Search

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.

Contains fulltext : 220564.pdf (Publisher’s version ) (Open Access)

Nora Volkow leads the world’s biggest funder of addiction research at a time when the United States is grappling with a devastating surge in drug use. Nora Volkow leads the world’s biggest funder of addiction research at a time when the United States is grappling with a devastating surge in drug use.

OBJECTIVE: To determine 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 than fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after participants consumed a meal to satiation and after they fasted overnight, and 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. RESULTS: 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

Herein we report an electrochemiluminescent nanocage array (ENA) in which luminophores are physically confined. The ENA can function as a solid sensor for the detection of dopamine released from living cells on the basis of its quenching effect on the ECL signal.

Modern techniques for estimating basal levels of electroactive neurotransmitters rely on the measurement of oxidative charges. This requires time integration of oxidation currents at certain intervals. Unfortunately, the selection of integration intervals relies on ad-hoc visual identification of peaks on the oxidation currents, which introduces sources of error and precludes the development of automated procedures necessary for analysis and quantification of neurotransmitter levels in large data sets. In an effort to improve charge quantification techniques, here we present novel methods for automatic selection of integration boundaries. Our results show that these methods allow quantification of oxidation reactions both in vitro and in vivo and of multiple analytes in vitro.

Similar to other neurodegenerative diseases, Parkinson’s disease (PD) has been extensively investigated with respect to its neuropathological background and possible treatment options. Since the symptomatic outcomes are generally related to dopamine deficiency, the current treatment strate-gies towards PD mainly employ dopaminergic agonists as well as the compounds acting on dopamine metabolism. These drugs do not provide disease modifying properties; therefore alternative drug dis-covery studies focus on targets involved in the progressive neurodegenerative character of PD. This study has aimed to present the pathophysiology of PD concomitant to the representation of drugs and promising molecules displaying activity against the validated and non-validated targets of PD.

ZusammenfassungKoffein ist das weltweit am häufigsten konsumierte Psychostimulans. Es ist nahezu unbeschränkt verfügbar und unterliegt in Europa keiner staatlichen Regulation. Neben seiner primären Rolle als Inhalts- oder Zusatzstoff in zahlreichen Getränken findet es auch medizinische Verwendung in der adjuvanten Schmerztherapie, bei primärem Atemstillstand bei Neugeborenen und es ist zugelassen für die kurzfristige Beseitigung von Ermüdungserscheinungen. Der Wirkmechanismus von Koffein als Psychostimulans in typischerweise aufgenommen Dosierungen basiert vermutlich in erster Linie auf einem zentralen Antagonismus von Adenosinrezeptoren (A1- und A2A-Rezeptoren), was zu einer zentralen Hemmung der Adenosin-vermittelten Reduktion der Aktivität des dopaminergen und aufsteigenden Aktivierungssystems führt. Die Metabolisierung von Koffein ist hautsächlich abhängig von Cytochrom P450 1A2, sodass Faktoren, die die Aktivität von CYP 1A2 beeinflussen (z. B. Medikamente, Schwangerschaft), erhebliche Veränderungen der pharmakokinetischen Parameter induzieren können. Koffein führt insbesondere bei Individuen mit Schlafentzug zu einer Verbesserung der Vigilanz, Aufmerksamkeit und Reaktionszeit. Zudem kann es sportliche Ausdauerleistungen und muskuläre Kraft verbessern. Intoxikationen mit Koffein sind selten, können jedoch letal verlaufen. In üblicherweise aufgenommenen Mengen gilt Koffeingebrauch als nicht gesundheitsschädlich. Koffein weist zahlreiche, jedoch nicht alle Merkmale einer Substanz mit „Abhängigkeitspotential“ auf; Entzugssyndrome nach Beendigung einer längeren Anwendung und Toleranz sind bekannt. Im DSM-5 wird die „Koffeingebrauchsstörung“ als mögliche künftige Störung, die gegenwärtig weiterer Forschung bedarf, rubriziert. Das Koffeingebrauchsmuster von Patienten sollte im Rahmen der ärztlichen Tätigkeit berücksichtigt werden.

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf). Release profile of MEM from MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague-Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy rats did not result in any significant changes. The in vivo study in an AlCl

The current report provides an updated review of sleep disturbance in posttraumatic stress disorder and anxiety-related disorders. First, this review provides a summary description of the unique and overlapping clinical characteristics and physiological features of sleep disturbance in specific DSM anxiety-related disorders. Second, this review presents evidence of a bidirectional relationship between sleep disturbance and anxiety-related disorders, and provides a model to explain this relationship by integrating research on psychological and neurocognitive processes with a current understanding of neurobiological pathways. A heuristic neurobiological framework for understanding the bidirectional relationship between abnormalities in sleep and anxiety-related brain pathways is presented. Directions for future research are suggested.

Dopamine controls motor functions, motivation, and reward-related learning through G-protein coupled receptor signaling. The current working model is that upon release, dopamine diffuses to influence many target cells via wide-spread receptors. Recent studies, however, suggest that dopamine release is fast and generates small signaling hotspots. In this review, we summarize progress on the understanding of the dopamine release apparatus and evaluate how its properties may shape dopamine signaling during firing. We discuss how mechanisms of regulation may act through this machinery and propose that striatal architecture for dopamine signaling may have evolved to support rapid dopamine coding.

One of the major problems in the translation of successful preclinical results to clinical studies and new therapies in Parkinson's disease is the use of preclinical models based on exogenous neurotoxins that do not replicate what happens in the disease. The loss of dopaminergic neurons containing neuromelanin in Parkinson´s disease takes years, contrasting the very rapid degeneration induced by exogenous neurotoxins. We discuss the role of endogenous neurotoxins generated during dopamine oxidation and its possible use as new preclinical models for Parkinson´s disease.

International audience; In a volatile environment where rewards are uncertain, successful performance requires a delicate balance between exploitation of the best option and exploration of alternative choices. It has theoretically been proposed that dopamine contributes to the control of this exploration-exploitation trade-off, specifically that the higher the level of tonic dopamine, the more exploitation is favored. We demonstrate here that there is a formal relationship between the rescaling of dopamine positive reward prediction errors and the exploration-exploitation trade-off in simple non-stationary multi-armed bandit tasks. We further show in rats performing such a task that systemically antagonizing dopamine receptors greatly increases the number of random choices without affecting learning capacities. Simulations and comparison of a set of different computational models (an extended Q-learning model, a directed exploration model, and a meta-learning model) fitted on each individual confirm that, independently of the model, decreasing dopaminergic activity does not affect learning rate but is equivalent to an increase in random exploration rate. this study shows that dopamine could adapt the exploration-exploitation trade-off in decision-making when facing changing environmental contingencies. All organisms need to make choices for their survival while being confronted to uncertainty in their environment. Animals and humans tend to exploit actions likely to provide desirable outcomes, but they must also take into account the possibility that environmental contingencies and the outcome of their actions may vary with time. Behavioral flexibility is thus needed in volatile environments in order to detect and learn new contingencies 1. This requires a delicate balance between exploitation of known resources and exploration of alternative options that may have become advantageous. How this exploration/exploitation dilemma may be resolved and regulated is still a subject of active research in the fields of Neuroscience and Machine Learning 2-5. Dopamine holds a fundamental place in contemporary theories of learning and decision-making. The temporal evolution of phasic dopamine signals across learning has been extensively replicated, and is most of the time considered as evidence of a role in learning 6-8 , but see alternative views in Coddington et al. 9. Dopamine reward prediction error (RPE) signals have been identified in a variety of instrumental and Pavlovian conditioning tasks 10-13. They affect plasticity and action value learning in cortico-basal networks 14-16 and have been directly related to behavioral adaptation in a number of decision-making tasks in humans, non-human primates 17 and rodents 18-21. Accordingly, it is commonly assumed that manipulations of dopamine activity affect the rate of learning, but this could represent a misconception. Besides learning, the role of dopamine in the control of behavioral performance is still unclear. Dopamine is known to modulate incentive choice (the tendency to differentially weigh costs and benefits) 22,23 , and risk-taking behavior 24 , as well as other motivational aspects such as effort and response vigour 25. Because dopamine is one of the key factors that may encode success or uncertainty, it might modulate decisions by biasing them toward options that present the largest uncertainty 26,27. This would correspond to a "directed" exploration strategy 5,28,29. Alternatively, success and failure could affect tonic dopamine levels and control random exploration of all options, as recently proposed by Humphries et al. 30. This form of undirected exploration, which is often difficult

The question of how general anesthetics suppress consciousness has persisted since the mid-19th century, but it is only relatively recently that the field has turned its focus to a systematic understanding of emergence. Once assumed to be a purely passive process, spontaneously occurring as residual levels of anesthetics dwindle below a critical value, emergence from general anesthesia has been reconsidered as an active and controllable process. Emergence is driven by mechanisms that can be distinct from entry to the anesthetized state. In this narrative review, we focus on the burgeoning scientific understanding of anesthetic emergence, summarizing current knowledge of the neurotransmitter, neuromodulators, and neuronal groups that prime the brain as it prepares for its journey back from oblivion. We also review evidence for possible strategies that may actively bias the brain back toward the wakeful state.

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented, however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2&ndash, induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens &gamma, aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.

Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2+/−) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2+/− mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2+/− mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2+/− mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2+/− mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions. © 2020 The Authors. The authors' work reported here was supported by Deutsche Forschungsgemeinschaft (DFG:CRC TRR58A1/A5), DAAD (to ES), the European Union's Seventh Framework Programme (FP7/2007–2013) under Grant No.602805 (Aggressotype) and the Horizon 2020 Research and Innovation Programme under Grant No.728018 (Eat2beNICE) (to KPL and TS) and the President's program of PhD Exchange of RF-2017 (to TS and DA). We appreciate the valuable technical help of Natalia Bazhenova, Drs. Alexander Trofimov and Natalia Markova with this project.

Neuromelanin-sensitive MRI (NM-MRI) provides a noninvasive measure of the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). NM-MRI has been validated as a measure of both dopamine neuron loss, with applications in neurodegenerative disease, and dopamine function, with applications in psychiatric disease. Furthermore, a voxelwise-analysis approach has been validated to resolve substructures, such as the ventral tegmental area (VTA), within midbrain dopaminergic nuclei thought to have distinct anatomical targets and functional roles. NM-MRI is thus a promising tool that could have diverse research and clinical applications to noninvasively interrogate in vivo the dopamine system in neuropsychiatric illness. Although a test-retest reliability study by Langley et al. using the standard NM-MRI protocol recently reported high reliability, a systematic and comprehensive investigation of the performance of the method for various acquisition parameters and preprocessing methods has not been conducted. In particular, most previous studies used relatively thick MRI slices (∼3 mm), compared to the typical in-plane resolution (∼0.5 mm) and to the height of the SN (∼15 mm), to overcome technical limitations such as specific absorption rate and signal-to-noise ratio, at the cost of partial-volume effects. Here, we evaluated the effect of various acquisition and preprocessing parameters on the strength and test-retest reliability of the NM-MRI signal to determine optimized protocols for both region-of-interest (including whole SN/VTA-complex and atlas-defined dopaminergic nuclei) and voxelwise measures. Namely, we determined a combination of parameters that optimizes the strength and reliability of the NM-MRI signal, including acquisition time, slice-thickness, spatial-normalization software, and degree of spatial smoothing. Using a newly developed, detailed acquisition protocol, across two scans separated by 13 days on average, we obtained intra-class correlation values indicating excellent reliability and high contrast-to-noise, which could be achieved with a different set of parameters depending on the measures of interest and experimental constraints such as acquisition time. Based on this, we provide detailed guidelines covering acquisition through analysis and recommendations for performing NM-MRI experiments with high quality and reproducibility. This work provides a foundation for the optimization and standardization of NM-MRI, a promising MRI approach with growing applications throughout clinical and basic neuroscience.HighlightsA detailed NM-MRI volume placement protocol is described.Guidelines covering acquisition through analysis for NM-MRI are given.A test-retest study in 10 healthy subjects shows high reproducibility for region-of-interest (ROI) and voxelwise analyses.∼3 minutes of NM-MRI data is needed for high-quality ROI-analysis.∼6 minutes of NM-MRI data is needed for high-quality voxelwise-analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metabolism is a set of chemical reactions that convert nutrients into energy and building blocks for growth or remove toxic end products. Most reactions are catalysed by specialised proteins, called enzymes, which are encoded in our genes. If such a gene is mutated, it may produce an inactive enzyme and lead to diseases. These are called inborn errors of metabolism. All the chemical reactions in our body, together with their enzymes, form a functional blueprint of an individual. This can be translated into mathematical terms. Eventually, we may create mathematical models that include patient-specific information. Such a “digital twin” can then be used to analyse the molecular blueprint of an individual patient, and to discover potential new biomarkers and targets for therapies. In her PhD thesis, Agnieszka Wegrzyn describes several ways to optimise and apply various computational modelling approaches for the analysis of patient data and disease mechanisms. She predicts new biomarkers for Refsum disease (a disease in which the food component phytanic acid is not degraded) and for vitamin B2 deficiency. Also, she presents a new model for brain metabolism in phenylketonuria patients, linking diet with serotonin and dopamine metabolism. Based on this model, she proposes a diet optimisation to reduce neurological symptoms in these patients. This model can also be applied to other neurodegenerative diseases, such as Alzheimer’s or Parkinson’s Disease, depression, or autism.

In the last few years, the importance of measuring gait characteristics has increased tenfold due to their direct relationship with various neurological diseases. As patients suffering from Parkinson’s disease (PD) are more prone to a movement disorder, the quantification of gait characteristics helps in personalizing the treatment. The wearable sensors make the measurement process more convenient as well as feasible in a practical environment. However, the question remains to be answered about the validation of the wearable sensor-based measurement system in a real-world scenario. This paper proposes a study that includes an algorithmic approach based on collected data from the wearable accelerometers for the estimation of the gait characteristics and its validation using the Tinetti mobility test and 3D motion capture system. It also proposes a machine learning-based approach to classify the PD patients from the healthy older group (HOG) based on the estimated gait characteristics. The results show a good correlation between the proposed approach, the Tinetti mobility test, and the 3D motion capture system. It was found that decision tree classifiers outperformed other classifiers with a classification accuracy of 88.46%. The obtained results showed enough evidence about the proposed approach that could be suitable for assessing PD in a home-based free-living real-time environment.

Substance use disorder is a chronic relapsing disorder characterized by transitioning from acute drug reward to compulsive drug use. Despite the heavy personal and societal burden of substance use disorders, current treatments are limited and unsatisfactory. For this reason, a deeper understanding of the mechanisms underlying addiction is required. Altered redox status, primarily due to drug-induced increases in dopamine metabolism, is a unifying feature of abused substances. In recent years, knowledge of the effects of oxidative stress in the nervous system has evolved from strictly neurotoxic to include a more nuanced role in redox-sensitive signaling. More specifically, S-glutathionylation, a redox-sensitive post-translational modification, has been suggested to influence the response to drugs of abuse. In this review we will examine the evidence for redox-mediating drugs as therapeutic tools focusing on N-acetylcysteine as a treatment for cocaine addiction. We will conclude by suggesting future research directions that may further advance this field.

PURPOSE OF REVIEW: Eating disorders are severe psychiatric disorders with a suspected complex bio-psycho-social etiology. The purpose of this review is to synthesize the recent literature on brain imaging in eating disorders. RECENT FINDINGS: Food restriction as well as binge eating and purging behaviors are associated with lower regional brain volumes or cortical thickness, but those changes largely return to normal with normalization of weight and eating behavior. Computational modeling has started to identify patterns of structural and functional imaging data that classify eating disorder subtypes, which could be used in the future diagnostically and to better understand disorder specific psychopathology. The prediction error model, a computational approach to assess dopamine related brain reward function, helped support a brain based model for anorexia nervosa. In that model, the conscious motivation to restrict conflicts with body signals that stimulate eating, which causes anxiety and drives a vicious cycle of food restriction. SUMMARY: Novel brain research supports the notion that eating disorders have distinct neurobiological underpinnings. This new knowledge can be used to describe disease models to patients and develop novel treatments.

Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease causes deficits in movement initiation and slowness of movement. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements.

To describe the development and resolution of corneal edema in 3 patients who were exposed to compounds that stimulate dopaminergic pathways.We conducted a review of the literature on bilateral corneal edema secondary to amantadine use and report a case series of corneal edema seen in an outpatient ophthalmology specialty clinic, shortly after exposure to agents that enhance dopamine transmission.Cases 1 and 2 report a 25-year-old man with attention-deficit hyperactivity disorder and a 73-year-old man with Parkinson disease who were placed on dopaminergic medications to treat their conditions. The former was administered methylphenidate and the latter patient was administered ropinirole. Both patients developed corneal edema soon afterward. Case 3 is a 67-year-old man with a recent exposure to resin from Euphorbia resinifera, a cactus in his garden. After cessation of the offending medications and treatment for exposure to resiniferatoxin, the corneal edema progressively resolved and visual acuity returned to baseline in all 3 cases.Methylphenidate, ropinirole, and resiniferatoxin have different mechanisms of actions but have a common end point leading to increased dopamine. We believe that these agents are linked with the reversible corneal edema seen in our 3 patients. This strongly correlates with previous studies that have linked amantadine, a drug that blocks dopamine reuptake, to reversible corneal edema.

Background One of the most widespread prokaryotic symbionts of invertebrates is the intracellular bacteria of Wolbachia genus which can be found in about 50% of insect species. Wolbachia causes both parasitic and mutualistic effects on its host that include manipulating the host reproductive systems in order to increase their transmission through the female germline, and increasing the host fitness. One of the mechanisms, promoting adaptation in biological organisms, is a non-specific neuroendocrine stress reaction. In insects, this reaction includes catecholamines, dopamine, serotonin and octopamine, which act as neurotransmitters, neuromodulators and neurohormones. The level of dopamine metabolism correlates with heat stress resistance in Drosophila adults. Results To examine Wolbachia effect on Drosophila survival under heat stress and dopamine metabolism we used five strains carrying the nuclear background of interbred Bi90 strain and cytoplasmic backgrounds with different genotype variants of Wolbachia (produced by 20 backcrosses of Bi90 males with appropriate source of Wolbachia). Non-infected Bi90 strain (treated with tetracycline for 3 generations) was used as a control group. We demonstrated that two of five investigated Wolbachia variants promote changes in Drosophila heat stress resistance and activity of enzymes that produce and degrade dopamine, alkaline phosphatase and dopamine-dependent arylalkylamine N-acetyltransferase. What is especially interesting, wMelCS genotype of Wolbachia increases stress resistance and the intensity of dopamine metabolism, whereas wMelPop strain decreases them. wMel, wMel2 and wMel4 genotypes of Wolbachia do not show any effect on the survival under heat stress or dopamine metabolism. L-DOPA treatment, known to increase the dopamine content in Drosophila, levels the difference in survival under heat stress between all studied groups. Conclusions The genotype of symbiont determines the effect that the symbiont has on the stress resistance of the host insect.

The Val158Met polymorphism influences the activity of the Catechol-O-Methyl-Transferase (COMT), an enzyme involved in dopamine metabolism. Dopamine availability is vital for prefrontal functions. Therefore researchers claimed that Val158Met is causal for cognitive abilities. Published findings from single studies report mixed results. This meta-analysis examines the COMT genotype associations with working memory and intelligence in healthy populations. A systematic literature search was conducted yielding 412 studies, 58 of which could be included in the meta-analyses. There were no substantial COMT Val158Met effects on cognitive abilities, showing that either the true effect is zero or too small to be uncovered due to insufficient power of the analysis. The discussion focuses on power issues in research synthesis in general and their implications concerning the relation of Val158Met with working memory and intelligence in specific. Desiderata for research synthesis closely resemble those formulated in the open science framework: fully transparent single study design and data use of scientifically recommended methodologies.

Dopamine, one of catecholamine neurotransmitters, plays an important role in many brain functions and behavioral responses. In this study, we developed a novel dual-signal whole-cell biosensor for the detection of dopamine through the generation of red fluorescent proteins and 6-decarboxylated betaxanthin pigments. The proposed system responses specifically to dopamine with a detection limit of 1.43 μM. Furthermore, a combination of dual output signals makes it possible to reduce the interference from other catecholamine neurotransmitters, including L-DOPA, epinephrine, and norepinephrine.

Drugs for psychosis and mood that bind dopamine D2 receptors can be classified not only by whether they also block serotonin 2A receptors, but by whether they also bind D3 or D1 receptors.

In the case of valbenazine, which was recently approved for tardive dyskinesia, a small company pursued thoughtful, efficient trial design and an unusual application of remote assessment in clinical trials, and the FDA took an engaged and flexible approach to review.

Oculogyric crises are a rare movement disorder characterized by paroxysmal, conjugate, tonic, usually upwards, deviation of the eyes. Causes for oculogyric crises are limited and include complications of dopamine-receptor blocking medications and neurometabolic disorders affecting dopamine metabolism, suggesting that an underlying hypodopaminergic state is important to the pathogenesis. Mimickers of oculogyric crises exist, and we propose diagnostic criteria to distinguish true oculogyric crises. Recognition of oculogyric crises is important for the diagnosis and appropriate treatment of rare disorders, and an approach to investigations in oculogyric crises is proposed. © 2017 International Parkinson and Movement Disorder Society.

Since dopamine (DA) was discovered as an essential neurotransmitter, with a profound impact on motor control, memory, and behavioral impulses, the pathogenesis of several neurodegenerative and neuropsychiatric disorders have been associated with the dysfunction of the dopaminergic system. Regarding this, the most common drugs used to treat these pathologies act on the dopaminergic neurons. Therefore, the measurement of DA and its precursors and metabolites levels can be a useful tool to help the diagnosis and development of targeted therapeutic approaches to neurological disorders. Furthermore, monitoring and detecting DA metabolism (DA, precursors, and metabolites) in biological samples, like plasma, urine, and cerebrospinal fluid, constitute an interesting subject from a clinical perspective. However, the development of suitable and efficient methods to determine these compounds in biological samples remains a challenge. Thus, this review provides an overview of the recent advances and available methodologies to quantify DA and its precursors and metabolites in plasma samples focusing on previous reports which used less than two milliliters. Also, it deals with the actual extraction and separation techniques, as well as detection modes; and it gives a perspective, on the present-day, about the use of analytical methods as a helpful tool to improve diagnosis.

A series of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives exhibited high antidepressant and adaptogen activities. We now report a more detailed analysis of the effects of those substances on dopamine metabolism. For that purpose, we decided to unite two techniques: evaluation of the impact of compounds with antidepressant activity on levodopa effects and the test of suspension by the tail. Caffeine-sodium benzoate, amitriptyline, and fluoxetine were chosen as references.

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards and reward-driven learning. How dopamine supports both functions is unclear. Dopaminecell spiking can encode prediction errors, which arevital learning signals in computational theories of adaptive behaviour. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioural tasks, slower changes in dopamine cell spiking or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues thatindicatean upcoming reward increased both spiking and release. However, NAc core dopamine release also covaried with dynamically evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, whereas local control drives motivation.

In this work, we aimed to prepare a monolithic capillary column that allowed an isocratic separation of ten dopamine precursors and metabolites in a single run. Segments of five zwitterion sulfobetaine polymer monoliths have been modified by zwitterion phoshorylcholine by using an ultraviolet-initiated two-step photografting. Columns with 0, 33, 50, 66, and 100% of modified length were prepared. Effect of length of the modified segment and mobile phase composition has been tested. All columns provided dual-retention mechanism with reversed-phase retention in highly aqueous mobile phase and hydrophilic interaction mechanism in highly organic mobile phase. The retention mechanism was controlled by the composition of the mobile phase and has been described by a three-parameter model. We have used regression parameters to characterize the retention of analyzed compounds and to study individual pathways of dopamine metabolism. Comprehensive optimization of mobile phase composition allowed to find an optimal composition of the mobile phase and stationary phase surface chemistry arrangement to achieve desired separation. Optimized columns provided an isocratic separation of all tested compounds in less than nine min.

Traveling waves are commonly observed across the brain. While previous studies have suggested the role of traveling waves in learning, the mechanism remains unclear. We adopted a computational approach to investigate the effect of traveling waves on synaptic plasticity. Our results indicate that traveling waves facilitate the learning of poly-synaptic network paths when combined with a reward-dependent local synaptic plasticity rule. We also demonstrate that traveling waves expedite finding the shortest paths and learning nonlinear input/output mapping, such as exclusive or (XOR) function., Author summary There are approximately 1011 neurons with 1014 connections in the human brain. Information transmission among neurons in this large network is considered crucial for our behavior. To achieve this, multiple synaptic connections along a poly-synaptic network path must be adjusted coherently during learning. Because the previously proposed reward-dependent synaptic plasticity rule requires coactivation of presynaptic and postsynaptic neurons, learning can fail if a subset of neurons along a distant network path is inactive at the beginning of learning. We suggest that traveling waves that are initiated at an information source can mitigate this problem. We performed computer simulations of spiking neural networks with reward-dependent local synaptic plasticity rules and traveling waves. Our results show that this combination facilitates the learning and refinement of synaptic network paths. We argue that these features are a general biological strategy for maintaining and optimizing our brain function. Our research provides new insights into how complex neural networks in the brain form during learning and memory consolidation.

To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride directly to subsecond dopamine release events. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C]raclopride signal. Hence, dopaminergic activity can be monitored via temporal fluctuations in the [11C]raclopride PET signal. We validate this theory using fast-scan cyclic voltammetry and [11C]raclopride PET in mice during chemogenetic activation of dopaminergic neurons. We then apply the method to data from human subjects given a palatable milkshake and discover immediate and—for the first time—delayed food-induced dopamine release. This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels., It has proven difficult to measure the release of neurotransmitters, such as dopamine, in the human brain. Here, the authors introduce and validate a new method that infers dopamine release based on minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride.

BackgroundTo evaluate whether patients with scans without evidence of dopaminergic deficit (SWEDD) have early Parkinson’s disease (PD).MethodsThe clinical characteristics, striatal specific binding ratios (SBRs), and the indices of I-123 FP-CIT SPECT images of 50 SWEDD patients, 304 PD patients, and 141 healthy controls were acquired from the Parkinson’s Progression Markers Initiative (PPMI) data and evaluated during a 2-year clinical follow-up period.ResultsOf the 50 subjects with SWEDD, PD was confirmed in 13 subjects (the PD-SWEDD group), while the remaining 37 subjects had other diseases (the Other-SWEDD group). Striatal SBR values and striatal asymmetry indices of the PD group were significantly different with those of the PD-SWEDD and Other-SWEDD groups at both baseline and after 2 years (p< 0.001). Putaminal SBR values of the PD-SWEDD group were significantly decreased after 2 years (p< 0.05). There was no difference of the SBR values between baseline and after 2 years in the Other-SWEDD group. A baseline MDS-UPDRS III score matched comparison of the PD and PD-SWEDD group was done due to the large difference of the subject numbers. Striatal SBR values and striatal asymmetry indices were significantly different (p< 0.001) between the two groups at both baseline and after 2 years, but there were no significant difference with respect to the MDS-UPDRS III scores after 2 years between the two groups.ConclusionThe different SBR values and asymmetry indices between the PD and PD-SWEDD groups at baseline and after 2 years indicate that SWEDD may not be early PD, but rather a different disease entity.

Dopamine (DA) is critical for reward processing, but significantly less is known about its role in punishment avoidance. Using a combined approach-avoidance task, we measured phasic DA release in the nucleus accumbens (NAc) of rats during presentation of cues that predicted reward, punishment or neutral outcomes and investigated individual differences based on avoidance performance. Here we show that DA release within a single microenvironment is higher for reward and avoidance cues compared with neutral cues and positively correlated with poor avoidance behaviour. We found that DA release delineates trial-type during sessions with good avoidance but is non-selective during poor avoidance, with high release correlating with poor performance. These data demonstrate that phasic DA is released during cued approach and avoidance within the same microenvironment and abnormal processing of value signals is correlated with poor performance., Reward seeking behaviors involve dopamine (DA) release but the circuits underlying avoidance behavior remain comparatively understudied. Here the authors show that phasic increases in DA release in rats are higher for reward and avoidance cues compared with neutral cues and are positively correlated with poor avoidance.

Although levodopa is widely recognized as the most effective therapy for Parkinson disease (PD), its introduction 5 decades ago was preceded by several years of uncertainty and equivocal clinical results. The translation of basic neuroscience research by Arvid Carlsson and Oleh Hornykiewicz provided a logical pathway for treating PD with levodopa. Yet the pioneering clinicians who transformed PD therapeutics with this drug--among them Walther Birkmayer, Isamu Sano, Patrick McGeer, George Cotzias, Melvin Yahr, and others--faced many challenges in determining whether the concept and the method for replenishing deficient striatal dopamine was correct. This article reviews highlights in the early development of levodopa therapy. In addition, it provides an overview of emerging drug delivery strategies that show promise for improving levodopa's pharmacologic limitations.

Our internal clock system is predominantly dopaminergic, but memory is predominantly cholinergic. Here, we examined the common sensibility encapsulated in the statement: “time goes faster as we get older”. Objective To measure a 2 min time interval, counted mentally in subjects of different age groups. Method 233 healthy subjects (129 women) were divided into three age groups: G1, 15-29 years; G2, 30-49 years; and G3, 50-89 years. Subjects were asked to close their eyes and mentally count the passing of 120 s. Results The elapsed times were: G1, mean = 114.9 ± 35 s; G2, mean = 96.0 ± 34.3 s; G3, mean = 86.6 ± 34.9 s. The ANOVA-Bonferroni multiple comparison test showed that G3 and G1 results were significantly different (P < 0.001). Conclusion Mental calculations of 120 s were shortened by an average of 24.6% (28.3 s) in individuals over age 50 years compared to individuals under age 30 years. RESUMO Nosso sistema de relógio interno é predominantemente dopaminérgico, mas a memória é predominantemente colinérgica. Neste estudo, examinamos a assertiva comum que “o tempo passa mais rápido para pessoas mais velhas”. Objetivo Medir o intervalo de tempo 2 min contados mentalmente em pessoas de diferentes faixas etárias. Método 233 pessoas saudáveis (129 mulheres) foram divididos em três grupos: G1, 15-29 anos; G2, 30-49 anos; e G3, 50-89 anos. Foi solicitado que contassem mentalmente, com os olhos fechados, a passagem de 120 s. Resultados Os tempos aferidos foram: G1, média = 114,9 ± 35 s; G2, média = 96,0 ± 34,3 s; G3, média = 86,6 ± 34,9 s. A comparação entre os tempos de G3 e G1 (teste de comparação múltipla ANOVA-Bonferroni) foi muito significante (P < 0,001). Conclusão Cálculo mental de 120 s foi encurtado em média 24,6% (28,3 s) em pessoas maiores que 50 anos quando comparado com pessoas menores que 30 anos.

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington's disease. Huntington's disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson's disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.