Dopamine Response Research Articles

One-step preparation of carbon quantum dots-reduced graphene oxide nanocomposite–modified glass carbon electrode for the simultaneous detection of ascorbic acid, dopamine, and uric acid

In this manuscript, carbon quantum dots-reduced graphene oxide (CQDs-rGO) nanocomposite was modified on the surface of glass carbon electrode (GCE) via an one-step co-deposition method to fabricate an effective electrochemical senor for the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA). Due to the strong synergetic effect between CQDs and rGO, the sensor exhibited good selectivity and high catalytic activity toward AA, DA, and UA. The peak potential differences of simultaneous detection for AA-DA, DA-UA, and AA-UA were calculated as 0.147 V, 0.135 V, and 0.282 V, respectively. And the linear responses of AA, DA, and UA were found in the ranges of 0.2–0.9 mM (R2 = 0.99) and 1.4–4.2 mM (R2 = 0.99), 5–9 μM (R2 = 0.98) and 11–81 μM (R2 = 0.99), and 20–90 μM (R2 = 0.99) and 140–300 μM (R2 = 0.99), respectively. The as-prepared sensor contributed a fresh idea to the simultaneous detection of AA, DA, and UA, and has a broad prospect in practical application.

Modulation of Dopamine for Adaptive Learning: A Neurocomputational Model.

There have been many proposals that learning rates in the brain are adaptive, in the sense that they increase or decrease depending on environmental conditions. The majority of these models are abstract and make no attempt to describe the neural circuitry that implements the proposed computations. This article describes a biologically detailed computational model that overcomes this shortcoming. Specifically, we propose a neural circuit that implements adaptive learning rates by modulating the gain on the dopamine response to reward prediction errors, and we model activity within this circuit at the level of spiking neurons. The model generates a dopamine signal that depends on the size of the tonically active dopamine neuron population and the phasic spike rate. The model was tested successfully against results from two single-neuron recording studies and a fast-scan cyclic voltammetry study. We conclude by discussing the general applicability of the model to dopamine mediated tasks that transcend the experimental phenomena it was initially designed to address.

Tremor pathophysiology: lessons from neuroimaging.

We discuss the latest neuroimaging studies investigating the pathophysiology of Parkinson's tremor, essential tremor, dystonic tremor and Holmes tremor. Parkinson's tremor is associated with increased activity in the cerebello-thalamo-cortical circuit, with interindividual differences depending on the clinical dopamine response of the tremor. Although dopamine-resistant Parkinson's tremor arises from a larger contribution of the (dopamine-insensitive) cerebellum, dopamine-responsive tremor may be explained by thalamic dopamine depletion. In essential tremor, deep brain stimulation normalizes cerebellar overactivity, which fits with the cerebellar oscillator hypothesis. On the other hand, disconnection of the dentate nucleus and abnormal white matter microstructural integrity support a decoupling of the cerebellum in essential tremor. In dystonic tremor, there is evidence for involvement of both cerebellum and basal ganglia, although this may depend on the clinical phenotype. Finally, in Holmes tremor, different causal lesions map to a common network consisting of the red nucleus, internal globus pallidus, thalamus, cerebellum and pontomedullary junction. The pathophysiology of all investigated tremors involves the cerebello-thalamo-cortical pathway, and clinical and pathophysiological features overlap among tremor disorders. We draw the outlines of a hypothetical pathophysiological axis, which may be used besides clinical features and cause in future tremor classifications.

Alterations of oscillatory neuronal activity during reward processing in schizophrenia

ObjectivesReward system dysfunctions are considered to be a pathophysiological mechanism in schizophrenia. Electrophysiological studies of reward system functions have identified frequency-specific brain networks for the processing of positive (high-beta frequency) and negative (theta frequency) events. Remarkably, midbrain dopaminergic signalling also includes theta and high-beta frequency modes, which have been assumed to reflect tonic and phasic dopamine responses, respectively. The aim of the present study was to identify alterations of oscillatory responses to reward feedback in patients with schizophrenia. MethodsSeventeen patients with schizophrenia and 18 healthy controls performed a gambling task during recording of 64-channel electroencephalography. The theta and high-beta band total power were investigated in response to feedback events depending on feedback valence (loss or gain) and magnitude (5 vs. 25 points). ResultsBoth the increase of theta oscillatory activity in response to loss feedback (compared to gain feedback) and the increase of high-beta oscillatory activity in response to gain feedback (compared to loss feedback) were reduced in patients. The difference in high-beta responses to gain versus loss feedback in patients was associated with the severity of negative symptoms. ConclusionsOur findings are consistent with current models of reward system dysfunction in schizophrenia, and indicate deficits in both cortical tonic and subcortical phasic dopamine activity, consistent with the complex dopaminergic abnormalities in schizophrenia.

Diverging changes in rat striatal extracellular dopamine and DOPAC levels and in frequency-modulated 50-kHz ultrasonic vocalizations rate during repeated amphetamine treatment

One characteristic feature of addictive drugs is their ability to induce, after a single exposure, a lasting sensitization to the next doses; the underlying neuroplastic changes supposedly involve the brain dopamine system. We aimed at identifying putative relationships between alterations in extracellular dorsal striatal dopamine, HVA and DOPAC levels and in frequency-modulated 50-kHz ultrasonic vocalizations rate response during repeated intraperitoneal amphetamine treatment. Measurements were performed before and after amphetamine doses 1, 2, 7 and 8 (Amph1, Amph2, Amph7 and Amph8; treatment days 1, 7, 12 and 23, respectively). Amphetamine was confirmed to induce sensitization of the vocalization response, but an extended recording time (180 instead of 20 min) revealed that sensitization of this response requires more time to develop than hitherto believed. Baseline extracellular dopamine level increased initially, declined after a series of daily amphetamine doses and showed some tendency for recovery after drug withdrawal. Baseline extracellular DOPAC (but not HVA) showed a continuous decline during the treatment. There was no significant change in the integrated short-term (3-h) extracellular dopamine response, whereas the respective DOPAC collection lowered significantly after repeated drug treatment. Extracellular DOPAC is believed to originate mostly from newly synthesized dopamine, hence the declines in its baseline and post-amphetamine levels suggest falling dopamine synthesis. These results indicate that sensitization of the appetitive vocalization response to amphetamine continues despite reduced dorsal striatal dopamine synthesis and involves no changes in amphetamine-induced dopamine release.

Neuromorphic Organic Devices that Specifically Discriminate Dopamine from Its Metabolites by Nonspecific Interactions

AbstractSpecific detection of dopamine (DA) is achieved with organic neuromorphic devices with no specific recognition function in an electrolyte solution. The response to voltage pulses consists of amplitude‐depressed current spiking mimicking the short‐term plasticity (STP) of synapses. An equivalent circuit hints that the STP timescale of the device arises from the capacitance and resistance of the poly(3,4‐ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) in series with the electrolyte resistance. Both the capacitance and resistance of PEDOT:PSS change with solution compositions. Dose curves are constructed from the STP timescale for each DA metabolite from pM to mM range of concentrations. The STP response of DA is distinctive from the other metabolites even when differences are by one functional group. Both STP and sensitivity to DA are larger across the patho‐physiological range with respect to those to DA metabolites. Density functional theory calculations hint to a stronger hydrogen bond pattern of DA ammonium compared to cationic metabolites. The exponential correlation between STP and the binding energy of DA metabolites interacting with PEDOT:PSS indicates that the slow dynamics of ionic species in and out PEDOT:PSS is the origin of the neuromorphic STP. The sensing framework discriminates differences of nonspecific interactions of few kcal mol−1, corresponding to one functional group in the molecule.

Effect of Ionic Liquid Structure on the Electrochemical Response of Dopamine at Room Temperature Ionic Liquid‐modified Carbon Paste Electrodes (IL–CPE)

AbstractIn this work 12 different ionic liquids (ILs) have been used added as co‐binders in the preparation of modified carbon paste electrodes (IL–CPEs) used for the voltammetric analysis of dopamine in Britton‐Robinson buffer. The ionic liquids studied were selected based on three main criteria: (1) increasing chain length of alkyl substituents (studying 1‐ethylimidazolium and ethyl, propyl, butyl, hexyl and decylmethylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids); (2) nature of the counter ion (dicyanamide, bis(trifluoromethylsulfonyl)imide and hexafluorophosphate) in 1‐butyl‐3‐methylimidazolium ionic liquids; and (3) cation ring structures (1‐butyl‐3‐methylimidazolium, 1‐butyl‐1‐methylpiperidinium, 1‐butyl‐1‐methylpyrrolidinium and 1‐butyl‐3‐methylpyridinium) in bis(trifluoromethylsulfonyl)imide or hexafluorophosphate (1‐butyl‐3‐methylimidazolium or 1‐butyl‐3‐methylpyridinium as cations) ionic liquids. The use of IL as co‐binders in IL–CPE results in a general enhancement of both the sensitivity and the reversibility of dopamine oxidation. In square wave voltammetry experiments, the peak current increased up to a 400 % when 1‐ethyl‐3‐methylimidazolium bis(trifluoromethylsulfonyl)imide was used as co‐binder, as compared to the response found with the unmodified CPE. Experimental data provide evidence that electrostatic and steric effects are the most important ones vis‐à‐vis these electrocatalytic effects on the anodic oxidation of dopamine on IL–CPE. The relative hydrophilicity of dicyanamide anions reduced the electrocatalytic effects of the corresponding ionic liquids, while the use of 1‐ethyl‐3‐methylimidazolium hexafluorophosphate or 1‐ethyl‐3‐methylimidazolium bis(trifluoromethylsulfonyl)imide (two relatively small and highly hydrophobic ionic liquids) as co‐binders in IL–CPE resulted in the highest electrocatalytic activity among all of the IL–CPE studied.

Beyond the Average View of Dopamine.

Dopamine (DA) responses are synonymous with the 'reward prediction error' of reinforcement learning (RL), and are thought to update neural estimates of expected value. A recent study by Dabney et al. enriches this picture, demonstrating that DA neurons track variability in rewards, providing a readout of risk in the brain.

Smartphone-Based Electrochemical Potentiostat Detection System Using PEDOT: PSS/Chitosan/Graphene Modified Screen-Printed Electrodes for Dopamine Detection.

In this work, a smartphone-based electrochemical detection system was designed and developed for rapid and real-time detection of dopamine (DA). The system included a screen-printed electrode (SPE) used as a sensor, a hand-held electrochemical potentiostat and a smart phone with a specially designed app. During the detection period, the SPEs modified with poly(3,4-ethylenedioxythiophene) (PEDOT), chitosan (CS) and graphene (G) were used to convert and amplify the electrochemical reaction signals. The electrochemical potentiostat was used to generate excitation electrical signals and collect the electrical signals converted from the sensor. The smartphone—connected to the detector via Bluetooth-was used to control the detector for tests, further process the uploaded data, and plot graphs in real time. Experimental results showed that the self-designed sensing system could be employed for highly selective detection of DA in the presence of interfering substances such as ascorbic acid (AA) and uric acid (UA). CV was carried out to characterize the electrochemical properties of the modified SPEs and the electrochemical behaviors of DA on the modified SPEs. Finally, according to the analysis of DPV responses of DA, the system could detect DA with a detection sensitivity of 0.52 ± 0.01 μA/μM and a limit of detection of 0.29 μM in the linear range of DA concentrations from 0.05 to 70 μM.

Tailoring Surface Chemistry of Graphene Ink for Highly-Sensitive Electrochemical Detection of Dopamine Down to 50 Picomolar

Rising populations and healthcare expenses have sparked a global interest in rapid, cost-effective, and simple-to-use diagnostics at the point-of-care (PoC). According to The World Health Organization, over half of the world’s population does not have access to “essential medical services”.1 Current techniques for dopamine detection include capillary electrophoresis,2 high-performance liquid chromatography,3 colorimetry,4 and enzyme linked immunosorbent assays (ELISA).5 These methods, although effective, can be expensive, cumbersome, and require highly-skilled operators. Additionally, these techniques can be difficult to scale to point-of-care and continuous monitoring applications. Owing to their low cost, portability, and ease of operation, electrochemical sensors provide a viable solution. In the case of dopamine (DA), a highly redox-active molecule involved in many cognitive and neurological processes, as well as a stress and fatigue indicator,6,7 electrochemical sensors are an innate choice for its detection.Herein, we have developed an electrochemical sensor for detection of DA down to ultralow concentrations of 50 picomolar (pM) by specifically tailoring the surface properties of commercially available graphene ink. Graphene ink is spin-coated and serves as an inexpensive, easily-processible, and biocompatible platform for sensitive and selective dopamine detection. As shown in Figure 1a, we have examined the effect of various annealing conditions on the surface chemistry and the sensor response to DA. It was found that the response varied as a function of annealing temperature, environment, and duration. Samples annealed at 300℃ for 30 minutes in Ar/H2 environment showed the strongest response, with a detection limit of ~ 50 pM in phosphate buffered solution using differential pulse voltammetry (DPV, shown in Figure 1b). It is worth noting that the DA level in plasma is ~ 780 pM,8 which indicates that the developed DA sensor can potentially be used for testing clinical samples. Importantly, the sensor shows selective response to DA compared to uric acid and ascorbic acid, two common interfering species. To the best of our knowledge, this is the lowest detection limit reported for DA sensors solely based on graphene and is among the lowest for all electrochemical DA sensors. We observe that the variation in the sensor response between different annealing conditions is due to the different decomposition profiles of the ink’s ethyl cellulose stabilizing polymer.9 X-ray photoelectron spectroscopic (XPS) measurements are employed to characterize the effect of annealing on the surface chemistry. Principal component analysis (PCA) indicates that the π-π interaction and oxygen-containing functional groups on the graphene surface are the primary contributors to the improved dopamine response. This is further verified by studying the non-Faradaic interaction of three amine-containing molecules (dopamine (DA), phenylethylamine (PEA), and propylamine (PA))10 with the graphene surface (shown in Figure 1c-e). No change is seen in the charge vs. time between the background and 5 µM PA solutions, indicating the inconsequential role of the amine group on adsorption. However, PEA and DA show a noticeable difference in charge accumulation between the background and 5 μM solution, indicating both the aromatic ring of dopamine and the -OH groups contribute to adsorption on the graphene surface, in agreement with computational reports of dopamine adsorption on graphene.11,12 Variation of the processing conditions of graphene ink films can offer an avenue for tuning the electrochemical response towards different target analytes. Here, graphene enables low-concentration detection of dopamine in the pM-regime. The easily-processible, low-cost graphene ink utilized here poses as a scalable sensor material for use in flexible PoC electronics. The planar nature of the graphene improves compatibility with established integrated circuit (IC) technology, which can enable large-scale fabrication of biocompatible, electrochemical sensor arrays for application in wearable electronics and PoC diagnostics. References (1) World Health Organization and International Bank for Reconstruction and Development / The World Bank; Tracking Universal Health Coverage: 2017 Global Monitoring Report; 2017.(2) Park, Y. H.; Zhang, X.; Rubakhin, S. S.; Sweedler, J. V. Anal. Chem. 1999, 71 (21), 4997–5002.(3) Carrera, V.; Sabater, E.; Vilanova, E.; Sogorb, M. A. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2007, 847 (2), 88–94.(4) Kong, B.; Zhu, A.; Luo, Y.; Tian, Y.; Yu, Y.; Shi, G. Angew. Chem., Int. Ed. 2011, 123 (8), 1877–1880.(5) Nichkova, M.; Wynveen, P. M.; Marc, D. T.; Huisman, H.; Kellermann, G. H. J. Neurochem. 2013, 125 (5), 724–735.(6) Foley, T. E.; Fleshner, M. NeuroMolecular Med. 2008, 10 (2), 67–80.(7) Hyman, S. E.; Malenka, R. C. Nat. Rev. Neurosci. 2001, 2, 695–703.(8) Da Prada, M.; Zürcher, G. Life Sci. 1976, 19 (8), 1161–1174.(9) Chakrabarti, A.; Gunjikar, V. G.; Choudhary, V. R. Thermochim. Acta 1989, 145, 173–178.(10) Bath, B. D.; Michael, D. J.; Trafton, B. J.; Joseph, J. D.; Runnels, P. L.; Wightman, R. M. Anal. Chem. 2000, 72 (24), 5994–6002.(11) Fernández, A. C. R.; Castellani, N. J. ChemPhysChem 2017, 18 (15), 2065–2080.(12) Ortiz-Medina, J.; López-Urías, F.; Terrones, H.; Rodríguez-Macías, F. J.; Endo, M.; Terrones, M. J. Phys. Chem. C 2015, 119 (24), 13972–13978. Figure 1

Monitoring Corona Exchange Dynamics on Single-Walled Carbon Nanotubes Using Multiplexed Fluorophore Quenching

Single-walled carbon nanotubes (SWCNTs) non-covalently modified with DNA have been widely implemented as probes for near-infrared molecular sensing and imaging in biological systems. However, these constructs show poor stability in biomolecule-rich, in vivo environments leading to attenuation of sensor response. To study the relevant interactions that occur between DNA-SWCNTs in a biological environment, we develop a method to capture real-time binding behavior of fluorophore-labeled biomolecules, utilizing the SWCNT surface as a fluorescence quencher. We apply this assay to monitor corona dynamics of proteins adsorbing on single-stranded DNA (ssDNA) functionalized SWCNT dopamine sensor. We show the proteins albumin and fibrinogen adsorb to varying degrees on the ssDNA-SWCNT surface. Fibrinogen adsorption was 168% greater than that of albumin on a mass basis. Furthermore, fibrinogen induced more DNA desorption than albumin. These results are recapitulated by the respective kinetic rate constants for adsorption and desorption, calculated by fitting experimental adsorption data to a competitive adsorption model. Greater fibrinogen adsorption and induced DNA desorption coincide with a 78.2% reduction in dopamine response compared to 52.2% for albumin. We use this method to further study the passivation of ssDNA-SWCNTs with PEGylated phospholipid, a molecule shown to improve biocompatibility of nanoparticle platforms. The non-covalent interaction causes marginal desorption of DNA but significantly reduces subsequent adsorption of fibrinogen. The mitigated protein adsorption by phospholipid-PEG coincides with a reduction in sensor response attenuation. This methodology presents a generic yet robust protocol to track solution-phase competitive adsorption of multiple chemical species on a nanoparticle surface and to relate these phenomena to sensor efficacy.

Combined Infusion and Stimulation with Fast-Scan Cyclic Voltammetry (CIS-FSCV) to Assess Ventral Tegmental Area Receptor Regulation of Phasic Dopamine.

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement learning. Understanding how the diverse neuronal inputs into the VTA control phasic DA release can provide a better picture of the circuitry that controls reward processing and reinforcement learning. Here, we describe a method that combines intra-VTA cannula infusions of pharmacological agonists and antagonists with stimulation-evoked phasic DA release (combined infusion and stimulation, or CIS) as measured by in vivo fast-scan cyclic voltammetry (FSCV). Using CIS-FSCV in anesthetized rats, a phasic DA response can be evoked by electrically stimulating the VTA with a bipolar electrode fitted with a cannula while recording in the nucleus accumbens core. Pharmacological agonists or antagonists can be infused directly at the stimulation site to investigate specific VTA receptors' roles in driving phasic DA release. A major benefit of CIS-FSCV is that VTA receptor function can be studied in vivo, building on in vitro studies.

Risk prediction error signaling: A two-component response?

Organisms use rewards to navigate and adapt to (uncertain) environments. Error-based learning about rewards is supported by the dopaminergic system, which is thought to signal reward prediction errors to make adjustments to past predictions. More recently, the phasic dopamine response was suggested to have two components: the first rapid component is thought to signal the detection of a potentially rewarding stimulus; the second, slightly later component characterizes the stimulus by its reward prediction error. Error-based learning signals have also been found for risk. However, whether the neural generators of these signals employ a two-component coding scheme like the dopaminergic system is unknown. Here, using human high density EEG, we ask whether risk learning, or more generally speaking surprise-based learning under uncertainty, is similarly comprised of two temporally dissociable components. Using a simple card game, we show that the risk prediction error is reflected in the amplitude of the P3b component. This P3b modulation is preceded by an earlier component, that is modulated by the stimulus salience. Source analyses are compatible with the idea that both the early salience signal and the later risk prediction error signal are generated in insular, frontal, and temporal cortex. The identified sources are parts of the risk processing network that receives input from noradrenergic cells in the locus coeruleus. Finally, the P3b amplitude modulation is mirrored by an analogous modulation of pupil size, which is consistent with the idea that both the P3b and pupil size indirectly reflect locus coeruleus activity.

Dopamine Signals Learn New Tricks

In this issue of Neuron, Morrens etal. (2020) show that stimulus-evoked dopamine responses are enhancedby novelty and increase the rate at which animals acquire conditioned responses. These results provide a candidate neural mechanism for latent inhibition and illustrate a new role of dopamine signals in learning.

Reinforcement Learning: Full Glass orEmpty - Depends Who You Ask.

An extension of the prediction error theory of dopamine, imported from artificial intelligence, represents thefull distribution over future rewards rather than only the average and better explains dopamine responses.

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

BackgroundMedium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)—mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain.ResultsA mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation.We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before.Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate.ConclusionBased on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

Intercalation Lithium Cobalt Oxide for the Facile Fabrication of a Sensitive Dopamine Sensor

AbstractIntercalation lithium cobalt oxide (LCO) with the properties of insertion and de‐intercalation of Li+ was utilized to fabricate the sensitive dopamine (DA) sensor, which has excellent adsorption and catalytic behavior. LCO mixed with graphite powder (LCO−G) for individual and simultaneous determination of DA and uric acid (UA) achieved the low detection limits and the wide concentration ranges without the interference of ascorbic acid (AA). For individual detection, the linear responses of DA and UA were in the concentration ranges of 0.020–20 μM and 0.500–200 μM with the detection limits of 4.0 nM and 0.18 μM (s/n=3), respectively. For simultaneous detection with UA and AA by the change of the concentrations of DA, the linear response ranges were 0.050–20 μM with the detection limit of 7.9 nM (s/n=3). The LCO−G/GCE was further applied to the detection of DA in human serum to illustrate its potential of highly sensitive and selective electrochemical sensing.

Striatal Dopamine Responses to Feeding are Altered in People with Obesity.

This study determined whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted thaninthe fed state in people with obesity. Striatal DA release was evaluated in 10 people with obesity and prediabetes after consuming a meal to satiation and afterfasting overnight as well as in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight by using positron emission tomography with [11 C]raclopride injection. Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (P < 0.05), but there was no difference in the magnitude of the response between fasting and fed conditions. People with obesity and prediabetes do not increase striatal DA release after eating a meal to satiation compared with fasting overnight and fail to inhibit DA release in response to high-calorie food stimuli after eating a meal to satiation. These data suggest that impaired DA signaling contributes to greater energy intake during meals in this population.

Regional Variation in Striatal Dopamine Spillover and Release Plasticity.

Recent optical observations of dopamine at axon terminals and kinetic modeling of evoked dopamine responses measured by fast scan cyclic voltammetry (FSCV) support local restriction of dopamine diffusion at synaptic release sites. Yet, how this diffusion barrier affects synaptic and volume transmission is unknown. Here, a deficiency in a previous kinetic model's fitting of stimulus trains is remedied by replacing an earlier assumption that dopamine transporters (DATs) are present only on the outer side of the diffusion barrier with the assumption that they are present on both sides. This is consistent with the known distribution of DATs, which does not show obvious DAT-free zones proximal to dopamine release sites. A simultaneous multifitting strategy is then shown to enable unique model fits to sets of evoked dopamine FSCV responses acquired in vivo or in brain slices. This data analysis technique permits, for the first time, the calculation of the fraction of dopamine which spills over from what appears to be the perisynaptic space, as well as other parameters such as dopamine release, release plasticity, and uptake. This analysis shows that dopamine's diffusion away from its release sites is remarkably hindered (τ = 5 s), but dopamine responses are rapid because of DAT activity. Furthermore, the new analysis reveals that uptake inhibitors can inhibit dopamine release during a stimulus train, apparently by depleting the releasable pool. It is suggested that ongoing uptake is critical for maintaining ongoing synaptic dopamine release and that the previously reported and also herein claimed increase of the initial dopamine release of some uptake inhibitors might be an important mechanism in addiction. Finally, brain mapping data reveal that the diffusion barrier is conserved, but there are variations in perisynaptic uptake, volume transmission, and release plasticity within the rat striatum. Therefore, an analysis paradigm is developed to quantify previously unmeasured features of brain dopaminergic transmission and to reveal regional functional differences among dopamine synapses.

Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression

BackgroundMedial forebrain bundle (MFB) deep brain stimulation (DBS) has anti-depressant effects clinically and in depression models. Currently, therapeutic mechanisms of MFB DBS or how stimulation parameters acutely impact neurotransmitter release, particularly dopamine, are unknown. Experimentally, MFB DBS has been shown to evoke dopamine response in healthy controls, but not yet in a rodent model of depression. ObjectiveThe study investigated the impact of clinically used stimulation parameters on the dopamine induced response in a validated rodent depression model and in healthy controls. MethodThe stimulation-induced dopamine response in Flinders Sensitive Line (FSL, n = 6) rat model of depression was compared with Sprague Dawley (SD, n = 6) rats following MFB DSB, using Fast Scan Cyclic Voltammetry to assess the induced response in the nucleus accumbens. Stimulation parameters were 130 Hz (“clinically” relevant) with pulse widths between 100 and 350 μs. ResultsLinear mixed model analysis showed significant impact in both models following MFB DBS both at 130 and 60 Hz with 100 μs pulse width in inducing dopamine response. Furthermore, at 130 Hz the evoked dopamine responses were different across the groups at the different pulse widths. ConclusionThe differential impact of MFB DBS on the induced dopamine response, including different response patterns at given pulse widths, is suggestive of physiological and anatomical divergence in the MFB in the pathological and healthy state. Studying how varying stimulation parameters affect the physiological outcome will promote a better understanding of the biological substrate of the disease and the possible anti-depressant mechanisms at play in clinical MFB DBS.