Dopamine Response Research Articles

Dopamine release and its control over early Pavlovian learning differs between the NAc core and medial NAc shell

Dopamine neurons respond to cues to reflect the value of associated outcomes. These cue-evoked dopamine responses can encode the relative rate of reward in rats with extensive Pavlovian training. Specifically, a cue that always follows the previous reward by a short delay (high reward rate) evokes a larger dopamine response in the nucleus accumbens (NAc) core relative to a distinct cue that always follows the prior reward by a long delay (low reward rate). However, it was unclear if these reward rate dopamine signals are evident during early Pavlovian training sessions and across NAc subregions. To address this, we performed fast-scan cyclic voltammetry recordings of dopamine levels to track the pattern of cue- and reward-evoked dopamine signals in the NAc core and medial NAc shell. We identified regional differences in the progression of cue-evoked dopamine signals across training. However, the dopamine response to cues did not reflect the reward rate in either the NAc core or the medial NAc shell during early training sessions. Pharmacological experiments found that dopamine-sensitive conditioned responding emerged in the NAc core before the medial NAc shell. Together, these findings illustrate regional differences in NAc dopamine release and its control over behavior during early Pavlovian learning.

Deletion of VGLUT2 in midbrain dopamine neurons attenuates dopamine and glutamate responses to methamphetamine in mice

Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release.

Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex

The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.

Early and late signals of unexpected reward contribute to low extraversion and high disinhibition, respectively.

Like socio-economic status and cognitive abilities, personality traits predict important life outcomes. Traits that reflect unusually low or high approach motivations, such as low extraversion and high disinhibition, are linked to various forms of mental disorder. Similarly, the dopamine system is theoretically linked to approach motivation traits and to various forms of mental disorder. Identifying neural contributions to extremes of such traits should map to neural sources of psychopathology, with dopamine a prime candidate. Notably, dopamine cells fire in response to unexpected reward, which suggests that the size of non-invasive, scalp-recorded potentials evoked by unexpected reward could reflect sensitivity in approach motivation traits. Here, we evaluated the validity of evoked electroencephalography (EEG) responses to unexpected reward in a monetary gain/loss task to assess approach motivation traits in 137 participants, oversampled for externalizing psychopathology symptoms. We demonstrated that over the 0-400ms period in which feedback on the outcome was presented, responses evoked by unexpected reward contributed to all theoretically relevant approach motivation trait domains (disinhibition, extraversion and the behavioural activation system); and did so only at times when dopamine responses normally peak and reportedly code salience (70-100ms) and valuation (200-300ms). In particular, we linked "dopaminergic" salience and valuation to the psychopathology-related constructs of low extraversion (social anxiety) and high disinhibition (impulsivity) respectively, making the evoked potential components biomarker candidates for indexing aberrant processing of unexpected reward.

Dopamine D1+D3 receptor density may correlate with parkinson disease clinical features.

ObjectiveDopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.MethodsWe analyzed the densities of D1R, D2R, and D3R in the striatum and substantia nigra (SN) using a novel quantitative autoradiography procedure previously developed by our group. We also examined the expression of D2R and D3R mRNA in the striatum by in situ hybridization.ResultsThe results showed that although no differences of striatal D1R were found among all groups; D2R was significantly decreased in the striatum of PD patients when compared with control and AD patients. Some clinical manifestations: age of onset, PD stage, dopamine responsiveness, and survival time after onset; showed a better correlation with striatal D1R + D3R densities combined compared to D1R or D3R alone.InterpretationThere is a possibility that we may infer the results in diagnosis, treatment, and prognosis of PD by detecting D1R + D3R as opposed to using dopamine D1 or D3 receptors alone. This is especially true for elderly patients with low D2R expression as is common in this disease.

Dissecting the role of CB1 and CB2 receptors in cannabinoid reward versus aversion using transgenic CB1- and CB2-knockout mice

Cannabinoids produce both rewarding and aversive effects in humans and experimental animals. However, the mechanisms underlying these conflicting findings are unclear. Here we examined the potential involvement of CB1 and CB2 receptors in cannabinoid action using transgenic CB1-knockout (CB1-KO) and CB2-knockout (CB2-KO) mice. We found that Δ9-tetrahydrocannabinol (Δ9-THC) induced conditioned place preference at a low dose (1 mg/kg) in WT mice that was attenuated by deletion of the CB1 receptor. At 5 mg/kg, no subjective effects of Δ9-THC were detected in WT mice, but CB1-KO mice exhibited a trend towards place aversion and CB2-KO mice developed significant place preferences. This data suggests that activation of the CB1 receptor is rewarding, while CB2R activation is aversive. We then examined the nucleus accumbens (NAc) dopamine (DA) response to Δ9-THC using in vivo microdialysis. Unexpectedly, Δ9-THC produced a dose-dependent decrease in extracellular DA in WT mice, that was potentiated in CB1-KO mice. However, in CB2-KO mice Δ9-THC produced a dose-dependent increase in extracellular DA, suggesting that activation of the CB2R inhibits DA release in the NAc. In contrast, Δ9-THC, when administered systemically or locally into the NAc, failed to alter extracellular DA in rats. Lastly, we examined the locomotor response to Δ9-THC. Both CB1 and CB2 receptor mechanisms were shown to underlie Δ9-THC-induced hypolocomotion. These findings indicate that Δ9-THC's variable subjective effects reflect differential activation of cannabinoid receptors. Specifically, the opposing actions of CB1 and CB2 receptors regulate cannabis reward and aversion, with CB2-mediated effects predominant in mice.

Thirst recruits phasic dopamine signaling through subfornical organ neurons

Thirst is a highly potent drive that motivates organisms to seek out and consume balance-restoring stimuli. The detection of dehydration is well understood and involves signals of peripheral origin and the sampling of internal milieu by first order homeostatic neurons within the lamina terminalis-particularly glutamatergic neurons of the subfornical organ expressing CaMKIIa (SFOCaMKIIa). However, it remains unknown whether mesolimbic dopamine pathways that are critical for motivation and reinforcement integrate information from these "early" dehydration signals. We used in vivo fiber photometry in the ventral tegmental area and measured phasic dopamine responses to a water-predictive cue. Thirst, but not hunger, potentiated the phasic dopamine response to the water cue. In euvolemic rats, the dipsogenic hormone angiotensin II, but not the orexigenic hormone ghrelin, potentiated the dopamine response similarly to that observed in water-deprived rats. Chemogenetic manipulations of SFOCaMKIIa revealed bidirectional control of phasic dopamine signaling during cued water reward. Taking advantage of within-subject designs, we found predictive relationships between changes in cue-evoked dopamine response and changes in behavioral responses-supporting a role for dopamine in motivation induced by homeostatic need. Collectively, we reveal a putative mechanism for the invigoration of goal-directed behavior: internal milieu communicates to first order, need state-selective circuits to potentiate the mesolimbic dopamine system's response to cues predictive of restorative stimuli.

Aptamer and molecularly imprinted polymer: Synergistic recognition and sensing of dopamine

Specifically sensitive determination of dopamine (DA) from complex real samples is very important since DA plays a major role in the function of central nervous, which presents the necessary to develop an effective sensor for the assay of DA. In this work, a dual recognition strategy was developed through introducing DA-aptamer and molecularly imprinted polymer (MIP) on gold nanoparticles (AuNPs) and reduced graphene oxide (rGO) modified electrode. The selectivity and sensitivity of the prepared sensor were investigated upon the current response of DA itself to better represent the performances of the sensor. Compared with the single recognition element (MIP or aptamer) based sensors, the prepared dual recognition sensor displayed the highest selectivity to DA, which facilitated the proposed sensor for the detection of DA in real samples. Owing to the high surface and good conductivity of the modified AuNPs and rGO, the sensor showed a wide linear range and a low limit of detection of 5.0 × 10-8 – 1.0 × 10-5 mol/L and 4.7 × 10-8 mol/L for the detection of DA, respectively. The proposed strategy of aptamer and MIP based sensor for electro-active target assay may be used as a general way for the development of other dual recognition based sensors.

Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212–2 and heroin in adult male rats

Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance. Because the endogenous cannabinoid and opioid systems exhibit considerable cross-talk and cross-tolerance frequently develops following repeated exposure to either opioids or cannabinoids, there is interest in investigating whether a history of synthetic cannabinoid exposure influences the ability of heroin to increase DA release. To test the effects of chronic cannabinoid exposure on cannabinoid- and heroin-evoked DA release, male adult rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2; WIN) using an intravenous (IV) dose escalation regimen (0.2–0.8 mg/kg IV over 9 treatments). As predicted, WIN-treated rats showed a rightward shift in the dose-response relationship across all behavioral/physiological measures when compared to vehicle-treated controls. Then, using fast-scan cyclic voltammetry to measure changes in the frequency of transient DA events in the nucleus accumbens shell of awake and freely-moving rats, it was observed that the DA releasing effects of both WIN and heroin were significantly reduced in male rats with a pharmacological history of cannabinoid exposure. These results demonstrate that repeated exposure to the synthetic cannabinoid WIN can produce tolerance to its DA releasing effects and cross-tolerance to the DA releasing effects of heroin.

A novel electrochemical platform based on mesoporous silica/titania and gold nanoparticles for simultaneous determination of norepinephrine and dopamine

An amorphous and mesoporous silica/titania (SiTi) material was synthesized by sol-gel method and its surface was modified with gold nanoparticles (AuNP) previously stabilized in a chitosan solution. The presence of small AuNP, with diameter lower than 10 nm was confirmed by transmission electron microscopy (TEM) and UV–Vis spectroscopy. Carbon paste electrodes were prepared to test the electrochemical properties by using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in [Fe(CN)6]3−/4− solution probe whereby the material silica-titania/gold nanoparticles (SiTi/AuNP) showed a huge improvement in the redox peak current and low charge transfer resistance. This electrode presented a good response for both norepinephrine and dopamine by means of square wave voltammetry (SWV) measurements; great sensitivity for both analytes, in an extensive linear range, was obtained. The limits of detection were 0.35 μmol L−1 and 0.57 μmol L−1 for norepinephrine and dopamine, respectively. Additionally, this electrode showed high selectivity for both analytes and it was applied in the simultaneous determination of norepinephrine and dopamine. The sensor was also tested in simulated biological fluids presenting a good recovery. The SWV electrochemical response of norepinephrine was also investigated in the presence of possible interferers such as uric acid, ascorbic acid and glucose and there was no significant interference. The prepared electrode also exhibits good reproducibility for norepinephrine detection, with relative standard deviation of 5.19%.

The mitigation effects of exogenous dopamine on low nitrogen stress in Malus hupehensis

Dopamine plays numerous physiological roles in plants. We explored its role in the regulation of growth, nutrient absorption, and response to nitrogen (N) deficiency in Malus hupehensis Rehd. Under low N condition, plant growth slowed, and the net photosynthetic rates, chlorophyll contents, and maximal quantum yield of PSII (Fv/Fm) decreased significantly. However, the application of 100 μmol L−1 exogenous dopamine significantly reduced the inhibition of low N stress on plant growth. In addition to modifying root system architecture under low N supply, exogenous dopamine also changed the uptake, transport, and distribution of N, P, and K. Furthermore, exogenous dopamine enhances the tolerance to low nitrogen stress by increasing the activity of enzymes (nitrate reductase, nitrite reductase, glutamic acid synthase and glutamine synthetase) involved in N metabolism. We also found that exogenous dopamine promoted the expression of ethylene signaling genes (ERF1, ERF2, EIL1, ERS2, ETR1, and EIN4) under low N stress. Therefore, we hypothesized that ethylene might be involved in dopamine response to low N stress in M. hupehensis. Our results suggest that exogenous dopamine can mitigate low N stress by regulating the absorption of mineral nutrients, possibly through the regulation of the ethylene signaling pathway.

The (b)link between amotivation and psychosis: Insights through phasic eye blink rate

Motivation deficits within Schizophrenia Spectrum Disorders (SSDs) are associated with abnormal striatal dopamine responses during reward processing. Eye blink rate (EBR) has been used as a proxy for striatal dopamine; however, it is unclear whether EBR is sensitive to individual differences in amotivation. Amotivation (clinician-rated and self-reported) and EBR during an effort-based reward task were assessed in 28 outpatients with SSDs. EBR was lower during more “active” task phases relative to rest periods. Higher EBR during reward anticipation was associated with lower self-reported, but not clinician-rated, motivation. These preliminary results support a task-engagement, rather than striatal dopamine, account of EBR.

High electrochemical detection of dopamine based on Cu doped single phase hexagonally ZnO plates

Dopamine is a chemical that plays a key role in various neurological diseases such as Parkinson's, depression, and some types of cancer. Hence, sensitive detection methods of dopamine are necessary for early discernment of diseases related to abnormal levels. In this study, Cu doped ZnO (Cu/ZnO) nanostructures, immobilized onto the surface of glassy carbon electrode (GCE), have been investigated as a highly efficient electrode material for the electrochemical detection of dopamine (DA). A simple hydrothermal process was used for the synthesis of the ZnO and Cu/ZnO nanostructures. Detailed characterization revealed that addition of Cu on the ZnO changed the morphology of ZnO creating a highly microporous nanostructure. The electrochemical response of DA on the Cu/ZnO/GC electrodes, determined using cyclic voltammetry (CV) and differential pulsed voltammetry (DPV), indicated that on these materials it is possible to achieve lower over-potentials for the DA oxidation and higher catalytic activity. Furthermore, the GCE modified with 50 % Cu doped ZnO showed the most promising performance with high stability in wide range of pH values (2–8 pH), and linear response for DA from 0.1–20 μM with high sensitivity of 2630 nA/μM and detection limit as low as 55 nM. The analytical performance of the developed sensor showed its potential capability for the DA quantification in complex biological systems.

Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats

Oxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin's anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and sucrose reward value encoding following a motivational shift (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of sucrose reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin's effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA.

Disposable pencil graphite electrode decorated with a thin film of electro-polymerized 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido [1, 2-a] azepine for simultaneous voltammetric analysis of dopamine, serotonin and tryptophan

A facile electrochemical sensor for the individual and simultaneous quantification for elevated levels of dopamine, tryptophan, and serotonin was fabricated on pencil graphite electrode modified with 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido[1, 2-a] azepine. The fabricated electrode was characterized by scanning electron microscopy and infrared spectroscopy. Voltammetric response of dopamine, tryptophan and serotonin on the electrode was attained by cyclic and differential pulse voltammetric techniques. Under experimental conditions, three well-separated irreversible oxidation peaks at +0.123 V, +0.302 V and +0.619 V were observed correspond to the oxidations of dopamine, serotonin and tryptophan. The anodic peak currents and the concentrations of dopamine, serotonin, and tryptophan were found to be linear in the range from 1 to 20 μM, 1–62 μM, and 1.5–750 μM with detection limits of 0.05, 0.27, and 0.05 μM, respectively. The linear ranges and the limits of detection for the simultaneous determination of these analytes are found to be superior to previously reported electrochemical sensors. The electropolymerization of 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido[1, 2-a] azepine on a pencil graphite electrode is reported for the first time and the fabricated electrode is suitable for the determination of dopamine, serotonin and tryptophan in human blood and urine samples with good reproducibility and stability.

Ligand with Two Modes of Interaction with the Dopamine D2 Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism.

A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D2 receptor (D2R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D2R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D2R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D2R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.

Distinguishing catecholamines: Dopamine determination in the presence of epinephrine in water/acetonitrile mixtures

Several neural circuits within the hypothalamus, cerebellum and frontal cortex are simultaneously regulated by multiple catecholamines (CA). Yet, analytical methods that allow determination of CA either have low time resolution (microdialysis) or have poor selectivity (electrochemistry). In this study we used the structural difference between dopamine (DA) and epinephrine (EP) (primary amine group vs. methylated amine) as a distinguishable feature for the electrochemical detection of DA in DA/EP mixtures. Primary amino group of DA was activated in acetonitrile-water mixtures which provided an additional oxidation peak absent in the methylated amino group from EP. First, a systematic study of the effect of the water content in water/acetonitrile mixtures on the electrochemical response of DA is presented. It was found that the electrochemical reversibility of the main redox processes of DA is affected by the water content in acidified (1.0 mM HClO4) water/ACN mixtures. Decreasing the water content from 100% to 5% results in a progressive decrease of the DA reversibility and more importantly, promotes the appearance of a new redox signal, presumably associated to the oxidation of the amine center. That oxidation signal was used to achieve a simultaneous determination of DA and EP in water/acetonitrile mixtures (5% H2O) using square wave voltammetry. Results show an accurate determination of DA while offering an estimate of the concentration of EP. Our study opens up a new strategy for simultaneous electrochemical detection of either DA-EP or NE-EP, which in the future could be applied to surface modified microelectrodes for in vivo applications using the time resolution provided by fast-scan cyclic voltammetry, FSCV.

Hypoxia-Associated Changes in Striatal Tonic Dopamine Release: Real-Time in vivo Measurements With a Novel Voltammetry Technique.

Introduction Striatal tonic dopamine increases rapidly during global cerebral hypoxia. This phenomenon has previously been studied using microdialysis techniques which have relatively poor spatio-temporal resolution. In this study, we measured changes in tonic dopamine during hypoxia (death) in real time with high spatio-temporal resolution using novel multiple cyclic square wave voltammetry (MCSWV) and conventional fast scan cyclic voltammetry (FSCV) techniques.MethodsMCSWV and FSCV were used to measure dopamine release at baseline and during hypoxia induced by euthanasia, with and without prior alpha-methyl-p-tyrosine (AMPT) treatment, in urethane anesthetized male Sprague-Dawley rats.ResultsBaseline tonic dopamine levels were found to be 274.1 ± 49.4 nM (n = 5; mean ± SEM). Following intracardiac urethane injection, the tonic levels increased to a peak concentration of 1753.8 ± 95.7 nM within 3.6 ± 0.6 min (n = 5), followed by a decline to 50.7 ± 21.5 nM (n = 4) at 20 min. AMPT pre-treatment significantly reduced this dopamine peak to 677.9 ± 185.7 nM (n = 3). FSCV showed a significantly higher (p = 0.0079) peak dopamine release of 6430.4 ± 1805.7 nM (n = 5) during euthanasia-induced cerebral hypoxia.ConclusionMCSWV is a novel tool to study rapid changes in tonic dopamine release in vivo during hypoxia. We found a 6-fold increase in peak dopamine levels during hypoxia which was attenuated with AMPT pre-treatment. These changes are much lower compared to those found with microdialysis. This could be due to improved estimation of baseline tonic dopamine with MCSWV. Higher dopamine response measured with FSCV could be due to an increased oxidation current from electroactive interferents.

Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction.

Cocaine is known to increase brain dopamine at supranormal levels in comparison to alternative nondrug rewards. According to the dopamine hypothesis of addiction, this abnormally large dopamine response would explain why cocaine use is initially highly rewarding and addictive. Though resting on solid neuroscientific foundations, this hypothesis has nevertheless proven difficult to reconcile with research on cocaine choice in experimental animals. When facing a choice between an intravenous bolus of cocaine and a nondrug alternative (e.g., sweet water), both delivered immediately after choice, rats do not choose the drug, as would be predicted, but instead develop a strong preference for the nondrug alternative. Here we report evidence that reconciles this finding with the dopamine hypothesis of addiction. First, a systematic literature analysis revealed that the delays of effects of intravenous cocaine on nucleus accumbens dopamine are of the order of tens of seconds and are considerably longer than those of nondrug reward. Second, this was confirmed by measuring response times to cocaine omission during self-administration as a behavioral proxy of these delays. Finally, when the influence of the drug delays was reduced during choice by adding an increasing delay to both the drug and nondrug rewards, rats shifted their choice to cocaine. Overall, this study suggests that cocaine is indeed supranormal in reward magnitude, as postulated by the dopamine hypothesis of addiction, but is less preferred during choice because its pharmacokinetics makes it an inherently more delayed reward than the alternative. Reframing previous drug choice studies in rats as intertemporal choice studies reveals that the discounting effects of delays spare no rewards, including supranormal ones, and that during choice, pharmacokinetics trumps pharmacodynamics.

Ternary Pt–Au–FeOOH-decorated polyaniline nanocomposite for sensitive dopamine electrochemical detection

Abstract Electrochemical dopamine sensing is crucial for neurological diseases, but its practical application is challenged by sensitivity and anti-interference. Pt-decorated polymer electrode is desirable for dopamine sensing, but its unsatisfactory sensitivity, anti-poisoning capability, and stability limit its application. A new ternary Pt–Au–FeOOH-decorated polyaniline (PANI) nanocomposite (PANI/Pt–Au–FeOOH) modified electrode was successfully fabricated for dopamine (DA) detection. The electrochemical response of DA on PANI/Pt–Au–FeOOH-modified electrode obtained by differential pulse voltammetry (DPV) showed higher electrocatalytic activity than its contrastive unitary and binary Pt-decorated PANI nanocomposites. Analysis of DPV performance for PANI/Pt–Au–FeOOH-modified electrode showed a wide bilinear response of 10–200 and 0.001–10 μM, a low limit of detection (LOD) of 1 nM (0.001 μM), and outstanding anti-interference and stability. Human serum experiment revealed PANI/Pt–Au–FeOOH as a potential sensing electrode and indicated its high detection accuracy for DA. The PANI/Pt–Au–FeOOH also showed its advantage for UA detection. The remarkable advantages of its analytical performance for ternary Pt–Au–FeOOH may be ascribed to the tuning electronic structure and chemical properties of Pt by adjacent metal atoms. This work provides a new choice for the fabrication of advanced Pt-based nanocatalysts with enhanced electrochemical activity.