Adrian C. Michael

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Name: Michael, Adrian

Organization: University of Pittsburgh , USA

Department: Department of Chemistry

Title: Professor(PhD)

Chemicals
References

Enhanced Intracranial Microdialysis by Reduction of Traumatic Penetration Injury at the Probe Track

Co-reporter:Erika L. Varner, Andrea Jaquins-Gerstl, and Adrian C. Michael

ACS Chemical Neuroscience 2016 Volume 7(Issue 6) pp:728

Publication Date(Web):March 22, 2016

DOI:10.1021/acschemneuro.5b00331

Microdialysis provides deep insight into chemical neuroscience by enabling in vivo intracranial chemical monitoring. Nevertheless, implanting a microdialysis probe causes a traumatic penetration injury (TPI) of brain tissue at the probe track. The TPI, which is clearly documented by voltammetry and histochemical imaging, is a drawback because it perturbs the exact tissue from which the brain dialysate samples are derived. Our goal is to reduce, if not eventually eliminate, the TPI and its detrimental effects on neurochemical monitoring. Here, we demonstrate that combining a 5-day wait period after probe implantation with the continuous retrodialysis of a low-micromolar concentration of dexamethasone vastly reduces the TPI. Our approach to reducing the TPI reinstates normal evoked dopamine release activity in the tissue adjacent to the microdialysis probe, brings evoked dopamine release at the probe outlet into quantitative agreement with evoked dopamine release next to the probe, reinstates normal immunoreactivity for tyrosine hydroxylase and the dopamine transporter near the probe track, and greatly suppresses glial activation and scaring near the probe track. This reduction of the TPI and reinstatement of normal evoked dopamine release activity adjacent to the probe track appears to be due to dexamethasone’s anti-inflammatory actions.Keywords: dexamethasone; dopamine; Microdialysis; penetration injury; retrodialysis; voltammetry

Kinetic diversity of dopamine transmission in the dorsal striatum

Co-reporter:I. Mitch Taylor;Kathryn M. Nesbitt;Seth H. Walters;Erika L. Varner;Zhan Shu;Kathleen M. Bartlow;Andrea S. Jaquins-Gerstl

Journal of Neurochemistry 2015 Volume 133( Issue 4) pp:522-531

Publication Date(Web):

DOI:10.1111/jnc.13059

A review of the effects of FSCV and microdialysis measurements on dopamine release in the surrounding tissue

Co-reporter:Andrea Jaquins-Gerstl and Adrian C. Michael

Analyst 2015 vol. 140(Issue 11) pp:3696-3708

Publication Date(Web):16 Apr 2015

DOI:10.1039/C4AN02065K

Microdialysis is commonly used in neuroscience to obtain information about the concentration of substances, including neurotransmitters such as dopamine (DA), in the extracellular space (ECS) of the brain. Measuring DA concentrations in the ECS with in vivo microdialysis and/or voltammetry is a mainstay of investigations into both normal and pathological function of central DA systems. Although both techniques are instrumental in understanding brain chemistry each has its shortcomings. The objective of this review is to characterize some of the tissue and DA differences associated with each technique in vivo. Much of this work will focus on immunohistochemical and microelectrode measurements of DA in the tissue next to the microdialysis probe and mitigating the response to the damage caused by probe implantation.

Comment on “Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo”

Co-reporter:Adrian C. Michael

ACS Chemical Neuroscience 2015 Volume 6(Issue 9) pp:1649

Publication Date(Web):June 29, 2015

DOI:10.1021/cn5002232

Microdialysis in the Rat Striatum: Effects of 24 h Dexamethasone Retrodialysis on Evoked Dopamine Release and Penetration Injury

Co-reporter:Kathryn M. Nesbitt, Erika L. Varner, Andrea Jaquins-Gerstl, and Adrian C. Michael

ACS Chemical Neuroscience 2015 Volume 6(Issue 1) pp:163

Publication Date(Web):December 10, 2014

DOI:10.1021/cn500257x

The power of microdialysis for in vivo neurochemical monitoring is a result of intense efforts to enhance microdialysis procedures, the probes themselves, and the analytical systems used for the analysis of dialysate samples. Our goal is to refine microdialysis further by focusing attention on what happens when the probes are implanted into brain tissue. It is broadly acknowledged that some tissue damage occurs, such that the tissue nearest the probes is disrupted from its normal state. We hypothesize that mitigating such disruption would refine microdialysis. Herein, we show that the addition of dexamethasone, an anti-inflammatory drug, to the perfusion fluid protects evoked dopamine responses as measured by fast-scan cyclic voltammetry next to the probes after 24 h. We also show that dexamethasone stabilizes evoked dopamine responses measured at the probe outlet over a 4–24 h postimplantation interval. The effects of dexamethasone are attributable to its anti-inflammatory actions, as dexamethasone had no significant effect on two histochemical markers for dopamine terminals, tyrosine hydroxylase and the dopamine transporter. Using histochemical assays, we confirmed that the actions of dexamethasone are tightly confined to the immediate, local vicinity of the probe.Keywords: dexamethasone; dopamine; immunohistochemistry; Microdialysis; penetration injury; voltammetry

A Novel Restricted Diffusion Model of Evoked Dopamine

Co-reporter:Seth H. Walters, I. Mitch Taylor, Zhan Shu, and Adrian C. Michael

ACS Chemical Neuroscience 2014 Volume 5(Issue 9) pp:776

Publication Date(Web):July 1, 2014

DOI:10.1021/cn5000666

In vivo fast-scan cyclic voltammetry provides high-fidelity recordings of electrically evoked dopamine release in the rat striatum. The evoked responses are suitable targets for numerical modeling because the frequency and duration of the stimulus are exactly known. Responses recorded in the dorsal and ventral striatum of the rat do not bear out the predictions of a numerical model that assumes the presence of a diffusion gap interposed between the recording electrode and nearby dopamine terminals. Recent findings, however, suggest that dopamine may be subject to restricted diffusion processes in brain extracellular space. A numerical model cast to account for restricted diffusion produces excellent agreement between simulated and observed responses recorded under a broad range of anatomical, stimulus, and pharmacological conditions. The numerical model requires four, and in some cases only three, adjustable parameters and produces meaningful kinetic parameter values.Keywords: diffusion; domain; dopamine; Model; restricted diffusion; voltammetry

Pharmacological Mitigation of Tissue Damage during Brain Microdialysis

Co-reporter:Kathryn M. Nesbitt, Andrea Jaquins-Gerstl, Erin M. Skoda, Peter Wipf, and Adrian C. Michael

Analytical Chemistry 2013 Volume 85(Issue 17) pp:8173

Publication Date(Web):August 8, 2013

DOI:10.1021/ac401201x

Microdialysis sampling in the brain is employed frequently in the chemical analysis of neurological function and disease, but implanting the probes, which are substantially larger than the size and spacing of brain cells and blood vessels, is injurious and triggers ischemia, gliosis, and cell death at the sampling site. The nature of the interface between the brain and the microdialysis probe is critical to the use of microdialysis as a neurochemical analysis technique. The objective of the work reported here was to investigate the potential of two compounds, dexamethasone, a glucocorticoid anti-inflammatory agent, and XJB-5-131, a mitochondrially targeted reactive oxygen species scavenger, to mitigate the penetration injury. Measurements were performed in the rat brain striatum, which is densely innervated by axons that release dopamine, an electroactive neurotransmitter. We used voltammetry to measure electrically evoked dopamine release next to microdialysis probes during the retrodialysis of dexamethasone or XJB-5-131. After the in vivo measurements, the brain tissue containing the microdialysis probe tracks was examined by fluorescence microscopy using markers for ischemia, neuronal nuclei, macrophages, and dopamine axons and terminals. Dexamethasone and XJB-5-131 each diminished the loss of evoked dopamine activity, diminished ischemia, diminished the loss of neuronal nuclei, diminished the appearance of extravasated macrophages, and diminished the loss of dopamine axons and terminals next to the probes. Our findings confirm the ability of dexamethasone and XJB-5-131 to mitigate, but not eliminate, the effects of the penetration injury caused by implanting microdialysis probes into brain tissue.

Restricted Diffusion of Dopamine in the Rat Dorsal Striatum

Co-reporter:I. Mitch Taylor, Alexandre I. Ilitchev, and Adrian C. Michael

ACS Chemical Neuroscience 2013 Volume 4(Issue 5) pp:870

Publication Date(Web):April 21, 2013

DOI:10.1021/cn400078n

Recent evidence has shown that the dorsal striatum of the rat is arranged as a patchwork of domains that exhibit distinct dopamine kinetics and concentrations. This raises the pressing question of how these distinct domains are maintained, especially if dopamine is able to diffuse through the extracellular space. Diffusion between the domains would eliminate the concentration differences and, thereby, the domains themselves. The present study is a closer examination of dopamine’s ability to diffuse in the extracellular space. We used voltammetry to record dopamine overflow in dorsal striatum while stimulating the medial forebrain bundle over a range of stimulus currents and frequencies. We also examined the effects of drugs that modulated the dopamine release (raclopride and quinpirole) and uptake (nomifensine). Examining the details of the temporal features of the evoked profiles reveals no clear evidence for long-distance diffusion of dopamine between fast and slow domains, even though uptake inhibition by nomifensine clearly prolongs the time that dopamine resides in the extracellular space. Our observations support the conclusion that striatal tissue has the capacity to retain dopamine molecules, thereby limiting its tendency to diffuse through the extracellular space.Keywords: diffusion; Dopamine; dopamine transporter; dorsal striatum; evoked release; voltammetry

Domain-dependent effects of DAT inhibition in the rat dorsal striatum

Co-reporter:I. Mitch Taylor;Andrea Jaquins-Gerstl;Susan R. Sesack

Journal of Neurochemistry 2012 Volume 122( Issue 2) pp:283-294

Publication Date(Web):

DOI:10.1111/j.1471-4159.2012.07774.x

J. Neurochem. (2012) 122, 283–294.

Abstract

The rat dorsal striatum exhibits domain-dependent kinetics of dopamine release and clearance. The present report describes the domain-dependent actions of nomifensine (20 mg/kg i.p.), a competitive dopamine uptake inhibitor, on evoked dopamine responses recorded by voltammetry during electrical stimulation of the medial forebrain bundle. In slow domains, nomifensine increases the initial rate of evoked overflow, increases response overshoot, does not affect the slope of the linear segment of the dopamine clearance profile, and slows the non-linear segment of the clearance profile. In fast domains, nomifensine does not affect the initial rate of overflow, increases the end-of-stimulus overshoot, and decreases the slope of the linear segment of the dopamine clearance profile. Collectively, these findings do not concur with existing models of evoked dopamine release that describe the effect of nomifensine as an increase in the effective K_M of dopamine uptake. These findings suggest that dopamine clearance after evoked release is affected by both dopamine uptake and a restricted extracellular diffusion process.

Effect of Dexamethasone on Gliosis, Ischemia, and Dopamine Extraction during Microdialysis Sampling in Brain Tissue

Co-reporter:Andrea Jaquins-Gerstl, Zhan Shu, Jing Zhang, Yansheng Liu, Stephen G. Weber, and Adrian C. Michael

Analytical Chemistry 2011 Volume 83(Issue 20) pp:7662

Publication Date(Web):August 22, 2011

DOI:10.1021/ac200782h

Microdialysis sampling of the brain is an analytical technique with numerous applications in neuroscience and the neurointensive care of brain-injured human patients. Even so, implanting microdialysis probes into brain tissue causes a penetration injury that triggers gliosis (the activation and proliferation of glial cells) and ischemia (the interruption of blood flow). Thus, the probe samples injured tissue. Mitigating the effects of the penetration injury might refine the technique. The synthetic glucocorticoid dexamethasone is a potent anti-inflammatory and immunosuppressant substance. We performed microdialysis in the rat brain for 5 days, with and without dexamethasone in the perfusion fluid (10 μM for the first 24 h and 2 μM thereafter). On the first and fourth day of the perfusion, we performed dopamine no-net-flux measurements. On the fifth day, we sectioned and stained the brain tissue and examined it by fluorescence microscopy. Although dexamethasone profoundly inhibited gliosis and ischemia around the probe tracks it had only modest effects on dopamine no-net-flux results. These findings show that dexamethasone is highly effective at suppressing gliosis and ischemia but is limited in its neuroprotective activity.

An inverse correlation between the apparent rate of dopamine clearance and tonic autoinhibition in subdomains of the rat striatum: a possible role of transporter-mediated dopamine efflux

Co-reporter:Keith F. Moquin

Journal of Neurochemistry 2011 Volume 117( Issue 1) pp:133-142

Publication Date(Web):

DOI:10.1111/j.1471-4159.2011.07183.x

J. Neurochem. (2011) 117, 133–142.

Abstract

The dopaminergic terminal field in the rat striatum is compartmentalized into sub-domains that exhibit distinct dynamics of electrically evoked dopamine release. The fast striatal domains, where dopamine release is predominantly vesicular, exhibit conventional dopaminergic activity. However, vesicular dopamine release is tonically autoinhibited in the slow domains, which suggests that dopamine reaches the autoreceptors via a non-vesicular route. Hence, it appears that the domains use distinct mechanisms to regulate the basal dopamine concentration available to activate, or not, pre-synaptic autoinhibitory receptors. However, direct detection of local variations in tonic extracellular dopamine concentrations is not yet possible. So, the present study employed voltammetry to test the hypothesis that the apparent rate of dopamine clearance from the extracellular space should be domain-dependent. The apparent rate of dopamine clearance is equal to the difference in the rates of dopamine release and uptake that determine extracellular dopamine concentrations. This study confirms that the apparent rate of dopamine clearance is slower in the slow striatal domains where vesicular dopamine release is tonically autoinhibited. These findings support the view that the basal concentration in slow domains is maintained by a non-vesicular release process, possibly transporter-mediated efflux.

Evidence for coupling between steady-state and dynamic extracellular dopamine concentrations in the rat striatum

Co-reporter:Yuexiang Wang;Keith F. Moquin

Journal of Neurochemistry 2010 Volume 114( Issue 1) pp:150-159

Publication Date(Web):

DOI:10.1111/j.1471-4159.2010.06740.x

J. Neurochem. (2010) 114, 150–159.

Abstract

A previous study from our laboratory demonstrated the presence within the rat striatum of dopaminergic terminals in different dynamical states, determined at least in part by the extent to which terminals are subject to autoinhibition. The present study is designed to test the hypothesis that heterogeneity in the basal tonic extracellular dopamine concentration contributes to the variable extent of autoinhibition. We probed basal extracellular dopamine concentrations using a previously demonstrated strategy that utilizes intrastriatal microinfusion of kynurenate, a substance that according to voltammetric measurements decreases extracellular dopamine from its basal concentration. In the striatum, however, we find that the response to kynurenate infusion is itself heterogeneous, allowing a broad classification of sites within the striatum as kynurenate-insensitive and kynurenate-sensitive, respectively. These newly identified kynurenate-insensitive and sensitive sites yield substantially and significantly different evoked dopamine release as measured by voltammetry during electrical stimulation of the medial forebrain bundle. Our findings confirm the hypothesis that heterogeneity in the local basal concentration of dopamine is responsible for the variable extent of autoinhibition within the striatum and support the conclusion that the steady state and dynamical components of extracellular dopamine in this brain region are coupled.

Tonic autoinhibition contributes to the heterogeneity of evoked dopamine release in the rat striatum

Co-reporter:Keith F. Moquin

Journal of Neurochemistry 2009 Volume 110( Issue 5) pp:1491-1501

Publication Date(Web):

DOI:10.1111/j.1471-4159.2009.06254.x

Abstract

Electrically evoked dopamine release as measured by voltammetry in the rat striatum is heterogeneous in both amplitude and temporal profile. Previous studies have attributed this heterogeneity to variations in the density of dopamine (DA) terminals at the recording site. We reach the alternate conclusion that the heterogeneity of evoked DA release derives from variations in the extent to which DA terminals are autoinhibited. We demonstrate that low-amplitude, slow evoked DA responses occur even though recording electrodes are close to DA terminals. Moreover, the D₂ agonist and antagonist, quinpirole and raclopride, respectively, affect the slow responses in a manner consistent with the known functions of pre-synaptic D₂ autoreceptors. Recording sites that exhibit autoinhibited responses are prevalent in the dorsal striatum. Autoinhibition preceded electrical stimulation, which is consistent with our prior reports that the striatum contains a tonic pool of extracellular DA at basal concentrations that exceed the affinity of D₂ receptors. We conclude that the striatum contains DA terminals operating on multiple time courses, determined at least in part by the local variation in autoinhibition. Thus, we provide direct, real-time observations of the functional consequence of tonic and phasic DAergic signaling in vivo.

Impact of microdialysis probes on vasculature and dopamine in the rat striatum: A combined fluorescence and voltammetric study

Co-reporter:Christina M. Mitala, Yuexiang Wang, Laura M. Borland, Moon Jung, Stuart Shand, Simon Watkins, Stephen G. Weber, Adrian C. Michael

Journal of Neuroscience Methods (30 September 2008) Volume 174(Issue 2) pp:177-185

Publication Date(Web):30 September 2008

DOI:10.1016/j.jneumeth.2008.06.034

Measuring extracellular dopamine in the brain of living animals by means of microdialysis and/or voltammetry is a route towards understanding both normal brain function and pathology. Previous reports, however, suggest that the tissue response to implantation of devices may affect the outcome of the measurements. To address the source of the tissue response and its impact on striatal dopamine systems microdialysis probes were placed in the striatum of anesthetized rats. Images obtained by dual-label fluorescence microscopy show signs of ischemia and opening of the blood–brain barrier near the probe tracks. Opening of the blood–brain barrier was further examined by determining dialysate concentrations of carbi-DOPA, a drug that normally does not penetrate the brain. Although carbi-DOPA was recovered in brain dialysate, it did not alter dialysate dopamine levels or evoked dopamine release as measured by voltammetry near the probes. Microdialysis probes also significantly diminished the effect of intrastriatal infusion of kynurenate on extracellular dopamine levels as measured by voltammetry near the probes.

Microdialysis probes alter presynaptic regulation of dopamine terminals in rat striatum

Co-reporter:Yuexiang Wang, Adrian C. Michael

Journal of Neuroscience Methods (30 June 2012) Volume 208(Issue 1) pp:34-39

Publication Date(Web):30 June 2012

DOI:10.1016/j.jneumeth.2012.04.009

The insertion of microdialysis probes into the rat striatum disrupts dopaminergic activity near the probe track. The present study suggests that a substantial fraction of DA terminals near the probe track (200 μm) survive the probe implantation itself but that the surviving terminals experience altered presynaptic inhibition. We found that probe implantation did not just alter the amplitude of evoked dopamine responses recorded by voltammetry, but also changed their temporal profile in a fashion similar to that previously observed by quinpirole, an agonist of dopamine D2 autoreceptors. Altered presynaptic inhibition is supported by a hypersensitivity of evoked dopamine responses recorded near to microdialysis probes to raclopride, a D2 antagonist. Further, we found that evoked dopamine release was also hypersensitive to a final dose of the dopamine transporter inhibitor, nomifensine.Highlights► Voltammetry near microdialysis probes quantifies the impact of probe implantation on striatal dopamine activity. ► Probe implantation causes a 90% loss of evoked DA at microelectrodes near the probe. ► DA near the probe is hypersensitive to raclopride and nomifensine. ► The loss of DA function near the probe is due to terminal loss and suppression of surviving terminals.

Comparison of the brain penetration injury associated with microdialysis and voltammetry

Co-reporter:Andrea Jaquins-Gerstl, Adrian C. Michael

Journal of Neuroscience Methods (15 October 2009) Volume 183(Issue 2) pp:127-135

Publication Date(Web):15 October 2009

DOI:10.1016/j.jneumeth.2009.06.023

Emerging evidence suggests that differences between microdialysis- and voltammetry-based estimates of extracellular dopamine in the brain might originate in the different penetration injury associated with each technique. To address this issue in a direct fashion, microdialysis probes and voltammetric microelectrodes were implanted in the rat striatum for 1, 4, or 24 h. Tissues were perfused with a suspension of fluorescently labeled nanobeads to assess blood vessels near the implant. Tissue sections (30 μm) were labeled with antibodies for PECAM, an endothelial cell marker, or GFAP, a glial marker. In non-implanted control tissue, blood vessels were reliably double-labeled with nanobeads and antiPECAM. Tissue near microdialysis probe tracks exhibited ischemia in the form of PECAM immunoreactive blood vessels devoid of nanobeads. Ischemia was most apparent after the 4-h implants. Probe tracks were surrounded by endothelial cell debris, which appeared as a diffuse halo of PECAM immunoreactivity. The halo intensity decreased with implant duration, indicative of an active wound-healing process. Consistent with this, after 24-h implants, the probe tracks were surrounded by hyperplasic and hypertrophic glia and glial processes were extending towards, and engulfing, the track. Carbon fiber microelectrodes produced a diffuse disruption of nanobead labeling but no focal disruption of blood vessels, no PECAM immunoreactive halo, and no glial activation. These findings illuminate the differences between the extent and nature of the penetration injuries associated with microdialysis and voltammetry.

A method for the intracranial delivery of reagents to voltammetric recording sites

Co-reporter:Keith F. Moquin, Andrea Jaquins-Gerstl, Adrian C. Michael

Journal of Neuroscience Methods (15 July 2012) Volume 208(Issue 2) pp:101-107

Publication Date(Web):15 July 2012

DOI:10.1016/j.jneumeth.2012.05.001

Carbon fiber microelectrodes are widely used for electrochemical monitoring in the intact brain. The local delivery of reagents to the recording site is often desirable. The approach of co-implanting a micropipette near the microelectrode presents some limitations that are overcome by the use of double-barreled devices. One barrel supports the carbon fiber and the other barrel serves as a pipet for local reagent delivery. Some studies have used iontophoretic delivery but here we consider the alternative approach of pressure ejection. However, placing the pipet so close to the electrode raises the risk that reagent can leak into the recording site. This problem is easily solved. We filled the tip of the pipet with vehicle solution, the barrel with a reagent solution, and separated the two solutions with an air gap to prevent their mixing. With this approach, reagent is delivered only after ‘priming’ pressure pulses: we show in two examples that unintended reagent delivery (leakage) prior to the priming pulses is non-detectable.Highlights► Double barrel electrodes combine detection and reagent delivery in a single device. ► This design enables electrode optimization and highly localized reagent delivery. ► However, capillary tips leak reagents at physiologically relevant concentrations. ► Segmenting the reagent solution from the tip solution prevents premature delivery. ► Pressure ejections mix reagent into the tip solution, enabling reagent delivery.