sombers_nicola_robinson_2018, title={Local μ-Opioid Receptor Antagonism Blunts Evoked Phasic Dopamine Release in the Nucleus Accumbens of Rats}, volume={10}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/acschemneuro.8b00437}, DOI={10.1021/acschemneuro.8b00437}, abstractNote={μ-opioid receptors (MORs) in the nucleus accumbens (NAc) can regulate reward-related behaviors that are dependent on mesolimbic dopamine, but the precise mechanism of this MOR regulation is unknown. We hypothesized that MORs within the NAc core regulate dopamine release. Specifically, we infused the MOR antagonist CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2) into the NAc core while dopamine release was evoked by electrical stimulation of the ventral tegmental area and measured by fast-scan cyclic voltammetry. We report that CTAP dose-dependently inhibited evoked dopamine release, with full blockade achieved with the 8 μg infusion. In contrast, evoked dopamine release increased after nomifensine infusion and was unchanged after vehicle infusion. These findings demonstrate profound local control of dopamine release by MORs within the NAc core, which has implications for regulation of reward processing.}, number={4}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Gómez-A, Alexander and Shnitko, Tatiana A. and Barefoot, Haley M. and Brightbill, Eleanor L. and Sombers, Leslie A. and Nicola, Saleem M. and Robinson, Donita L.}, year={2018}, month={Nov}, pages={1935–1940} }
 @article{spanos_xie_gras-najjar_white_sombers_2018, title={NMDA Receptor-Dependent Cholinergic Modulation of Mesolimbic Dopamine Cell Bodies: Neurochemical and Behavioral Studies}, volume={10}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/acschemneuro.8b00492}, DOI={10.1021/acschemneuro.8b00492}, abstractNote={Substance abuse disorders are devastating, costly, and difficult to treat. Identifying the neurochemical mechanisms underlying reinforcement promises to provide critical information in the development of effective treatments. Several lines of evidence suggest that striatal dopamine (DA) release serves as a teaching signal in reinforcement learning, and that shifts in DA release from the primary reward to reward-predicting stimuli play a critical role in the self-administration of both natural and non-natural rewards. However, far less is known about the reinforcing effects of motivationally neutral sensory stimuli, or how these signals can facilitate self-administration behavior. Thus, we trained rats (n = 7) to perform a visual stimulus-induced instrumental task, which involved lever pressing for activation of a stimulus light. We then microinfused vehicle (phosphate buffered saline), carbachol (acetylcholine receptor agonist), or carbachol in the presence of an N-methyl-d-aspartate (NMDA) receptor-specific drug (NMDA itself, or the antagonist, AP5) into the ventral tegmental area (VTA). This enabled us to directly evaluate how chemical modulation of dopamine cell bodies affects the instrumental behavior, as well as the nature of extracellular dopamine transients recorded in the nucleus accumbens shell (NAc shell) using fast-scan cyclic voltammetry (FSCV). Intra-VTA infusion of carbachol enhanced the magnitude and frequency of dopamine transients in the NAc shell and potentiated active lever responding without altering inactive lever responding, as compared to infusion of vehicle. Coinfusion of carbachol with AP5 abolished dopamine transients recorded in the NAc and attenuated active lever responding without altering inactive lever responding. Finally, coadministration of carbachol and NMDA into the VTA restored both lever pressing and dopaminergic signals recorded in the striatum. Together, these results suggest that acetylcholine and glutamate synergistically act at dopamine cells in the VTA to modulate VTA-NAc shell dopaminergic output, and this underlies motivation to lever press for a motivationally neutral visual stimulus.}, number={3}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Spanos, Marina and Xie, Xiaohu and Gras-Najjar, Julie and White, Stephanie C. and Sombers, Leslie A.}, year={2018}, month={Nov}, pages={1497–1505} }
 @article{smith_lugo-morales_tang_gosrani_lee_roberts_morton_mccarty_khan_sombers_2018, title={Quantitative Comparison of Enzyme Immobilization Strategies for Glucose Biosensing in Real-Time Using Fast-Scan Cyclic Voltammetry Coupled with Carbon-Fiber Microelectrodes}, volume={19}, ISSN={1439-4235}, url={http://dx.doi.org/10.1002/CPHC.201701235}, DOI={10.1002/CPHC.201701235}, abstractNote={Abstract Electrochemical monitoring of non‐electroactive species requires a biosensor that is stable and selective, with sensitivity to physiological concentrations of targeted analytes. We have combined glucose oxidase‐modified carbon‐fiber microelectrodes with fast‐scan cyclic voltammetry for real‐time measurements of glucose fluctuations in brain tissue. Work presented herein quantitatively compares three approaches to enzyme immobilization on the microelectrode surface—physical adsorption, hydrogel entrapment, and entrapment in electrospun nanofibers. The data suggest that each of these methods can be used to create functional microbiosensors. Immobilization of glucose oxidase by physical adsorption generates a biosensor with poor sensitivity to glucose and unstable performance. Entrapment of glucose oxidase in poly(vinyl alcohol) nanofibers generates microbiosensors that are effective for glucose measurements over a large linear range, and that may be particularly useful when targeting glucose concentrations in excess of 3 m m , such as in blood. Hydrogel entrapment is the most effective in terms of sensitivity and stability. These microbiosensors can be used for simultaneous monitoring of glucose and dopamine in real time. The findings outlined herein should be applicable to other oxidase enzymes, and thus they are broadly important for the development of new tools for real‐time measurements of fluctuating molecules that are not inherently electroactive.}, number={10}, journal={ChemPhysChem}, publisher={Wiley}, author={Smith, Samantha K. and Lugo-Morales, Leyda Z. and Tang, C. and Gosrani, Saahj P. and Lee, Christie A. and Roberts, James G. and Morton, Stephen W. and McCarty, Gregory S. and Khan, Saad A. and Sombers, Leslie A.}, year={2018}, month={Feb}, pages={1197–1204} }
 @article{lee_qi_amos_blanton_mccarty_sombers_2018, title={Reducing Data Density in Fast-Scan Cyclic Voltammetry Measurements of Dopamine Dynamics}, volume={165}, ISSN={0013-4651 1945-7111}, url={http://dx.doi.org/10.1149/2.0081812jes}, DOI={10.1149/2.0081812jes}, number={12}, journal={Journal of The Electrochemical Society}, publisher={The Electrochemical Society}, author={Lee, Christie A. and Qi, Lingjiao and Amos, Alison and Blanton, Kristen and McCarty, Gregory S. and Sombers, Leslie A.}, year={2018}, pages={G3042–G3050} }
 @article{meunier_roberts_mccarty_sombers_2017, title={Background Signal as an in Situ Predictor of Dopamine Oxidation Potential: Improving Interpretation of Fast-Scan Cyclic Voltammetry Data}, volume={8}, ISSN={["1948-7193"]}, DOI={10.1021/acschemneuro.6b00325}, abstractNote={Background-subtracted fast-scan cyclic voltammetry (FSCV) has emerged as a powerful analytical technique for monitoring subsecond molecular fluctuations in live brain tissue. Despite increasing utilization of FSCV, efforts to improve the accuracy of quantification have been limited due to the complexity of the technique and the dynamic recording environment. It is clear that variable electrode performance renders calibration necessary for accurate quantification; however, the nature of in vivo measurements can make conventional postcalibration difficult, or even impossible. Analyte-specific voltammograms and scaling factors that are critical for quantification can shift or fluctuate in vivo. This is largely due to impedance changes, and the effects of impedance on these measurements have not been characterized. We have previously reported that the background current can be used to predict electrode-specific scaling factors in situ. In this work, we employ model circuits to investigate the impact of impedance on FSCV measurements. Additionally, we take another step toward in situ electrode calibration by using the oxidation potential of quinones on the electrode surface to accurately predict the oxidation potential for dopamine at any point in an electrochemical experiment, as both are dependent on impedance. The model, validated both in adrenal slice and live brain tissue, enables information encoded in the shape of the background voltammogram to determine electrochemical parameters that are critical for accurate quantification. This improves data interpretation and provides a significant next step toward more automated methods for in vivo data analysis.}, number={2}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Meunier, Carl J. and Roberts, James G. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2017}, month={Feb}, pages={411–419} }
 @inproceedings{sombers_wilson_mason_lee_2017, title={Real-Time Striatal Measurements of Oxidative Stress and Dopamine in the Dyskinetic Rat during Chronic L-DOPA Treatment for Parkinson's Disease}, DOI={10.1149/MA2017-02/55/2303}, abstractNote={Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the preferential loss of dopaminergic neurons stemming from the substantia nigra pars compacta and innervating the dorsal striatum. The substantial decreases in striatal dopamine (DA) result in devastating hypokinetic movements and motor disturbances. Increased generation of reactive oxygen species, such as hydrogen peroxide (H 2 O 2 ), is also thought to contribute to Parkinsonian symptoms. However, the precise role of H 2 O 2 in the initiation, progression, and maintenance of the disease remains unclear, as reactive oxygen species are difficult to monitor in brain tissue. Further, several lines of evidence suggest that the standard treatment strategy of dopaminergic replacement therapy via administration of Levodopa (L-DOPA; L-3,4 dihydroxyphenylalanine) may serve to increase oxidative stress and potentiate cell death. We are investigating how striatal H 2 O 2 and DA dynamics underlie behavioral changes that result from chronic L-DOPA administration in a rodent model of PD (unilateral 6-OHDA lesion) using fast-scan cyclic voltammetry, an electrochemical technique that affords precise spatial and temporal resolution, as well as selective detection of these neurochemicals. Specifically, carbon-fiber microelectrodes are used to simultaneously quantify rapid H 2 O 2 and DA fluctuations at single recording sites in the dorsal striatum over several weeks of L-DOPA administration. The chemical fluctuations are correlated with behavioral abnormalities that develop over the course of treatment. These studies are advancing our understanding of how oxidative stress modulates nigrostriatal DA signaling, and are demonstrating how these signals correspond with dyskinetic movements in the treatment of PD.}, booktitle={ECS Meeting Abstracts}, publisher={IOP Publishing}, author={Sombers, L.A. and Wilson, L.R. and Mason, C.F. and Lee, C.A.}, year={2017}, month={Sep}, pages={MA2017–02 2303} }
 @article{wilson_panda_schmidt_sombers_2017, title={Selective and Mechanically Robust Sensors for Electrochemical Measurements of Real-Time Hydrogen Peroxide Dynamics in Vivo}, volume={90}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/acs.analchem.7b03770}, DOI={10.1021/acs.analchem.7b03770}, abstractNote={Hydrogen peroxide (H2O2) is an endogenous molecule that plays several important roles in brain function: it is generated in cellular respiration, serves as a modulator of dopaminergic signaling, and its presence can indicate the upstream production of more aggressive reactive oxygen species (ROS). H2O2 has been implicated in several neurodegenerative diseases, including Parkinson’s disease (PD), creating a critical need to identify mechanisms by which H2O2 modulates cellular processes in general and how it affects the dopaminergic nigrostriatal pathway, in particular. Furthermore, there is broad interest in selective electrochemical quantification of H2O2, because it is often enzymatically generated at biosensors as a reporter for the presence of nonelectroactive target molecules. H2O2 fluctuations can be monitored in real time using fast-scan cyclic voltammetry (FSCV) coupled with carbon-fiber microelectrodes. However, selective identification is a critical issue when working in the presence of other molecules that generate similar voltammograms, such as adenosine and histamine. We have addressed this problem by fabricating a robust, H2O2-selective electrode. 1,3-Phenylenediamine (mPD) was electrodeposited on a carbon-fiber microelectrode to create a size-exclusion membrane, rendering the electrode sensitive to H2O2 fluctuations and pH shifts but not to other commonly studied neurochemicals. The electrodes are described and characterized herein. The data demonstrate that this technology can be used to ensure the selective detection of H2O2, enabling confident characterization of the role this molecule plays in normal physiological function as well as in the progression of PD and other neuropathies involving oxidative stress.}, number={1}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Wilson, Leslie R. and Panda, Sambit and Schmidt, Andreas C. and Sombers, Leslie A.}, year={2017}, month={Dec}, pages={888–895} }
 @article{smith_lee_dausch_horman_patisaul_mccarty_sombers_2017, title={Simultaneous Voltammetric Measurements of Glucose and Dopamine Demonstrate the Coupling of Glucose Availability with Increased Metabolic Demand in the Rat Striatum}, volume={8}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/acschemneuro.6b00363}, DOI={10.1021/acschemneuro.6b00363}, abstractNote={Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain. This work evaluates several waveforms to enable the first simultaneous detection of endogenous glucose and dopamine at single recording sites. These molecules, one electroactive and one nonelectroactive, were found to fluctuate in the dorsal striatum in response to electrical stimulation of the midbrain and systemic infusion of cocaine/raclopride. The data reveal the second-by-second dynamics of these species in a striatal microenvironment, and directly demonstrate the coupling of glucose availability with increased metabolic demand. This work provides a foundation that will enable detailed investigation of local mechanisms that regulate the coupling of cerebral blood flow with metabolic demand under normal conditions, and in animal studies of drug abuse and addiction.}, number={2}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Smith, Samantha K. and Lee, Christie A. and Dausch, Matthew E. and Horman, Brian M. and Patisaul, Heather B. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2017}, month={Jan}, pages={272–280} }
 @article{mitchell_dunaway_mccarty_sombers_2017, title={Spectroelectrochemical Characterization of the Dynamic Carbon-Fiber Surface in Response to Electrochemical Conditioning}, volume={33}, ISSN={0743-7463 1520-5827}, url={http://dx.doi.org/10.1021/acs.langmuir.7b01443}, DOI={10.1021/acs.langmuir.7b01443}, abstractNote={The effects of electrochemical preconditioning of P-55 pitch-based carbon-fiber microelectrodes were quantitatively examined in this study. Microstructural characterization of the electrode surface was done using Raman spectroscopy and scanning electron microscopy. Electrochemical performance was evaluated using cyclic voltammetry. The data show that application of positive potentials provides beneficial structural modifications to the electrode surface. Electrodes that were preconditioned using a static potential of +1.0 V exhibited enhanced sensitivity and electron transfer properties when compared to electrodes conditioned for the same amount of time with dynamic (triangular) waveforms reaching +1.0 V. Conditioning elicited microstructural changes to the electrode surface that were dependent on the amount of time spent at potentials greater than ∼1.0 V. Importantly, the data demonstrate that the carbon-fiber microstructure is dynamic. It is able to quickly and continuously undergo rapid structural reorganization as potential is applied, repeatedly alternating between a relatively ordered state and one that exhibits greater disorder in response to applied electrochemical potentials that span the range commonly used in voltammetric experiments.}, number={32}, journal={Langmuir}, publisher={American Chemical Society (ACS)}, author={Mitchell, Edwin C. and Dunaway, Lars E. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2017}, month={Aug}, pages={7838–7846} }
 @article{roberts_voinov_schmidt_smirnova_sombers_2016, title={The Hydroxyl Radical is a Critical Intermediate in the Voltammetric Detection of Hydrogen Peroxide}, volume={138}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/JACS.5B13376}, DOI={10.1021/jacs.5b13376}, abstractNote={Cyclic voltammetry is a widely used and powerful tool for sensitively and selectively measuring hydrogen peroxide (H2O2). Herein, voltammetry was combined with electron paramagnetic resonance spectroscopy to identify and define the role of an oxygen-centered radical liberated during the oxidation of H2O2. The spin-trap reagents, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO), were employed. Spectra exhibit distinct hyperfine patterns that clearly identify the DMPO(•)-OH and EMPO(•)-OH adducts. Multiple linear regression analysis of voltammograms demonstrated that the hydroxyl radical is a principal contributor to the voltammetry of H2O2, as signal is attenuated when this species is trapped. These data incorporate a missing, fundamental element to our knowledge of the mechanisms that underlie H2O2 electrochemistry.}, number={8}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Roberts, James G. and Voinov, Maxim A. and Schmidt, Andreas C. and Smirnova, Tatyana I. and Sombers, Leslie A.}, year={2016}, month={Feb}, pages={2516–2519} }
 @article{qi_thomas_white_smith_lee_wilson_sombers_2016, title={Unmasking the Effects of L-DOPA on Rapid Dopamine Signaling with an Improved Approach for Nafion Coating Carbon-Fiber Microelectrodes}, volume={88}, ISSN={["1520-6882"]}, DOI={10.1021/acs.analchem.6b01871}, abstractNote={L-DOPA has been the gold standard for symptomatic treatment of Parkinson’s disease. However, its efficacy wanes over time as motor complications develop. Very little is known about how L-DOPA therapy affects the dynamics of fluctuating dopamine concentrations in the striatum on a rapid time scale (seconds). Electrochemical studies investigating the effects of L-DOPA treatment on electrically evoked dopamine release have reported conflicting results with significant variability. We hypothesize that the uncertainty in the electrochemical data is largely due to electrode fouling caused by polymerization of L-DOPA and endogenous catecholamines on the electrode surface. Thus, we have systematically optimized the procedure for fabricating cylindrical, Nafion-coated, carbon-fiber microelectrodes. This has enabled rapid and reliable detection of L-DOPA’s effects on striatal dopamine signaling in intact rat brain using fast-scan cyclic voltammetry. An acute dose of 5 mg/kg L-DOPA had no significant effect on dopamine dynamics, demonstrating the highly efficient regulatory mechanisms at work in the intact brain. In contrast, administration of 200 mg/kg L-DOPA significantly increased the amplitude of evoked dopamine release by ∼200%. Overall, this work describes a reliable tool that allows a better measure of L-DOPA augmented dopamine release in vivo, measured using fast-scan cyclic voltammetry. It provides a methodology that improves the stability and performance of the carbon-fiber microelectrode when studying the molecular mechanisms underlying L-DOPA therapy and also promises to benefit a wide variety of studies because Nafion is so commonly used in electroanalytical chemistry.}, number={16}, journal={ANALYTICAL CHEMISTRY}, author={Qi, Lingjiao and Thomas, Elina and White, Stephanie H. and Smith, Samantha K. and Lee, Christie A. and Wilson, Leslie R. and Sombers, Leslie A.}, year={2016}, month={Aug}, pages={8129–8136} }
 @article{lugo-morales_sombers_2015, title={Enzyme-based microbiosensors for selective quantification of rapid molecular fluctuations in brain tissue}, DOI={10.1142/9789814619776_0006}, journal={Compendium of In Vivo Monitoring in Real-Time Molecular Neuroscience, vol 1: Fundamentals and Applications}, author={Lugo-Morales, L. Z. and Sombers, Leslie}, year={2015}, pages={137–160} }
 @article{schmidt_dunaway_roberts_mccarty_sombers_2014, title={Multiple Scan Rate Voltammetry for Selective Quantification of Real-Time Enkephalin Dynamics}, volume={86}, ISSN={["1520-6882"]}, DOI={10.1021/ac501725u}, abstractNote={Methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) are small endogenous opioid peptides that have been implicated in a wide variety of complex physiological functions, including nociception, reward processing, and motivation. However, our understanding of the role that these molecules play in modulating specific brain circuits remains limited, largely due to challenges in determining where, when, and how specific neuropeptides are released in tissue. Background-subtracted fast-scan cyclic voltammetry coupled with carbon-fiber microelectrodes has proven to be sensitive and selective for detecting rapidly fluctuating neurochemicals in vivo; however, many challenges exist for applying this approach to the detection of neuropeptides. We have developed and characterized a novel voltammetric waveform for the selective quantification of small tyrosine-containing peptides, such as the ENKs, with rapid temporal (subsecond) and precise spatial (10s of micrometers) resolution. We have established that the main contributor to the electrochemical signal inherent to M-ENK is tyrosine and that conventional waveforms provide poor peak resolution and lead to fouling of the electrode surface. By employing two distinct scan rates in each anodic sweep of this analyte-specific waveform, we have selectively distinguished M-ENK from common endogenous interfering agents, such as ascorbic acid, pH shifts, and even L-ENK. Finally, we have used this approach to simultaneously quantify catecholamine and M-ENK fluctuations in live tissue. This work provides a foundation for real-time measurements of endogenous ENK fluctuations in biological locations, and the underlying concept of using multiple scan rates is adaptable to the voltammetric detection of other tyrosine-containing neuropeptides.}, number={15}, journal={ANALYTICAL CHEMISTRY}, author={Schmidt, Andreas C. and Dunaway, Lars E. and Roberts, James G. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2014}, month={Aug}, pages={7806–7812} }
 @article{barrios_d’antonio_mccombs_zhao_franzen_schmidt_sombers_ghiladi_2014, title={Peroxygenase and Oxidase Activities of Dehaloperoxidase-Hemoglobin from Amphitrite ornata}, volume={136}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja500293c}, DOI={10.1021/ja500293c}, abstractNote={The marine globin dehaloperoxidase-hemoglobin (DHP) from Amphitrite ornata was found to catalyze the H2O2-dependent oxidation of monohaloindoles, a previously unknown class of substrate for DHP. Using 5-Br-indole as a representative substrate, the major monooxygenated products were found to be 5-Br-2-oxindole and 5-Br-3-oxindolenine. Isotope labeling studies confirmed that the oxygen atom incorporated was derived exclusively from H2O2, indicative of a previously unreported peroxygenase activity for DHP. Peroxygenase activity could be initiated from either the ferric or oxyferrous states with equivalent substrate conversion and product distribution. It was found that 5-Br-3-oxindole, a precursor of the product 5-Br-3-oxindolenine, readily reduced the ferric enzyme to the oxyferrous state, demonstrating an unusual product-driven reduction of the enzyme. As such, DHP returns to the globin-active oxyferrous form after peroxygenase activity ceases. Reactivity with 5-Br-3-oxindole in the absence of H2O2 also yielded 5,5'-Br2-indigo above the expected reaction stoichiometry under aerobic conditions, and O2-concentration studies demonstrated dioxygen consumption. Nonenzymatic and anaerobic controls both confirmed the requirements for DHP and molecular oxygen in the catalytic generation of 5,5'-Br2-indigo, and together suggest a newly identified oxidase activity for DHP.}, number={22}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Barrios, David A. and D’Antonio, Jennifer and McCombs, Nikolette L. and Zhao, Jing and Franzen, Stefan and Schmidt, Andreas C. and Sombers, Leslie A. and Ghiladi, Reza A.}, year={2014}, month={May}, pages={7914–7925} }
 @article{amos_roberts_qi_sombers_mccarty_2014, title={Reducing the Sampling Rate of Biochemical Measurements Using Fast-Scan Cyclic Voltammetry for In Vivo Applications}, volume={14}, ISSN={["1558-1748"]}, DOI={10.1109/jsen.2014.2321479}, abstractNote={Recent advances in science and technology have permitted the development of wireless systems that can make biochemical measurements within functioning tissue in behaving animals. However, data transfer requirements and power limitations have significantly limited the applicability of these systems. In an effort to create protocols that will reduce the density of the data to be transferred and the power consumption of wireless systems, this paper evaluates reducing the sampling rate of a proven in vivo measurement technology, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes. Existing FSCV protocols to measure biochemical signaling in the brain were created without consideration for data density or power consumption. In this paper, the sampling rate of the FSCV protocol for detecting the neurotransmitter dopamine in functioning brain tissue was reduced from 10 to 1 Hz. In vitro experiments showed that the 1-Hz protocol did not negatively affect sensor responsivity or selectivity. The reduced sampling rate was verified in vivo by directly monitoring dopamine fluctuations in intact brain tissue. The 1-Hz sampling rate reduces the quantity of data generated by an order of magnitude compared with the existing protocol, and with duty cycling is expected to decrease power consumption by a similar value in wireless systems.}, number={9}, journal={IEEE SENSORS JOURNAL}, author={Amos, Alison N. and Roberts, James G. and Qi, Lingjiao and Sombers, Leslie A. and McCarty, Gregory S.}, year={2014}, month={Sep}, pages={2975–2980} }
 @article{schmidt_wang_zhu_sombers_2013, title={Carbon Nanotube Yarn Electrodes for Enhanced Detection of Neurotransmitter Dynamics in Live Brain Tissue}, volume={7}, ISSN={["1936-086X"]}, DOI={10.1021/nn402857u}, abstractNote={This work demonstrates the potential of nanoscale carbon electrode materials for improved detection of electroactive neurotransmitter dynamics in the brain. Individual multiwalled carbon nanotubes were synthesized via chemical vapor deposition, spun into yarns, and used in the fabrication of disk microelectrodes that were subsequently characterized using scanning electron and atomic force microscopies. The carbon nanotube yarn electrodes were coupled with fast-scan cyclic voltammetry and used to discriminately detect rapid neurotransmitter fluctuations in acute brain slices. The results demonstrate that the distinct structural and electronic properties of the nanotubes result in improved selectivity, sensitivity, and spatial resolution, as well as faster apparent electron transfer kinetics when compared to the conventional carbon-fiber microelectrodes typically used in vivo.}, number={9}, journal={ACS NANO}, author={Schmidt, Andreas C. and Wang, Xin and Zhu, Yuntian and Sombers, Leslie A.}, year={2013}, month={Sep}, pages={7864–7873} }
 @article{lugo-morales_loziuk_corder_toups_roberts_mccaffrey_sombers_2013, title={Enzyme-Modified Carbon-Fiber Microelectrode for the Quantification of Dynamic Fluctuations of Nonelectroactive Analytes Using Fast-Scan Cyclic Voltammetry}, volume={85}, ISSN={["1520-6882"]}, DOI={10.1021/ac4017852}, abstractNote={Neurotransmission occurs on a millisecond time scale, but conventional methods for monitoring nonelectroactive neurochemicals are limited by slow sampling rates. Despite a significant global market, a sensor capable of measuring the dynamics of rapidly fluctuating, nonelectroactive molecules at a single recording site with high sensitivity, electrochemical selectivity, and a subsecond response time is still lacking. To address this need, we have enabled the real-time detection of dynamic glucose fluctuations in live brain tissue using background-subtracted, fast-scan cyclic voltammetry. The novel microbiosensor consists of a simple carbon fiber surface modified with an electrodeposited chitosan hydrogel encapsulating glucose oxidase. The selectivity afforded by voltammetry enables quantitative and qualitative measurements of enzymatically generated H2O2 without the need for additional strategies to eliminate interfering agents. The microbiosensors possess a sensitivity and limit of detection for glucose of 19.4 ± 0.2 nA mM–1 and 13.1 ± 0.7 μM, respectively. They are stable, even under deviations from physiological normoxic conditions, and show minimal interference from endogenous electroactive substances. Using this approach, we have quantitatively and selectively monitored pharmacologically evoked glucose fluctuations with unprecedented chemical and spatial resolution. Furthermore, this novel biosensing strategy is widely applicable to the immobilization of any H2O2 producing enzyme, enabling rapid monitoring of many nonelectroactive enzyme substrates.}, number={18}, journal={ANALYTICAL CHEMISTRY}, author={Lugo-Morales, Leyda Z. and Loziuk, Philip L. and Corder, Amanda K. and Toups, J. Vincent and Roberts, James G. and McCaffrey, Katherine A. and Sombers, Leslie A.}, year={2013}, month={Sep}, pages={8780–8786} }
 @article{roberts_toups_eyualem_mccarty_sombers_2013, title={In Situ Electrode Calibration Strategy for Voltammetric Measurements In Vivo}, volume={85}, ISSN={["1520-6882"]}, DOI={10.1021/ac402884n}, abstractNote={Technological advances have allowed background-subtracted fast-scan cyclic voltammetry to emerge as a powerful tool for monitoring molecular fluctuations in living brain tissue; however, there has been little progress to date in advancing electrode calibration procedures. Variability in the performance of these handmade electrodes renders calibration necessary for accurate quantification; however, experimental protocol makes standard postcalibration difficult or in some cases impossible. We have developed a model that utilizes information contained in the background charging current to predict electrode sensitivity to dopamine, ascorbic acid, hydrogen peroxide, and pH shifts at any point in an electrochemical experiment. Analysis determined a high correlation between predicted sensitivity and values obtained using the traditional postcalibration method, across all analytes. To validate this approach in vivo, calibration factors obtained with this model at electrodes in brain tissue were compared to values obtained at these electrodes using a traditional ex vivo calibration. Both demonstrated equal power of predictability for dopamine concentrations. This advance enables in situ electrode calibration, allowing researchers to track changes in electrode sensitivity over time and eliminating the need to generalize calibration factors between electrodes or across multiple days in an experiment.}, number={23}, journal={ANALYTICAL CHEMISTRY}, author={Roberts, James G. and Toups, J. Vincent and Eyualem, Eyob and McCarty, Gregory S. and Sombers, Leslie A.}, year={2013}, month={Dec}, pages={11568–11575} }
 @article{spanos_gras-najjar_letchworth_sanford_toups_sombers_2013, title={Quantitation of Hydrogen Peroxide Fluctuations and Their Modulation of Dopamine Dynamics in the Rat Dorsal Striatum Using Fast-Scan Cyclic Voltammetry}, volume={4}, ISSN={["1948-7193"]}, DOI={10.1021/cn4000499}, abstractNote={The dopaminergic neurons of the nigrostriatal dopamine (DA) projection from the substantia nigra to the dorsal striatum become dysfunctional and slowly degenerate in Parkinson’s disease, a neurodegenerative disorder that afflicts more than one million Americans. There is no specific known cause for idiopathic Parkinson’s disease; however, multiple lines of evidence implicate oxidative stress as an underlying factor in both the initiation and progression of the disease. This involves the enhanced generation of reactive oxygen species, including hydrogen peroxide (H2O2), whose role in complex biological processes is not well understood. Using fast-scan cyclic voltammetry at bare carbon-fiber microelectrodes, we have simultaneously monitored and quantified H2O2 and DA fluctuations in intact striatal tissue under basal conditions and in response to the initiation of oxidative stress. Furthermore, we have assessed the effect of acute increases in local H2O2 concentration on both electrically evoked DA release and basal DA levels. Increases in endogenous H2O2 in the dorsal striatum attenuated electrically evoked DA release, and also decreased basal DA levels in this brain region. These novel results will help to disambiguate the chemical mechanisms underlying the progression of neurodegenerative disease states, such as Parkinson’s disease, that involve oxidative stress.}, number={5}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Spanos, Marina and Gras-Najjar, Julie and Letchworth, Jeremy M. and Sanford, Audrey L. and Toups, J. Vincent and Sombers, Leslie A.}, year={2013}, month={May}, pages={782–789} }
 @inbook{roberts_lugo-morales_loziuk_sombers_2012, title={Real-Time Chemical Measurements of Dopamine Release in the Brain}, ISBN={9781627032506 9781627032513}, ISSN={1064-3745 1940-6029}, url={http://dx.doi.org/10.1007/978-1-62703-251-3_16}, DOI={10.1007/978-1-62703-251-3_16}, abstractNote={Rapid changes in extracellular dopamine concentrations in freely moving or anesthetized rats can be detected using fast-scan cyclic voltammetry (FSCV). Background-subtracted FSCV is a real-time electrochemical technique that can monitor neurochemical transmission in the brain on a subsecond timescale, while providing chemical information on the analyte. Also, this voltammetric approach allows for the investigation of the kinetics of release and uptake of molecules in the brain. This chapter describes, completely, how to make these measurements and the properties of FSCV that make it uniquely suitable for performing chemical measurements of dopaminergic neurotransmission in vivo.}, booktitle={Methods in Molecular Biology}, publisher={Humana Press}, author={Roberts, James G. and Lugo-Morales, Leyda Z. and Loziuk, Philip L. and Sombers, Leslie A.}, year={2012}, month={Oct}, pages={275–294} }
 @article{owesson-white_roitman_sombers_belle_keithley_peele_carelli_wightman_2012, title={Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens}, volume={121}, ISSN={["0022-3042"]}, DOI={10.1111/j.1471-4159.2012.07677.x}, abstractNote={J. Neurochem. (2012) 121, 252–262. Abstract Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study, we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine caused by phasic firing – that is, the measurement of dopamine ‘transients’. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ∼500 nM, presumably by inducing reverse transport by dopamine transporter (DAT). Taken together, data presented here show that average extracellular dopamine in the NAc is low (20–30 nM) and largely arises from phasic dopamine transients.}, number={2}, journal={JOURNAL OF NEUROCHEMISTRY}, author={Owesson-White, Catarina A. and Roitman, Mitchell F. and Sombers, Leslie A. and Belle, Anna M. and Keithley, Richard B. and Peele, Jessica L. and Carelli, Regina M. and Wightman, R. Mark}, year={2012}, month={Apr}, pages={252–262} }
 @article{harrington_bargar_jarzecki_roberts_sombers_duckworth_2012, title={Trace metal complexation by the triscatecholate siderophore protochelin: structure and stability}, volume={25}, ISSN={["1572-8773"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84861693339&partnerID=MN8TOARS}, DOI={10.1007/s10534-011-9513-7}, number={2}, journal={BIOMETALS}, author={Harrington, James M. and Bargar, John R. and Jarzecki, Andrzej A. and Roberts, James G. and Sombers, Leslie A. and Duckworth, Owen W.}, year={2012}, month={Apr}, pages={393–412} }
 @article{roberts_hamilton_sombers_2011, title={Comparison of electrode materials for the detection of rapid hydrogen peroxide fluctuations using background-subtracted fast scan cyclic voltammetry}, volume={136}, ISSN={0003-2654 1364-5528}, url={http://dx.doi.org/10.1039/c1an15337d}, DOI={10.1039/c1an15337d}, abstractNote={Hydrogen peroxide (H2O2) is a critically important signaling molecule. Endogenous H2O2 mediates diverse physiological processes both intra- and intercellularly; and enzymatically generated H2O2 is a widely used reporter molecule at biosensors that rely on enzymes to detect non-electroactive species. However, the development and application of electroanalytical methods for the direct detection of this molecule has been challenging because the electron transfer kinetics for the irreversible oxidation of H2O2 are slow. We comparatively characterize the electrochemical oxidation of H2O2 on bare and Nafion®-coated platinum and carbon-fiber microdisc electrodes using fast-scan cyclic voltammetry (FSCV). Using a waveform ranging from +0.2 to +1.3 V at 400 V s−1, the electrocatalytic properties of the platinum surface were not readily apparent, and the carbon-fiber microelectrode demonstrated greater sensitivity and selectivity toward H2O2. Nafion®-coating further enhanced detection on carbon electrodes. These results confirm that platinum electrodes, with or without Nafion®, will not work acceptably with this approach, and confirm the value of carbon-fiber microelectrodes relative to more traditionally used platinum electrodes in the direct detection of rapid H2O2 fluctuations using FSCV.}, number={17}, journal={The Analyst}, publisher={Royal Society of Chemistry (RSC)}, author={Roberts, James G. and Hamilton, Keri L. and Sombers, Leslie A.}, year={2011}, pages={3550} }
 @inproceedings{sanford_letchworth_sombers_2010, place={Brussels, Belgium}, title={Application of Fast-Scan Cyclic Voltammetry to Monitoring Endogenous Hydrogen Peroxide Fluctuations In Vivo}, ISBN={9789090256726}, booktitle={Monitoring Molecules in Neuroscience}, publisher={Vrije Universiteit}, author={Sanford, A.L. and Letchworth, J. and Sombers, L.A}, editor={Westerink, B. and Clinckers, R. and Smolders, I. and Sarre, S. and Michotte, YEditors}, year={2010}, pages={89–91} }
 @article{roberts_moody_mccarty_sombers_2010, title={Specific Oxygen-Containing Functional Groups on the Carbon Surface Underlie an Enhanced Sensitivity to Dopamine at Electrochemically Pretreated Carbon Fiber Microelectrodes}, volume={26}, ISSN={["0743-7463"]}, DOI={10.1021/la9048924}, abstractNote={The in vivo use of carbon-fiber microelectrodes for neurochemical investigation has proven to be selective and sensitive when coupled with background-subtracted fast-scan cyclic voltammetry (FSCV). Various electrochemical pretreatments have been established to enhance the sensitivity of these sensors; however, the fundamental chemical mechanisms underlying these enhancement strategies remain poorly understood. We have investigated an electrochemical pretreatment in which an extended triangular waveform from -0.5 to 1.8 V is applied to the electrode prior to the voltammetric detection of dopamine using a more standard waveform ranging from -0.4 to 1.3 V. This pretreatment enhances the electron-transfer kinetics and significantly improves sensitivity. To gain insight into the chemical mechanism, the electrodes were studied using common analytical techniques. Contact atomic force microscopy (AFM) was used to demonstrate that the surface roughness was not altered on the nanoscale by electrochemical pretreatment. Raman spectroscopy was utilized to investigate oxide functionalities on the carbon surface and confirmed that carbonyl and hydroxyl functional groups were increased by electrochemical conditioning. Spectra collected after the selective chemical modification of these groups implicate the hydroxyl functionality, rather than the carbonyl, as the major contributor to the enhanced electrochemical signal. Finally, we have demonstrated that this electrochemical pretreatment can be used to create carbon microdisc electrodes with sensitivities comparable to those associated with larger, conventionally treated cylindrical carbon fiber microelectrodes.}, number={11}, journal={LANGMUIR}, author={Roberts, James G. and Moody, Benjamin P. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2010}, month={Jun}, pages={9116–9122} }
 @article{sanford_morton_whitehouse_oara_lugo-morales_roberts_sombers_2010, title={Voltammetric Detection of Hydrogen Peroxide at Carbon Fiber Microelectrodes}, volume={82}, ISSN={["1520-6882"]}, DOI={10.1021/ac100536s}, abstractNote={Hydrogen peroxide is a reactive oxygen species that is implicated in a number of neurological disease states and that serves a critical role in normal cell function. It is commonly exploited as a reporter molecule enabling the electrochemical detection of nonelectroactive molecules at electrodes modified with substrate-specific oxidative enzymes. We present the first voltammetric characterization of rapid hydrogen peroxide fluctuations at an uncoated carbon fiber microelectrode, demonstrating unprecedented chemical and spatial resolution. The carbon surface was electrochemically conditioned on the anodic scan and the irreversible oxidation of peroxide was detected on the cathodic scan. The oxidation potential was dependent on scan rate, occurring at +1.2 V versus Ag/AgCl at a scan rate of 400 V·s−1. The relationship between peak oxidation current and concentration was linear across the physiological range tested, with deviation from linearity above 2 mM and a detection limit of 2 μM. Peroxide was distinguished from multiple interferents, both in vitro and in brain slices. The enzymatic degradation of peroxide was monitored, as was peroxide evolution in response to glucose at a glucose oxidase modified carbon fiber electrode. This novel approach provides the requisite sensitivity, selectivity, spatial and temporal resolution to study dynamic peroxide fluctuations in discrete biological locations.}, number={12}, journal={ANALYTICAL CHEMISTRY}, author={Sanford, Audrey L. and Morton, Stephen W. and Whitehouse, Kelsey L. and Oara, Hannah M. and Lugo-Morales, Leyda Z. and Roberts, James G. and Sombers, Leslie A.}, year={2010}, month={Jun}, pages={5205–5210} }
 @article{sombers_beyene_carelli_mark wightman_2009, title={Synaptic Overflow of Dopamine in the Nucleus Accumbens Arises from Neuronal Activity in the Ventral Tegmental Area}, volume={29}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.5562-08.2009}, DOI={10.1523/jneurosci.5562-08.2009}, abstractNote={Dopamine concentrations fluctuate on a subsecond time scale in the nucleus accumbens (NAc) of awake rats. These transients occur in resting animals, are more frequent following administration of drugs of abuse, and become time–locked to cues predicting reward. Despite their importance in various behaviors, the origin of these signals has not been demonstrated. Here we show that dopamine transients are evoked by neural activity in the ventral tegmental area (VTA), a brain region containing dopaminergic cell bodies. The frequency of naturally occurring dopamine transients in a resting, awake animal was reduced by a local VTA microinfusion of either lidocaine or (±)2-amino,5-phosphopentanoic acid (AP-5), an NMDA receptor antagonist that attenuates phasic firing. When dopamine increases were pharmacologically evoked by noncontingent administration of cocaine, intra-VTA infusion of lidocaine or AP-5 significantly diminished this effect. Dopamine transients acquired in response to a cue during intracranial self-stimulation were also attenuated by intra-VTA microinfusion of AP-5, and this was accompanied by an increase in latency to lever press. The results from these three distinct experiments directly demonstrate, for the first time, how neuronal firing of dopamine neurons originating in the VTA translates into synaptic overflow in a key terminal region, the NAc shell.}, number={6}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Sombers, L. A. and Beyene, M. and Carelli, R. M. and Mark Wightman, R.}, year={2009}, month={Feb}, pages={1735–1742} }
 @article{hermans_keithley_kita_sombers_wightman_2008, title={Dopamine Detection with Fast-Scan Cyclic Voltammetry Used with Analog Background Subtraction}, volume={80}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/ac800108j}, DOI={10.1021/ac800108j}, abstractNote={Fast-scan cyclic voltammetry has been used in a variety of applications and has been shown to be especially useful to monitor chemical fluctuations of neurotransmitters such as dopamine within the mammalian brain. A major limitation of this procedure, however, is the large amplitude of the background current relative to the currents for the solution species of interest. Furthermore, the background tends to drift, and this drift limits the use of digital background subtraction techniques to intervals less than 90 s before distortion of dopamine signals occurs. To minimize the impact of the background, a procedure termed analog background subtraction is reported here. The background is recorded, and its inverse is played back to the current transducer during data acquisition so that it cancels the background in subsequent scans. Background drift still occurs and is recorded, but its magnitude is small compared to the original background. This approach has two advantages. First it allows the use of higher gains in the current transducer, minimizing quantization noise. Second, because the background amplitude is greatly reduced, principal component regression could be used to separate the contributions from drift, dopamine, and pH when appropriate calibrations were performed. We demonstrate the use of this approach with several applications. First, transient dopamine fluctuations were monitored for 15 min in a flowing injection apparatus. Second, evoked release of dopamine was monitored for a similar period in the brain of an anesthetized rat. Third, dopamine was monitored in the brain of freely moving rats over a 30 min interval. By analyzing the fluctuations in each resolved component, we were able to show that cocaine causes significant fluctuations in dopamine concentration in the brain while those for the background and pH remain unchanged from their predrug value.}, number={11}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Hermans, Andre and Keithley, Richard B. and Kita, Justin M. and Sombers, Leslie A. and Wightman, R. Mark}, year={2008}, month={Jun}, pages={4040–4048} }
 @article{wightman_heien_wassum_sombers_aragona_khan_ariansen_cheer_phillips_carelli_2007, title={Dopamine release is heterogeneous within microenvironments of the rat nucleus accumbens}, volume={26}, ISSN={0953-816X}, url={http://dx.doi.org/10.1111/j.1460-9568.2007.05772.x}, DOI={10.1111/j.1460-9568.2007.05772.x}, abstractNote={Many individual neurons within the intact brain fire in stochastic patterns that arise from interactions with the neuronal circuits that they comprise. However, the chemical communication that is evoked by these firing patterns has not been characterized because sensors suitable to monitor subsecond chemical events in micron dimensions have only recently become available. Here we employ a voltammetric sensor technology coupled with principal component regression to examine the dynamics of dopamine concentrations in the nucleus accumbens (NAc) of awake and unrestrained rats. The sensor has submillimeter dimensions and provides high temporal (0.1 s) resolution. At select locations spontaneous dopamine transient concentration changes were detected, achieving instantaneous concentrations of approximately 50 nm. At other locations, transients were absent even though dopamine was available for release as shown by extracellular dopamine increases following electrical activation of dopaminergic neurons. At sites where dopamine concentration transients occur, uptake inhibition by cocaine enhances the frequency and magnitude of the rapid transients while also causing a more gradual increase in extracellular dopamine. These effects were largely absent from sites that did not support ongoing transient activity. These findings reveal an unanticipated spatial and temporal heterogeneity of dopamine transmission within the NAc that may depend upon the firing of specific subpopulations of dopamine neurons.}, number={7}, journal={European Journal of Neuroscience}, publisher={Wiley}, author={Wightman, R. Mark and Heien, Michael L.A.V. and Wassum, Kate M. and Sombers, Leslie A. and Aragona, Brandon J. and Khan, Amina S. and Ariansen, Jennifer L. and Cheer, Joseph F. and Phillips, Paul E. M. and Carelli, Regina M.}, year={2007}, month={Sep}, pages={2046–2054} }
 @article{sombers_wittenberg_maxson_adams_ewing_2007, title={High Osmolarity andL-DOPA Augment Release via the Fusion Pore in PC12 Cells}, volume={8}, ISSN={1439-4235 1439-7641}, url={http://dx.doi.org/10.1002/cphc.200700291}, DOI={10.1002/cphc.200700291}, abstractNote={We have amperometrically measured dopamine release from rat pheochromocytoma cells (PC12 cells) in high osmolarity conditions with and without L-3,4-dihydroxyphenylalanine (L-DOPA) treatment. We observe an increase in the number of release events displaying a prespike feature or "foot" when the cells are stimulated in high osmolarity saline. We also see an increase in foot area and duration when cells are stimulated in high osmolarity saline, or high osmolarity saline subsequent to incubation with the dopamine precursor L-DOPA in isotonic saline, which serves to increase the vesicle size. The data suggest that membrane biophysics are an important component in defining the rate, duration and amount of neurotransmitter release via the fusion pore.}, number={17}, journal={ChemPhysChem}, publisher={Wiley}, author={Sombers, Leslie A. and Wittenberg, Nathan J. and Maxson, Marc M. and Adams, Kelly L. and Ewing, Andrew G.}, year={2007}, month={Dec}, pages={2471–2477} }
 @article{sombers_maxson_ewing_2007, title={Multicore Vesicles: Hyperosmolarity and l-DOPA Induce Homotypic Fusion of Dense Core Vesicles}, volume={27}, ISSN={0272-4340 1573-6830}, url={http://dx.doi.org/10.1007/S10571-007-9156-Y}, DOI={10.1007/S10571-007-9156-Y}, abstractNote={A fraction of vesicles in cells treated with hypertonic solution exhibit multiple dense cores and this is enhanced by treatment with l-3,4–dihydroxyphenylalanine (l-DOPA). These cells were examined to determine if the multicore vesicles are the product of endocytosis or homotypic fusion. Electron microscopy was used to determine the number of multicore vesicles and amperometry was used to examine if the multicore vesicles are a competent fraction of the readily releasable pool. In this study, we observed that a substantial portion (15.3%) of large dense core vesicles in PC12 cells contained multiple cores in hypertonic saline loaded with l-DOPA, and amperometric measurements show a bimodal distribution of quantal sizes in treated cells. The results suggest that the multicored vesicles are formed from homotypic fusion of LCDVs prior to exocytosis.}, number={5}, journal={Cellular and Molecular Neurobiology}, publisher={Springer Science and Business Media LLC}, author={Sombers, Leslie A. and Maxson, Marc M. and Ewing, Andrew G.}, year={2007}, month={Jun}, pages={681–685} }
 @article{cheer_wassum_sombers_heien_ariansen_aragona_phillips_wightman_2007, title={Phasic Dopamine Release Evoked by Abused Substances Requires Cannabinoid Receptor Activation}, volume={27}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.4152-06.2007}, DOI={10.1523/jneurosci.4152-06.2007}, abstractNote={Transient surges of dopamine in the nucleus accumbens are associated with drug seeking. Using a voltammetric sensor with high temporal and spatial resolution, we demonstrate differences in the temporal profile of dopamine concentration transients caused by acute doses of nicotine, ethanol, and cocaine in the nucleus accumbens shell of freely moving rats. Despite differential release dynamics, all drug effects are uniformly inhibited by administration of rimonabant, a cannabinoid receptor (CB1) antagonist, suggesting that an increase in endocannabinoid tone facilitates the effects of commonly abused drugs on subsecond dopamine release. These time-resolved chemical measurements provide unique insight into the neurobiological effectiveness of rimonabant in treating addictive disorders.}, number={4}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Cheer, J. F. and Wassum, K. M. and Sombers, L. A. and Heien, M. L. A. V. and Ariansen, J. L. and Aragona, B. J. and Phillips, P. E. M. and Wightman, R. M.}, year={2007}, month={Jan}, pages={791–795} }
 @inproceedings{sombers_beyene_ariansen_owesson white_cheer_wightman_2006, place={Italy}, title={Burst Firing of Midbrain Dopamine Neurons Contributes to Transient Dopamine Fluctuations Time-Locked to Behavioral Responses in the Nucleus Accumbens of Freely-Moving Rats}, booktitle={Monitoring molecules in neuroscience: proceeding of the 11.th International conference on in Vivo Methods 2006 : University of Cagliari, Italy}, publisher={Grafiche Sainas}, author={Sombers, L.A. and Beyene, M. and Ariansen, J.L. and Owesson White, C.A. and Cheer, J.F. and Wightman, R.M.}, editor={Di Chiara, G. and Carboni, E. and Valentini, V. and Acquas, E. and Bassareo, V. and Cadoni, CEditors}, year={2006}, pages={560–562} }
 @article{amatore_arbault_bonifas_bouret_erard_ewing_sombers_2005, title={Correlation between Vesicle Quantal Size and Fusion Pore Release in Chromaffin Cell Exocytosis}, volume={88}, ISSN={0006-3495}, url={http://dx.doi.org/10.1529/biophysj.104.053736}, DOI={10.1529/biophysj.104.053736}, abstractNote={A significant number of exocytosis events recorded with amperometry demonstrate a prespike feature termed a “foot” and this foot has been correlated with messengers released via a transitory fusion pore before full exocytosis. We have compared amperometric spikes with a foot with spikes without a foot at chromaffin cells and found that the probability of detecting a distinct foot event is correlated to the amount of catecholamine released. The mean charge of the spikes with a foot was found to be twice that of the spikes without a foot, and the frequency of spikes displaying a foot was zero for small spikes increasing to ∼50% for large spikes. It is hypothesized that in chromaffin cells, where the dense core is believed to nearly fill the vesicle, the expanding core is a controlling factor in opening the fusion pore, that prefusion of two smaller vesicles leads to excess membrane, and that this slows pore expansion leading to an increased observation of events with a foot. Clearly, the physicochemical properties of vesicles are key factors in the control of the dynamics of release through the fusion pore and the high and variable frequency of this release makes it highly significant.}, number={6}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Amatore, Christian and Arbault, Stéphane and Bonifas, Imelda and Bouret, Yann and Erard, Marie and Ewing, Andy G. and Sombers, Leslie A.}, year={2005}, month={Jun}, pages={4411–4420} }
 @article{sombers_maxson_ewing_2005, title={Loaded dopamine is preferentially stored in the halo portion of PC12 cell dense core vesicles}, volume={93}, ISSN={0022-3042 1471-4159}, url={http://dx.doi.org/10.1111/j.1471-4159.2005.03087.x}, DOI={10.1111/j.1471-4159.2005.03087.x}, abstractNote={Large dense core vesicles in rat pheochromocytoma cells are morphologically distinct from dense core vesicles in mast and chromaffin cells in that the dense core occupies a much smaller fraction of the vesicular volume, allowing for a much larger vesicular clear space, or halo. In this work, we present evidence indicating that upon treatment with L-DOPA the majority of the dopamine loaded into these vesicles is preferentially compartmentalized into the halo portion of the vesicle. Amperometry was used to monitor release of loaded neurotransmitter from cells in both isotonic and hypertonic extracellular conditions, with the latter condition causing inhibition of dense core dissociation. In combination with this we have used transmission electron microscopy to determine the morphological characteristics of dense core vesicles before and after treatment with L-DOPA in solutions of varied osmolarity. The results provide a more complete understanding of the complex interaction of molecules within dense core vesicles, suggesting that newly loaded dopamine is located in the halo of the vesicle. This finding has fundamental significance for studies of neurotransmitter release from dense core vesicles, as the core appears to have a function involving more than simple storage of neurotransmitter and associated molecules, and the often overlooked vesicular halo appears to be an important storage compartment for neurotransmitter.}, number={5}, journal={Journal of Neurochemistry}, publisher={Wiley}, author={Sombers, L. A. and Maxson, M. M. and Ewing, A. G.}, year={2005}, month={Apr}, pages={1122–1131} }
 @article{sombers_2004, title={The Effects of Vesicular Volume on Secretion through the Fusion Pore in Exocytotic Release from PC12 Cells}, volume={24}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1119-03.2004}, DOI={10.1523/jneurosci.1119-03.2004}, abstractNote={Many spikes in amperometric records of exocytosis events initially exhibit a prespike feature, or foot, which represents a steady-state flux of neurotransmitter through a stable fusion pore spanning both the vesicle and plasma membranes and connecting the vesicle lumen to the extracellular fluid. Here, we present the first evidence indicating that vesicular volume before secretion is strongly correlated with the characteristics of amperometric foot events. L-3,4-dihydroxyphenylalanine and reserpine have been used to increase and decrease, respectively, the volume of single pheochromocytoma cell vesicles. Amperometry and transmission electron microscopy have been used to determine that as vesicle size is decreased the frequency with which foot events are observed increases, the amount and duration of neurotransmitter released in the foot portion of the event decreases, and vesicles release a greater percentage of their total contents in the foot portion of the event. This previously unidentified correlation provides new insight into how vesicle volume can modulate the activity of the exocytotic fusion pore.}, number={2}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Sombers, L. A.}, year={2004}, month={Jan}, pages={303–309} }
 @inbook{sombers_hanchar_colliver_wittenberg_cans_arbault_amatore_ewing_2004, place={Spain}, title={The Modulation of Vesicular Volume and its Effect on Neurotransmitter Secretion through the Fusion Pore in PC12 Cells}, booktitle={Cell Biology of the Chromaffin Cell}, publisher={Instituto Teófilo Hernando}, author={Sombers, L.A. and Hanchar, H.J. and Colliver, T.L. and Wittenberg, N. and Cans, A. and Arbault, S. and Amatore, C. and Ewing, A.G}, editor={Borges, Ricardo and Gandia, LuisEditors}, year={2004}, pages={43–46} }
 @inproceedings{ewing_cans_sombers_wittenberg_eves_karlsson_karlsson_karlsson_orwar_2003, place={Stockholm, Sweden}, title={Amperometric Detection of Exocytosis at Cells and Artificial Cells}, booktitle={Monitoring molecules in neuroscience : proceedings of the 10th International Conference on In Vivo Methods : Karolinska Institutet, Stockholm, Sweden June 24-27, 2003}, publisher={Karolinska University Press}, author={Ewing, A.G. and Cans, A.S. and Sombers, L. and Wittenberg, N. and Eves, D. and Karlsson, R. and Karlsson, M. and Karlsson, A. and Orwar, O}, editor={Kehr, J. and Fuxe, K. and Ungerstedt, U. and Svensson, TEditors}, year={2003}, pages={171–173} }
 @article{cans_wittenberg_karlsson_sombers_karlsson_orwar_ewing_2003, title={Artificial cells: Unique insights into exocytosis using liposomes and lipid nanotubes}, volume={100}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.232702599}, DOI={10.1073/pnas.232702599}, abstractNote={Exocytosis is the fundamental process underlying neuronal communication. This process involves fusion of a small neurotransmitter-containing vesicle with the plasma membrane of a cell to release minute amounts of transmitter molecules. Exocytosis is thought to go through an intermediate step involving formation of a small lipid nanotube or fusion pore, followed by expansion of the pore to the final stage of exocytosis. The process of exocytosis has been studied by various methods; however, when living cells are used it is difficult to discriminate between the molecular effects of membrane proteins relative to the mechanics of lipid-membrane-driven processes and to manipulate system parameters (e.g., membrane composition, pH, ion concentration, temperature, etc.). We describe the use of liposome-lipid nanotube networks to create an artificial cell model that undergoes the later stages of exocytosis. This model shows that membrane mechanics, without protein intervention, can drive expansion of the fusion pore to the final stage of exocytosis and can affect the rate of transmitter release through the fusion pore.}, number={2}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Cans, A.-S. and Wittenberg, N. and Karlsson, R. and Sombers, L. and Karlsson, M. and Orwar, O. and Ewing, A.}, year={2003}, month={Jan}, pages={400–404} }
 @inproceedings{sombers_maxson_ewing_2003, place={Stockholm, Sweden}, title={Vesicular Volume, the Fusion Pore and Potential ‘Presynaptic’ Mechanisms Modulating Neurotransmitter Release}, booktitle={Monitoring molecules in neuroscience : proceedings of the 10th International Conference on In Vivo Methods : Karolinska Institutet, Stockholm, Sweden June 24-27, 2003}, publisher={Karolinska University Press}, author={Sombers, L. and Maxson, M. and Ewing, A.G}, editor={Kehr, J. and Fuxe, K. and Ungerstedt, U. and Svensson, TEditors}, year={2003}, pages={189–191} }
 @article{sombers_colliver_ewing_2002, title={Differentiated PC12 Cells}, volume={971}, ISSN={0077-8923 1749-6632}, url={http://dx.doi.org/10.1111/j.1749-6632.2002.tb04439.x}, DOI={10.1111/j.1749-6632.2002.tb04439.x}, abstractNote={Annals of the New York Academy of SciencesVolume 971, Issue 1 p. 86-88 Differentiated PC12 Cells A Better Model System for the Study of the VMAT's Effects on Neuronal Communication LESLIE A. SOMBERS, LESLIE A. SOMBERS Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USASearch for more papers by this authorTOM L. COLLIVER, TOM L. COLLIVER Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USASearch for more papers by this authorANDREW G. EWING, Corresponding Author ANDREW G. EWING Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USAAddress for correspondence: Andrew G. Ewing, Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, PA 16802-6300. Voice: 814-863-4653; fax: 814-863-8081; age@psu.edu.Search for more papers by this author LESLIE A. SOMBERS, LESLIE A. SOMBERS Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USASearch for more papers by this authorTOM L. COLLIVER, TOM L. COLLIVER Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USASearch for more papers by this authorANDREW G. EWING, Corresponding Author ANDREW G. EWING Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802, USA Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USAAddress for correspondence: Andrew G. Ewing, Department of Chemistry, 152 Davey Laboratory, The Pennsylvania State University, University Park, PA 16802-6300. Voice: 814-863-4653; fax: 814-863-8081; age@psu.edu.Search for more papers by this author First published: 24 January 2006 https://doi.org/10.1111/j.1749-6632.2002.tb04439.xCitations: 17Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume971, Issue1THE CHROMAFFIN CELL: TRANSMITTER BIOSYNTHESIS, STORAGE, RELEASE, ACTIONS, AND INFORMATICS: 11th INTERNATIONAL SYMPOSIUM ON CHROMAFFIN CELL BIOLOGYOctober 2002Pages 86-88 RelatedInformation}, number={1}, journal={Annals of the New York Academy of Sciences}, publisher={Wiley}, author={Sombers, Leslie A. and Colliver, Tom L. and Ewing, Andrew G.}, year={2002}, month={Oct}, pages={86–88} }
 @inbook{sombers_ewing_2002, place={New York}, title={Electrochemical Monitoring of Exocytosis from Individual PC12 Cells in Culture}, ISBN={0824707311}, DOI={10.1201/9780203908907.pt3}, booktitle={Electroanalytical Methods for Biological Materials}, publisher={Marcel Dekker}, author={Sombers, Leslie and Ewing, Andrew}, editor={Brajter-Toth, Anna and Chambers, James Q.Editors}, year={2002}, month={Mar}, pages={279–327} }
 @inbook{ewing_sombers_woods_colliver_achalabun_moran_lapos_paxon_cans_2001, place={Dublin}, title={Electrochemical or Separations-Based Sensing of Neurotransmitter Dynamics and Storage at Cells and Varicosities in Culture}, booktitle={Monitoring molecules in neuroscience : proceedings of the 9th International Conference on In Vivo Methods, June 16-19, 2001, University College Dublin, Ireland}, publisher={University College Dublin}, author={Ewing, A.G. and Sombers, L.A. and Woods, L.A. and Colliver, T.L. and Achalabun, M. and Moran, K. and Lapos, J. and Paxon, T. and Cans, A.S}, editor={O'Connor, W. T. and Lowry, J. P. and O'Connor, J. J. and O'Neill, R. D.Editors}, year={2001}, pages={57–58} }