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Rationale: Attention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown. Objectives: We applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes. Methods: Rats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent of motor reaction times, as measures of attentional capacity. Results: Atomoxetine and phenylephrine decreased response frequencies, including premature responses, increased omissions and slowed responding. In contrast, methylphenidate, amphetamine and atipamezole sped up responding and increased premature responses. Visual processing speed was also affected differentially. Atomoxetine and phenylephrine slowed, whereas methylphenidate and atipamezole sped up, visual processing, both for correct and incorrect categorisations. Amphetamine selectively improved visual processing for correct, though not incorrect, responses in high-attention rats only, possibly reflecting improved attention. Conclusions: These data indicate that the application of TVA to the 5CSRTT provides an enhanced sensitivity to capturing attentional effects. Unexpectedly, we found overall slowing effects, including impaired visual processing, following drugs either increasing extracellular noradrenaline (atomoxetine) or activating the α1-adrenoceptor (phenylephrine), while also ameliorating premature responses (impulsivity). In contrast, amphetamine had potential pro-attentional effects by enhancing visual processing, probably due to central dopamine upregulation. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the association between dopaminergic-induced complications and satisfaction with life in patients with Parkinson's disease. Methods: A cross-sectional study was carried out. Subjects were recruited from two movement disorders clinics in Mexico, from May to October 2019. Dopaminergic drug-induced complications were assessed with the movement disorders society -- unified Parkinson's disease rating scale items 4.1-4.5 where satisfaction with life scale score was used as the outcome variable. Correlation coefficients were utilized. results: Sixty-eight patients were included in the study. The mean satisfaction with life scale score was 25.7 (SD = 5.3), with 66.1% of them scoring higher than average scores. Age at diagnosis (rs = 0.256, p = 0.035), education (rs = 0.240, p = 0.048), geographic region (r2 = 0.180, p = 0.034), movement disorders society - unified Parkinson's disease rating scale part I (rs = -0.378, p = 0.002) and II (rs = -0.280, p = 0.021), and Hoehn and Yahr stage (rs = -0.295, p = 0.015) were significantly correlated with satisfaction with life scale scores. Partial correlation coefficient analysis revealed a statistically significant but moderate correlation between motor fluctuations and satisfaction with life scale scores (rs = -0.408, p = 0.001). No significant correlation was observed with dyskinesias. Conclusions: Motor fluctuations but not dyskinesias have a detrimental effect on patients' life satisfaction. Strategies to reduce motor fluctuations and better understanding the contribution of these to patients' lives may help minimize the negative impact of these complications on patients with PD. [ABSTRACT FROM AUTHOR]

Psychosis is the most common neuropsychiatric side-effect of dopaminergic therapy in Parkinson's disease (PD). It is still unknown which factors determine individual proneness to psychotic symptoms. Schizotypy is a multifaceted personality trait related to psychosis-proneness and dopaminergic neurotransmission in healthy subjects. We investigated whether (1) PD patients exhibit lower schizotypy than controls and (2) dopamine-related neuropsychiatric side-effects can be predicted by higher schizotypy. In this cross-sectional study, we used the Oxford-Liverpool Inventory of Feelings and Experiences in 56 PD patients (12 women, mean ± sd age: 61 ± 11 years) receiving their usual dopaminergic medication and 32 age-matched healthy controls (n = 32; 18 women, mean ± sd age: 57 ± 6 years). We further compared schizotypy scores of patients with (n = 18, 32.1%) and without previously experienced psychosis. We found that patients exhibited lower schizotypy than controls. Further, patients with a history of psychosis exhibited higher schizotypy than patients without these symptoms. Using an information theoretic measure and a machine learning approach, we show that schizotypy yields the greatest predictive value for dopamine-associated hallucinations compared to other patient characteristics and disease related factors. Our results indicate an overlap between neural networks associated with schizotypy and the pathophysiology of PD and a relationship between schizotypy and psychotic side-effects of dopaminergic medication. [ABSTRACT FROM AUTHOR]

Dopamine guides behavior and learning through pleasure, according to classic understanding. Dopaminergic neurons are traditionally thought to signal positive or negative prediction errors (PEs) when reward expectations are, respectively, exceeded or not matched. These signed PEs are quite different from the unsigned PEs, which report surprise during sensory processing. But mounting theoretical accounts from the predictive processing framework postulate that dopamine, as a neuromodulator, could potentially regulate the postsynaptic gain of sensory neurons, thereby scaling unsigned PEs according to their expected precision or confidence. Despite ample modeling work, the physiological effects of dopamine on the processing of surprising sensory information are yet to be addressed experimentally. In this study, we tested how dopamine modulates midbrain processing of unexpected tones. We recorded extracellular responses from the rat inferior colliculus to oddball and cascade sequences, before, during, and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected sensory input without significantly altering the processing of expected input. We conclude that dopaminergic projections from the thalamic subparafascicular nucleus to the inferior colliculus could encode the expected precision of unsigned PEs, attenuating via D2-like receptors the postsynaptic gain of sensory inputs forwarded by the auditory midbrain neurons. This direct dopaminergic modulation of sensory PE signaling has profound implications for both the predictive coding framework and the understanding of dopamine function. Information about unexpected stimuli is encoded in the form of prediction error signals. The earliest prediction error signals identified in the auditory brain emerge subcortically in the inferior colliculus. This study reveals the essential role of dopamine in encoding the precision of prediction errors at the auditory midbrain. [ABSTRACT FROM AUTHOR]

Anxiety, stress and tension are absolutely habitual human feelings. Persistence of these feelings for a longer period will affects physical and mental health both. It is considered to be the major cause of disability in world. It comprises of post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, panic attacks, phobias as well as depression. The neurotransmitters involved in brain involves in anxiety include GABA, serotonin, nor-epinephrine and dopamine. The developed ethological animal models (behavioural) demonstrated the anxiolytic properties of neurotransmitters, with the help of various models neuropeptide receptor agonist and antagonists, the potency in human clinical samples has concluded. Anti-anxiety medicines are used to treat anxiety. These medicines act by decreasing brain activity to mitigate the symptoms of anxiety, apprehensiveness and improving sleep. Prolonged use of these agents can cause serious side-effects such as cholinergic symptoms, weight gain, paradoxil effects, disturbed sleep etc. Thus, urgent need for new antianxiety drugs is a global concern. Thus, the insistence of herbal medicines is expanding due to their immense role and therapeutic efficacy with minimum side effects. [ABSTRACT FROM AUTHOR]

Withaferin A (WA) was evaluated for its neuro-protective efficacy on ageing induced striatal dopamine (DA) and behavioural changes in aged rats. Wistar albino rats were divided into group I – young (3 months), Group II – aged (24 months), Group III – aged rats supplemented with WA (50 mg/kg b.w once in a day for 30 days) and Group IV – young rats supplemented with WA (50 mg/kg b.w). The HPLC assay revealed significant decline in the levels of DA and homovanillic acid (HVA) in substantia nigra (SN) and striatum (ST) of aged rat. A marked decline in motor activity of aged rat was observed through open field, beam walking and grid walking motor experiments. These results indicate that ageing reduces nigro-striatal activity as well as nigro-striatal DA levels. Interestingly, the administration of WA (50 mg\kg b.w) resulted in a substantial resurge of DA and HVA in SN and ST and a significant reversal of motor impairment in aged rats. This study is the first report that evidently determines the neuro-protective efficacy of WA on dopaminergic system of SN and ST in aged rats. [ABSTRACT FROM AUTHOR]

Estrogens are well known to increase locomotor activity in laboratory rodents; however, the underlying mechanism remains unclear. We used voluntary wheel running by female rats as an index of locomotor behavior to investigate this issue. We first determined whether the estrogen‐induced increase in locomotion was susceptible to inhibition by a physiological challenge, and next whether it was associated with dopaminergic activation in the central reward area, nucleus accumbens. Ovariectomized rats were given estradiol or the oil vehicle and housed in cages with or without running wheels. All rats were given regular rodent chow for 1 week, a sodium‐deficient diet for the next week, and then were returned to a regular diet for another week. At the end of the last week, all rats were killed, brains were extracted and dopamine levels in the nucleus accumbens were measured. As expected, estradiol treatment increased distance run. Surprisingly, dietary sodium deprivation further increased running, but this appeared to be related to experience with wheel running, rather than to sodium deprivation, per se. Dopamine was greater in the nucleus accumbens of estradiol‐treated rats that ran compared to all other groups. Thus, the estrogen‐induced increase in locomotion is a robust phenomenon that is not inhibited by a body sodium challenge and is associated with elevated levels of dopamine in reward pathways. These findings raise the possibility that the estrogen‐induced increase in locomotor activity, which occurs during a hormonal milieu conducive to reproduction, may reflect mate‐seeking behavior and, thereby, maximize reproductive success. [ABSTRACT FROM AUTHOR]

Abstract In neuroscience literature, dopamine is often considered as a pleasure chemical of the brain. Dopaminergic neurons respond to rewarding stimuli which include primary rewards like opioids or food, or more abstract forms of reward like cash rewards or pictures of pretty faces. It is this reward-related aspect of dopamine, particularly its association with reward prediction error, that is highlighted by a large class of computational models of dopamine signaling. Dopamine is also a neuromodulator, controlling synaptic plasticity in several cortical and subcortical areas. But dopamine's influence is not limited to the nervous system; its effects are also found in other physiological systems, particularly the circulatory system. Importantly, dopamine agonists have been used as a drug to control blood pressure. Is there a theoretical, conceptual connection that reconciles dopamine's effects in the nervous system with those in the circulatory system? This perspective article integrates the diverse physiological roles of dopamine and provides a simple theoretical framework arguing that its reward related function regulates the processes of energy consumption and acquisition in the body. We conclude by suggesting that energy-related book-keeping of the body at the physiological level is the common motif that links the many facets of dopamine and its functions. Highlights • We seek to present a conceptual synthesis of the manifold physiological functions of dopamine, and the reward system of the brain with which the molecule is closely associated. • We review the diverse role of dopamine as a reward signal, in regulation of appetite, circulation and energy management. • We propose a theoretical frame work that the functions of dopamine in neural and physiological domains can be linked through its actions vis a vis the reward system of the brain, as a part of an extensive energy management system of the body [ABSTRACT FROM AUTHOR]

Background Parkinson’s disease (PD) is caused by the gradual loss of dopamine-producing cells in the brain. This study evaluated the potential neuroprotective role of puerarin (PR) on dopamine (DA)-producing cells in vitro and in vivo . Method In vitro , the effects of PR on proliferation and differentiation and DA releases of mesenchymal stem cells (MSCs) were assayed by CCK-8, flow cytometry, real-time PCR and ELISA respectively. Then the differentiated cells were labeled with enhanced green fluorescent protein (EGFP) and administrated into PD animal models induced by 6-OHDA. The proliferation and differentiation of labeled cells were identified by fluorescence microscopy and immunostaining. Results In vitro , after being treated with different concentrations of PR for 1 week, the TUJ1, TH and DAT protein and mRNA expression and DA releases increased significantly. In vivo , after transplantation of PR-treated DA-producing cells, the symptoms of PD improved significantly from the second week after transplantation; more transplanted cells survived and migrated to wider region along injection line; more transplanted cells proliferated and differentiated into TH + cells; more DA was detected in the striatum during 6 weeks’ observation. Conclusion The results suggest that PR promote DA neuron survival, proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • ERK1/2 inhibition stimulates dopamine release. • U0126 increases PKG activity proposing stimulation of DA release. • DA secretion is regulated by balancing feedback between ERK1/2 and PKG. Abstract The release of dopamine (DA) is one of the main steps in the control of neuronal functioning and all CNS. It was demonstrated that many factors such as protein kinases and synaptic proteins are tightly involved in the regulation of DA secretion, but the data are contradictory. Here we analysed an effect of ERK1/2 inhibition on DA secretion from differentiated PC12 cells and evaluated the correlation between the activity of kinases/synaptic proteins and the level of released DA. PC12 cells were differentiated by NGF for 6 days. On the 7th day the cells were incubated for 1, 2 and 4 h with 10μM U0126. Obtained data demonstrated a significant accumulation of DA in the media after 4 h incubation with U0126 that accompanied with upregulation of PKG activity. Analysis of exocytosis proteins demonstrated decreased phosphorylation level of synapsin I and content of SNAP25. Taken together our data proposed an inhibitory role of ERK1/2 in the regulation of catecholamine secretion and demonstrated that balance between PKG and ERK1/2 activity could have a substantial impact on the regulation of DA release from the cells. [ABSTRACT FROM AUTHOR]

Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Autophagy (ATG) and the Ubiquitin Proteasome (UP) are the main clearing systems of eukaryotic cells, in that being ultimately involved in degrading damaged and potentially harmful cytoplasmic substrates. Emerging evidence implicates that, in addition to their classic catalytic function in the cytosol, autophagy and the proteasome act as modulators of neurotransmission, inasmuch as they orchestrate degradation and turnover of synaptic vesicles (SVs) and related proteins. These findings are now defining a novel synaptic scenario, where clearing systems and secretory pathways may be considered as a single system, which senses alterations in quality and distribution (in time, amount and place) of both synaptic proteins and neurotransmitters. In line with this, in the present manuscript we focus on evidence showing that, a dysregulation of secretory and trafficking pathways is quite constant in the presence of an impairment of autophagy-lysosomal machinery, which eventually precipitates synaptic dysfunction. Such a dual effect appears not to be just incidental but it rather represents the natural evolution of archaic cell compartments. While discussing these issues, we pose a special emphasis on the role of autophagy upon dopamine (DA) neurotransmission, which is early affected in several neurological and psychiatric disorders. In detail, we discuss how autophagy is engaged not only in removing potentially dangerous proteins, which can interfere with the mechanisms of DA release, but also the fate of synaptic DA vesicles thus surveilling DA neurotransmission. These concepts contribute to shed light on early mechanisms underlying intersection of autophagy with DA-related synaptic disorders. [ABSTRACT FROM AUTHOR]

Tremella-like ZnIn 2 S 4 (ZISt) and flower-like microsphere ZnIn 2 S 4 (ZISm) were synthesized via a straightforward hydrothermal method. It was found that the ZISt was superior to ZISm for photoelectrochemical (PEC) sensing because of its large surface area and high photocatalytic activity. A composite of ZISt and graphene (GR) was prepared and used for the PEC sensing of dopamine (DA). Here DA acted as an electron donor to scavenge the hole and inhibit the charge recombination. The GR enhanced visible light absorption and accelerated electron transfer, amplifying the photocurrent signal. The strong chelating coordination interaction between DA and Zn(II) in ZISt guaranteed the selective adsorption of target analyte. Thus the resulting ZISt/GR photoelectrode showed sensitive and selective PEC response to DA. Under the optimized conditions, the linear response range was from 0.01 to 20 μM, and the detection limit was down to 0.001 μM. Additionally, the sensor had good stability and reproducibility, and it could be used for the detection of DA in real samples. [ABSTRACT FROM AUTHOR]

Reinforcement learning is the process by which an agent learns to predict long-term future reward. We now understand a great deal about the brain's reinforcement learning algorithms, but we know considerably less about the representations of states and actions over which these algorithms operate. A useful starting point is asking what kinds of representations we would want the brain to have, given the constraints on its computational architecture. Following this logic leads to the idea of the successor representation, which encodes states of the environment in terms of their predictive relationships with other states. Recent behavioral and neural studies have provided evidence for the successor representation, and computational studies have explored ways to extend the original idea. This paper reviews progress on these fronts, organizing them within a broader framework for understanding how the brain negotiates tradeoffs between efficiency and flexibility for reinforcement learning. [ABSTRACT FROM AUTHOR]

Dopaminergic deficits in the prefrontal cortex and striatum have been attributed to the pathogenesis of attention-deficit hyperactivity disorder (ADHD). Our recent study revealed that high-dose taurine improves hyperactive behavior and brain-functional signals in SHR rats. This study investigates the effect of taurine on the SHR striatum by detecting the spontaneous alternation, DA transporter (DAT) level, dopamine uptake and brain-derived neurotrophic factor (BDNF) expression. A significant increase in the total arm entries was detected in both WKY and SHR rats fed with low-dose taurine but not in those fed with high-dose taurine. Notably, significantly increased spontaneous alternation was observed in SHR rats fed with high-dose taurine. Significantly higher striatal DAT level was detected in WKY rats fed with low-dose taurine but not in SHR rats, whereas significantly reduced striatal DAT level was detected in SHR rats fed with high-dose taurine but not in WKY rats. Significantly increased dopamine uptake was detected in the striatal synaptosomes of both WKY and SHR rats fed with low-dose taurine. Conversely, significantly reduced dopamine uptake was detected in the striatal synaptosomes of SHR rats fed with high-dose taurine. Accordingly, a negative correlation was detected between striatal dopamine uptake and spontaneous alternation in SHR rats fed with low or high-dose taurine. Significantly increased BDNF was detected in the striatum of both WKY and SHR rats fed with low or high-dose taurine. These findings indicate that different dosages of taurine have opposite effects on striatal DAT expression and dopamine uptake, suggesting high-dose taurine as a possible candidate for ADHD treatment. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake. Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened. Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E−08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes. Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition. [ABSTRACT FROM AUTHOR]

Current study showed that Dopamine deficiency can cause several diseases and effect the constriction of students. This study was conducted to find out the relation between the academic achievement of undergraduate students for both genders and their dopamine level for two months. Experimental of research approach were involving random selection of 55 students from College of Basic Education at University of Babylon. The result showed that undergraduate students who were exposed normal level of dopamine, they had considerably a good standing of their academic achievement. These findings indicate that dopamine was effective in improving academic achievement. [ABSTRACT FROM AUTHOR]

Neuropathology suggests that Parkinson’s disease (PD) with depression may involve a progressive degeneration of the nigrostriatal and mesocorticolimbic dopaminergic systems. Previous positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies have shown that dopamine changes in individual brain regions constituting the nigrostriatal and mesocorticolimbic circuits are associated with depression in PD. However, few studies have been conducted on the circuit-level alterations in this disease. The present study used resting-state fMRI and seed-based functional connectivity of putative dopaminergic midbrain regions (i.e., substantia nigra (SN) and ventral tegmental area (VTA)) to investigate the circuit-related abnormalities in PD with depression. The results showed that depressed PD (DPD) patients relative to healthy controls (HC) and non-depressed PD (NDPD) patients had increased functional connectivity between VTA and anterior cingulate cortex (ACC), demonstrating that dysfunctional mesocorticolimbic dopaminergic neurotransmission may be associated with depression in PD. Compared with HC, DPD and NDPD patients showed increased functional connectivity from SN to sensorimotor cortex, validating that alterations in the nigrostriatal circuitry could be responsible for cardinal motor features in PD. In addition, aberrant connectivity between VTA and ACC was correlated with the severity of depression in PD patients, further supporting that abnormal mesocorticolimbic system may account for depressive symptoms in PD. These results have provided potential circuit-level biomarkers of depression in PD, and suggested that resting state functional connectivity of midbrain dopaminergic nuclei may be useful for understanding the underlying pathology in PD with depression. [ABSTRACT FROM AUTHOR]

The frequency and intensity of water deficits is expected to increase because of global warming. Drought stress is often one of the most limiting factors for plant growth. We conducted greenhouse pot experiments to address how dopamine affects the droughtresistance traits of apple trees at the physiological and molecular levels. Our factorial design consisted of dopamine and no-dopamine applications combined with wellwatered and moderate-drought conditions. Seedling biomass, photosynthesis rates, chlorophyll concentrations, and stomatal apertures were markedly reduced under stress but dopamine treatment mitigated the inhibiting effects of drought on plant growth and helped maintain strong photosynthesis, chlorophyll levels, and stomatal functioning. Concentrations of most macro-, micro-, and trace elements decreased in response to drought. This stress also diminished the uptake and transport of elements in the leaves and stems, but increased the partitioning of elements in the roots. Nutrient resorption proficiency decreased while nutrient resorption efficiency increased for most analyzed elements. Exogenous dopamine significantly increased the concentrations, uptake, and transport of nutrients under drought stress, and also altered their distribution within the whole plant. However, this molecule had a negative effect on nutrient resorption. Although transcript levels of a key chlorophyll degradation gene, pheide a oxygenase, and senescence-associate gene 12 were elevated upon drought treatment, dopamine significantly suppressed the upregulation of those genes under such stress conditions. These observations indicate that dopamine has an important anti-senescence effect that might be helpful for regulating nutrient uptake, transport, and resorption, and ultimately influencing overall plant growth. Thus, understanding the role of dopamine in drought tolerance introduces new possibilities to use this compound for agricultural purposes. [ABSTRACT FROM AUTHOR]

For sensitive immunoassay, it is essentially important to immobilize antibody on a surface with high density and full retention of their recognition activity. Bio-inspired polydopamine (PDA) thin film has been widely utilized as a reactive coating to immobilize antibody on various surfaces. We herein report that the antibody immobilization capacity of PDA thin film is electrochemically enhanced by applying an oxidative potential to convert the surface catechol group to reactive quinone group. Quantitative surface plasmon resonance (SPR) investigation unveils that upon proper electrochemical oxidization, the antibody loading capacity of PDA film is significantly improved (up to 27%) and is very close to the theoretically maximal capacity of a planar surface if concentrated antibody solution is used. Using prostate-specific antigen (PSA) as a model target, it is further demonstrated that the SPR immunoassay sensitivity is greatly enhanced due to the improved antibody immobilization. This work offers an efficient strategy to enhance the reactivity of PDA film towards nucleophiles, and may also facilitate its immunoassay application among others. [ABSTRACT FROM AUTHOR]

Dopamine (DA) and noradrenaline (NA) are important neurotransmitters, which are suggested to play a vital role in modulating the neural circuitry involved in the executive control of cognition. One way to investigate the functions of these neurotransmitter systems is to assess physiological indices of DA and NA transmission. Here we examined how variations of spontaneous eye-blink rate and pupil size, as indirect measures of DA and NA activity, respectively, are related to performance in a hallmark aspect of executive control: attentional set shifting. We used the Intra/Extradimensional Set Shifting Task, where participants have to choose between different compound stimuli while the stimulus-reward contingencies change periodically. During such rule shifts, participants have to refresh their attentional set while they reassess which stimulus-features are relevant. We found that both eye-blink rate (EBR) and pupil size increased after rule shifts, when explorative processes are required to establish stimulus-reward contingencies. Furthermore, baseline pupil size was related to performance during the most difficult, extradimensional set shifting stage, whereas baseline EBR was associated with task performance prior to this stage. Our results support a range of neurobiological models suggesting that the activity of DA and NA neurotransmitter systems determines individual differences in executive functions (EF), possibly by regulating neurotransmission in prefrontal circuits. We also suggest that assessing specific, easily accessible indirect physiological markers, such as pupil size and blink rate, contributes to the comprehension of the relationship between neurotransmitter systems and EF. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by a developmentally inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity and impulsivity. Despite onset in early childhood, ADHD may continue into adulthood with substantial impairment in social, academic and occupational functioning. A new animal model of this disorder was developed in rats with genetic deletion of the dopamine transporter (DAT) gene (dopamine transporter knockout rats; DAT‐KO rats). We analyzed the behavior of DAT‐KO rats for a deeper phenotypical characterization of this model. We first tested rats of the 3 genotypes at different ages (preadolescent, adolescent and adult), in a novelty‐seeking test using a black/white box (Experiment 1). After that, we tested adult rats in a novelty‐preference test using a 3‐chamber apparatus with different shapes (Experiment 2). Experiment 1: as evidenced by analysis of time spent in the novel environment, adult DAT heterozygous (DAT‐HET) rats show an increased curiosity‐driven exploration compared with wild‐type (WT) controls while DAT‐KO rats did not recognize novelty. The locomotor activity data show a minimal difference between genotypes at adolescent age while the preadolescent and adult DAT‐KO rats have significantly increased activity rate compared with WT and DAT‐HET subjects. Experiment 2: in this case, due to more clearly evident spatial differences, time spent in novel environment was not significantly different among genotypes. During first 10 minutes, DAT‐KO rats showed a decreased hyperactivity, apparently related to curiosity and attention to the new environments. In conclusion, DAT‐KO rats may show some inattention while more novelty‐seeking traits appear in DAT‐HET rats. [ABSTRACT FROM AUTHOR]

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear–induced striatal asymmetries identified here intersect with non–ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left–right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is known as a hormone neurotrasnmitter molecule involved in several stress reactions in both vertebrates and invertebrates. Following infections with the fungi Metarhizium robertsii or Beauveria bassiana and the bacterium Bacillus thuringiensis , dopamine the concentration was measured at different time points in the haemolymph of the Colorado potato beetle, Leptinotarsa decemlineata and the larvae of the greater wax moth Galleria mellonella . The infection with M. robertsii increased (4 to 12-fold) DA concentrations in the haemolymph of the potato beetle larvae and the oral infection by B. thuringiensis also lead to a 30 and 45-fold increase. During infection of the greater wax moth larvae with Beauveria bassiana and B. thuringiensis DA increased 4 to 20-fold and about 2 to 2,5-fold respectively, compared to non-infected insects. The relative DA concentrations varied between the two insects and depended on the pathogens and post infection time. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is a growing concern as the longevity of the world's population steadily increases. Both ageing and Parkinson's disease have an impact on dopamine neurotransmission. It is therefore important to investigate their relative impact on the fronto-striatal reward system. There has been little investigation of reward processing in terms of anticipation and reward outcome in Parkinson's disease. Abnormal responses during reward processing have previously been demonstrated in whole-brain analysis of Parkinson's patients with mild lateralized disease, but the exact impact in regions specific to reward processing is still unknown.Objective: Here we aim to investigate the impact of Parkinson's disease on the orbitofrontal ventral striatal reward system in patients with moderate to severe clinical symptoms.Methods: We utilized a monetary incentive delay (MID) task in 17 Parkinson's patients who were compared to two control groups stratified by age. The MID paradigm reliably activates the ventral striatum during reward anticipation and the orbitofrontal cortex during reward outcome processing.Results: Relative to the two control groups, Parkinson's disease patients had abnormal task related activity during both reward anticipation in the ventral striatum and reward outcome in the orbitofrontal cortex. There were no effects of ageing.Conclusion: These findings demonstrate abnormalities in anticipatory as well as reward outcome processing while treated primarily with levodopa. The orbitofrontal dysfunction during reward outcome processing may have specificity in Parkinson's disease, as it has been shown to be relatively unaffected by normal ageing. [ABSTRACT FROM AUTHOR]

Objective: To describe chorea/ballism triggered by a hyperglycemic event.Methods: We used the electronic records system at Mayo Clinic-Rochester to identify patients diagnosed with chorea or ballism from January 1st, 2000 through December 31st, 2014. Each record was reviewed to confirm chorea/ballism. From these cases we selected those that developed chorea/ballism within a month after a hyperglycemic episode (blood glucose >300 mg/dL). Clinical, laboratory, and imaging findings were analyzed.Results: Of the 596 chorea cases, we identified 7 patients (5 women) whose chorea was preceded by a hyperglycemic episode (range 3-30 days) during 15 years of surveillance, including new-onset diabetes in four cases. Median age was 80 years (range, 53-86). The chorea/ballism was unilateral in 6/7 cases and half of these unilateral cases had contralateral putamen T1-hyperintensity on brain MRI. After glucose correction, the chorea resolved within one week without recurrence in only one case. Among the 6 cases with persistent chorea, it was controlled with dopamine blocking/depleting medications.Conclusions: Chorea triggered by hyperglycemia is a rare complication of diabetes, with only seven cases identified at our tertiary medical center during 15 years of surveillance. This comprised about 1% of all chorea cases at our center during this time. Hyperglycemic chorea primarily developed in later life, with new-onset diabetes in the majority (4/7). Although MRI putamen T1-hyperintensity is reportedly typical, it was only seen in 3/6 cases. This MRI appearance may be mistaken for a hemorrhagic stroke, given the usual unilateral presentation. The chorea was controlled with dopamine blocking/depleting medications. [ABSTRACT FROM AUTHOR]

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward- related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders. [ABSTRACT FROM AUTHOR]

In the striatum, long term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are believed to underlie motor learning and are impaired in animal models of Parkinson’s disease. High frequency stimulation (HFS) is often used to induce synaptic plasticity in the brain. In the striatum, the polarity of HFS-induced plasticity is influenced by the recording conditions, which can differ between various studies. Here, we examined the ability of HFS to induce synaptic plasticity in the dorsolateral striatum in the presence of extracellular Mg 2+ ions, with no GABA A receptor blocker, and without membrane depolarization during HFS. We found that HFS induced a LTD of excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors (AMPARs) in medium spiny neurons (MSNs) recorded with whole-cell voltage-clamp. However, HFS induced a LTP of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs), which was dependent on the stimulation intensity applied. The rate of synaptically-evoked spiking in MSNs, measured with cell-attached recordings, showed LTP following HFS. LTD and LTP were impaired in the dopamine-depleted striatum of 6-hydroxydopamine (6-OHDA) lesioned mice, a model of Parkinson’s disease. This study shows that HFS induces opposing forms of dopamine-dependent synaptic plasticity in the striatum, i.e . LTD of AMPAR-EPSCs and LTP of both fEPSP/PS and synaptically-evoked firing in MSNs. [ABSTRACT FROM AUTHOR]

Ghrelin has been attributed various physiological processes including food intake and reward regulation, through activation of the mesolimbic dopamine system. Reward modulation involves the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA) dopamine neurons targeting nucleus accumbens (NAc), a system that ghrelin activates through VTA-dependent mechanisms. In the first study, we found that systemic intraperitoneal (ip) administration of rimonabant attenuated intracerebroventricular (icv) ghrelin's ability to cause locomotor stimulation and NAc dopamine release in mice. Ghrelin-induced (icv) chow intake was not altered by rimonabant administration (ip). Finally, we showed that bilateral VTA administration of rimonabant blocks the ability of intra-VTA administered ghrelin to increase locomotor activity, but does not affect food intake in mice. Collectively, these data indicate clear dissociation between regulation of food intake and activation of the mesolimbic dopamine system. [ABSTRACT FROM AUTHOR]

Age-related motor deficits, such as loss of balance and coordination, are caused, in part, by loss of dopaminergic neurons. Oxidative stress is known to play a role in this neuronal loss. Resveratrol, a natural antioxidant with anticancer and anti-inflammatory potential, has been shown to protect dopaminergic-like cells (SH-SY5Y) against oxidative stress. However, the low bioavailability of resveratrol makes it worthwhile to explore newer compounds with similar properties. Piceid (RV8), an analog of resveratrol, has greater bioavailability than resveratrol, and our studies found that piceid (10, 20, 30 µM) protects SH-SY5Y cells against oxidative stress. Our investigations also found that the neuroprotection afforded by piceid was decreased when the MAP kinases, ERK1/2 and ERK5, were independently inhibited. Since oxidative stress is considered a master operator of apoptosis, our study also scrutinized dopamine-induced apoptosis and whether caspase-3/7 and Bcl-2 are involved, following piceid pretreatment followed by dopamine exposure. Our findings suggested that piceid pretreatment inhibited the dopamine-induced increase in caspase-3/7 activity and dopamine-induced loss of Bcl-2 expression. Overall, these findings suggest that the neuroprotective effects of piceid are mediated via the activation of ERK1/2, ERK5, and inhibition of apoptosis caused by oxidative stress. [ABSTRACT FROM AUTHOR]

Abnormal levels of dopamine and uric acid are closely relative to some diseases of human body and can serve as key indicators for human health monitoring. As the primary products of purine metabolism, dopamine and uric acid generally coexist in the extracellular fluid of central nervous system and serum. The sensitive and simultaneous analysis of dopamine and uric acid is urgent in clinical diagnosis of some diseases. Herein, carboxylated-multiwall carbon nanotubes (MWCNTs) were functionalized with N -acetyl- l -cystein (NAC) stabilized Au clusters to generate Au@NAC- MWCNTs complex. By drop-coating the complex on glassy carbon electrode (GCE) surface, the complex-modified GCE was fabricated and used for a new working electrode for electrochemical sensing applications. Using cyclic voltammetry and differential pulse voltammetry measurements, the complex-modified GCE showed the capacity of highly sensitive, individual, and simultaneous electrochemical sensing of dopamine and uric acid. The linear detection ranges of dopamine and uric acid were 0.1–250 μM and 0.1–300 μM, respectively, accompanied by low detection limits of 30 nM of dopamine and 40 nM uric acid. In real human serum and urine samples, the complex- modified GCE exhibited a high performance for simultaneous and selective detection of dopamine and uric acid, together with high detection recoveries of 96.9–104.7% and low relative standard deviation of 1.1–3.7%. [ABSTRACT FROM AUTHOR]

A novel mechano-chemical strategy using dopamine to modify UiO-66(Zr) by N-coordination was proposed to enhance its competitive adsorption for acetaldehyde, chlorobenzene/H 2 O, both thermodynamically and kinetically. The newly synthesized material was characterized by SEM, EDX, XPS, PXRD, FT-IR, TGA/DTG and BET techniques. Results showed that N was successfully grafted into UiO-66(Zr) frameworks through coordination interaction with Zr-O clusters resulting in M-UiO-66(Zr-N 3.0 ). The obtained M-UiO-66(Zr-N 3.0 ) exhibited a significant increase in adsorption of chlorobenzene (4.94 mmol/g) and acetaldehyde (9.42 mmol/g) compared to parent UiO-66(Zr) and UiO-66(Zr)-NH 2 . The H 2 O adsorption uptake of M-UiO-66(Zr-N 3.0 ) decreased by 20% that of UiO-66(Zr) and 47% of UiO-66(Zr)-NH 2 indicating higher hydrophobicity of the modified material. Kinetic performance indicated that diffusivity of chlorobenzene on M-UiO-66(Zr-N 3.0 ) was about 7.8 and 40 times higher than that of the parent UiO-66(Zr) and UiO-66(Zr)-NH 2 respectively and 15.4 times higher than that of H 2 O on itself. Based on the results, the current N-modification strategy can be deemed as an efficient way to improve MOFs competitive adsorption towards VOCs under humid conditions and it might play active role in industries involving adsorbent applications. [ABSTRACT FROM AUTHOR]

Background: We have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods.Objectives: Our aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status.Methods: 192 four-year old children from a community sample from Montreal and Hamilton, Canada, were classified according to birth weight and administered a snack test meal containing regular as well as palatable foods. Intrauterine growth restriction was based on the birth weight ratio below 0.85; children were genotyped for polymorphisms associated with dopamine (DA) signaling, with the hypofunctional variants (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10-repeat, Met/Met-COMT) receiving the lowest scores, and a composite score was calculated reflecting the total number of the five genotypes. Macronutrient intake during the Snack Test was the outcome.Results: Adjusting for z-score BMI at 48 months and sex, there was a significant interaction of the genetic profile and fetal growth on sugar intake [βˆ = -4.56, p = 0.04], showing a positive association between the genetic score and sugar intake in IUGR children, and no association in non-IUGR children. No significant interactions were seen in other macronutrients.Conclusions: Variations in a genetic score reflecting DA signaling are associated with differences in sugar intake only in IUGR children, suggesting that DA function is involved in this behavioral feature in these children. This may have important implications for obesity prevention in this population. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the efficacy of homemade tolcapone in treatment of patients with Parkinson's disease (PD). Eighty patients with PD were subjected to randomized, double-blind, placebo-controlled and parallel-group study. PD patients were randomly divided into the tolcapone treatment group (41 cases) and placebo group (39 cases). Each patient received 1 pill of tolcapone or placebo, 3 times per day for 26 weeks. Efficacy was evaluated using the internationally used unified Parkinson's disease rating scale (UPDRS) scoring system for PD symptoms. After the treatment for 26 weeks, the cognitive function, tremor, muscle stiffness, voluntary movement and autonomic nerve symptoms were compared between the two groups using UPDRS scores. Compared with the placebo group, cognitive function, muscle stiffness, voluntary movement and autonomic nerve symptoms were compared between the two group using UPDRS scores. Compared with the placebo group, cognitive function, muscle stiffness and voluntary movement reduction were significantly improved in patients of the tolcapone group (P<0.05). However, no significant differences in UPDRS scores of autonomic nerve symptoms and tremor were found between two groups after treatment (P>0.05). Tolcapone, a catechol-O-methyl transferase (COMT) inhibitor, can improve the motor function of patients with PD, especially exercise and muscle stiffness. Tolcapone can also improve the cognitive function of patients. [ABSTRACT FROM AUTHOR]

Background Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC − MS based approach. Methods Rats (n = 24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61 μmol/kg, i.e. 0.56 mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n = 7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC − MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. Results In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10 − h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO < 10%), sub-pharmacological dose (RO 10%− 30%) and pharmacological dose (RO > 30%). Conclusion For the first time a predictive model that could describe the quantitative in vivo relationship between dose, PK and D2 RO of raclopride in non-anesthetized rat was established. The PK-RO model could facilitate the selection of optimal dose and dosing time when raclopride is used as tracer or as pharmacological blocker in various rat studies. The LC − MS based approach, which doses and quantifies a non-radiolabeled tracer, could be useful in evaluating the systemic disposition and brain kinetics of tracers. [ABSTRACT FROM AUTHOR]

Background Mania/hypomania is the cardinal feature of bipolar disorder. Recently, single administration of the dopamine transporter (DAT) inhibitor, GBR12909, was related to mania-like alterations. In the present study we aimed at testing behavioral and brain oxidant/neurotrophic alterations induced by the repeated administration of GBR12909 and its prevention/reversal by the mood stabilizing drugs, lithium (Li) and valproate (VAL) as well as by the neuroprotective drug, minocycline (Mino). Methods Adult Swiss mice were submitted to 14 days protocols namely prevention and reversal. In the reversal protocol mice were given GBR12909 or saline and between days 8 and 14 received Li, VAL, Mino (25 or 50 mg/kg) or saline. In the prevention treatment, mice were pretreated with Li, VAL, Mino or saline prior to GBR12909. Results GBR12909 repeated administration induced hyperlocomotion and increased risk taking behavior that were prevented and reversed by the mood stabilizers and both doses of Mino. Li, VAL or Mino were more effective in the reversal of striatal GSH alterations induced by GBR12909. Regarding lipid peroxidation Mino was more effective in the prevention and reversal of lipid peroxidation in the hippocampus whereas Li and VAL prevented this alteration in the striatum and PFC. Li, VAL and Mino25 reversed the decrease in BDNF levels induced by GBR12909. Conclusion GBR12909 repeated administration resembles manic phenotype. Similarly to classical mood-stabilizing agents, Mino prevented and reversed GBR12909 manic-like behavior in mice. Thus, our data provide preclinical support to the design of trials investigating Mino's possible antimanic effects. [ABSTRACT FROM AUTHOR]

We developed a new strategy for construction of a biosensor for the neurotransmitter dopamine. The biosensor was constructed by one-step electrochemical deposition of a nanocomposite in aqueous solution at pH 7.0, consisting of molybdenum disulfide, multi-walled carbon nanotubes, and polypyrrole. A series of analytical methods was performed to investigate the surface characteristics and the improved electrocatalytic effect of the nanocomposite, including cyclic voltammetry, electrochemical impedance spectroscopy, field-emission scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. The constructed biosensor showed high sensitivity (1.130 μAμM −1 cm −2 ) with a dynamic linearity range of 25–1000 nM and a detection limit of 10 nM. Additionally, the designed sensor exhibited strong anti-interference ability and satisfactory reproducibility. The practical application of the sensor was manifested for the ex vivo determination of dopamine neurotransmitters using brain tissue samples of a mouse Parkinson's disease model. [ABSTRACT FROM AUTHOR]

Dopamine synthesis in the ventral tegmental area (VTA) is necessary for the reinforcement of sexual behavior. The objective of this study determined if sexual stimuli initiates reward, and whether reward is attenuated in sexually inactive rams. Sexually active rams were exposed to urine from estrous (n = 4) or ovariectomized (n = 3) ewes with inactive rams (n = 3) exposed to urine from estrous ewes. Following exposure, rams were exsanguinated and brains perfused. Alternating sections of the VTA were stained for Fos related antigens (FRA), tyrosine hydroxylase, and dopamine beta-hydroxylase activity. Forebrain tissue, mid-sagittal ventral to the anterior corpus callosum, was stained for dopamine D 2 receptors. Concentrations of cortisol was determined prior to and following exposure. Exposure to ovariectomized-ewe urine in sexually active rams did not influence ( P = 0.6) FRA expression, but fewer ( P < 0.05) neurons were positive for tyrosine hydroxylase in the VTA. Sexually inactive rams had fewer ( P < 0.05) FRA and tyrosine hydroxylase positive neurons in the VTA than sexually active rams following exposure to estrous ewe urine. VTA neurons staining positive for dopamine beta-hydroxylase did not differ by sexual activity ( P = 0.44) or urine exposure ( P = 0.07). Exposure to stimulus did not influence ( P = 0.46) numbers of forebrain neurons staining positive for dopamine D2 receptors in sexually active rams, but fewer ( P = 0.04) neurons stain positive in inactive rams. Serum concentrations of cortisol did not differ ( P ≥ 0.52) among rams prior to or following stimulus. In conclusion sexual inactivity is unlikely due to stress, but may be partially a result of decreased tyrosine hydroxylase and/or the response to dopamine. [ABSTRACT FROM AUTHOR]

Dopamine signaling encodes reward learning and motivated behavior through modulation of synaptic signaling in the nucleus accumbens, and aberrations in these processes are thought to underlie obsessive behaviors associated with alcohol abuse. The nucleus accumbens is divided into core and shell sub-regions with overlapping but also divergent contributions to behavior. Here we optogenetically targeted dopamine projections to the accumbens allowing us to isolate stimulation of dopamine terminals ex vivo. We applied 5 pulse (phasic) light stimulations to probe intrinsic differences in dopamine release parameters across regions. Also, we exposed animals to 4 weeks of chronic intermittent ethanol vapor and measured phasic release. We found that initial release probability, uptake rate and autoreceptor inhibition were greater in the accumbens core compared to the shell, yet the shell showed greater phasic release ratios. Following chronic ethanol, uptake rates were increased in the core but not the shell, suggesting region-specific neuronal adaptations. Conversely, kappa opioid receptor function was upregulated in both regions to a similar extent, suggesting a local mechanism of kappa opioid receptor regulation that is generalized across the nucleus accumbens. These data suggest that dopamine axons in the nucleus accumbens core and shell display differences in intrinsic release parameters, and that ethanol-induced adaptations to dopamine neuron terminal fields may not be homogeneous. Also, chronic ethanol exposure induces an upregulation in kappa opioid receptor function, providing a mechanism for potential over-inhibition of accumbens dopamine signaling which may negatively impact downstream synaptic function and ultimately bias choice towards previously reinforced alcohol use behaviors. [ABSTRACT FROM AUTHOR]

A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. [ABSTRACT FROM AUTHOR]

The neural circuits involved in oculomotor control are well described; however, neuromodulation of eye movements is still hardly understood. Memory guided saccades have been extensively studied and in particular neurophysiological evidence from monkey studies points to a crucial functional role of prefrontal dopamine activity. We exploited individual differences in dopamine regulation due to the well established COMT (catechol-O-methyltransferase) Val158Met polymorphism to explore the link between prefrontal dopamine activity and memory guided saccades in healthy subjects. The COMT genotype is thought to modulate dopamine metabolism in prefrontal cortex producing differences in dopamine availability. We investigated memory guided saccades in 111 healthy subjects and determined individual genotypes. Accuracy and precision were reduced in subjects with putatively higher prefrontal dopamine levels. In contrast, we found no modulation of saccade parameters by genotype in a visually guided control task. Our results suggest that increased dopamine activity can have a detrimental effect on saccades that rely on spatial memory representations. Although these findings await replication in larger and more diverse sample sizes, they provide persuasive support that specific oculomotor parameters are sensitive to dopaminergic variation in healthy subjects and add to a better understanding of how dopamine modulates saccadic control. [ABSTRACT FROM AUTHOR]

Objectives: Dopamine dysregulation syndrome (DDS) is an uncommon complication of the treatment of Parkinson's disease, characterised by addictive behaviour and excessive use of dopaminergic medication. DDS may frequently go unrecognised or misdiagnosed. We aimed to clarify current understanding of presentation, risk factors, comorbidities and management of DDS.Methods: Case reports were identified through a systematic search of databases (PubMed, Embase) with the following terms: dopaminergic dysregulation syndrome, hedonistic homeostatic dysregulation, dopamine/levodopa addiction.Results: We reviewed 390 articles, identifying 98 cases of DDS. Early-onset Parkinson's disease (67%) and male gender (83%) were common. DDS presented with significant physical and social impairment, actions to enable or prevent detection of overuse, as well as mood, anxiety and motor fluctuations. All DDS cases met DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) substance use disorder criteria. Past substance and psychiatric history was present in 15.3% and 10.2% of cases. Comorbid impulse control disorders (61%), psychosis (32%) and panic attacks (14%) were common. A large variety of management strategies were used; only 56% of cases resolving. Sodium valproate was successful in 5/5 cases. The response to deep brain stimulation varied.Conclusions: Given the functional impairment, medical and psychiatric consequences and the difficulties of treatment, early identification of DDS should be a priority. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6-hydroxydopamine (6-OHDA)-induced endoplasmic reticulum stress (ERS) in vivo and in vitro. ECH rescued cell viability in damaged cells and decreased 6-OHDA-induced reactive oxygen species accumulation in vitro. It also rescued tyrosine hydroxylase and dopamine transporter expression in the striatum, and decreased α-synuclein aggregation following 6-OHDA treatment in vivo. The validated mechanism of ECH activity was the reduction in the 6-OHDA-induced accumulation of seipin (Berardinelli-Seip congenital lipodystrophy 2). Seipin has been shown to be a key molecule related to motor neuron disease and was tightly associated with ERS in a series of in vivo studies. ECH attenuated seipinopathy by promoting seipin degradation via ubiquitination. ERS was relieved by ECH through the Grp94/Bip-ATF4-CHOP signal pathway. [ABSTRACT FROM AUTHOR]

Two-dimensional transition metal carbides, MXenes, with large surface area, excellent electrical conductivity and chemical stability, have proved promising for energy storage. However, the irreversible re-stacking and low capacity of MXenes restrict their development and practical applications. Here, the N-doped carbon decorated MXene (Ti 3 C 2 T x @NC) composites were synthesized via an in-situ self-polymerization of dopamine on the surface of Ti 3 C 2 T x followed by a carbonization process. The Ti 3 C 2 T x and Ti 3 C 2 T x @NC were systematically characterized, which have been manifested that NC were equably decorated on the surface and interlayer of Ti 3 C 2 T x sheets and a unique three-dimensional composited nanostructure was fabricated. Such nanostructure can confer both high surface area of NC layer and effective avoidance of the restacking of Ti 3 C 2 T x sheets, whilst, importantly, rendering the composites good conductivity and additional pseudocapacitance. As a result, the optimized Ti 3 C 2 T x @NC-2 composite exhibited a high specific capacitance of 442.2 F g −1 under a current density of 1 A g −1 , which is 281% higher than that of Ti 3 C 2 T x . As a further description, Ti 3 C 2 T x @NC achieved an excellent cycling stability with capacitance retaining 91.9% after 5000 cycles and a high rate capability of 92.5% at 10 A g −1 . Besides, the Ti 3 C 2 T x @NC-2-based symmetric supercapacitor presents a delighted energy density and power density. Therefore, the elaborately designed Ti 3 C 2 T x @NC composites provided a pregnant exploration for energy-related applications. [ABSTRACT FROM AUTHOR]

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2–0.8 mg/kg), cotinine (0.5–5.0 mg/kg), anatabine (0.5–5.0 mg/kg), and myosmine (5.0–20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated. [ABSTRACT FROM AUTHOR]

The medial shell region of the nucleus accumbens (msNAc) is a key center for the regulation of goal-directed behavior and is likely to be dysfunctional in neuropsychiatric disorders such as addiction, depression and schizophrenia. Nitric oxide (NO)-producing interneurons in the msNAc are potently modulated by dopamine (DA) and may play an important role in synaptic integration in msNAc networks. In this study, neuronal NO synthase (nNOS) activity was measured in anesthetized rats using amperometric microsensors implanted into the msNAc or via histochemical techniques. In amperometric studies, NO oxidation current was recorded prior to and during electrical stimulation of the ipsilateral fimbria. Fimbria stimulation elicited a frequency and intensity-dependent increase in msNAc NO efflux which was attenuated by systemic administration of the nNOS inhibitor N G -propyl- l -arginine. Parallel studies using NADPH-diaphorase histochemistry to assay nNOS activity produced highly complementary outcomes. Moreover, systemic administration of either a DA D1 receptor agonist or a DA D2 receptor antagonist potentiated nNOS activity in the msNAc elicited by fimbria stimulation. These observations demonstrate for the first time that NO synthesis in nNOS expressing interneurons in the msNAc is facilitated by robust activation of hippocampal afferents in a manner that is differentially modulated by DA D1 and D2 receptor activation. [ABSTRACT FROM AUTHOR]

The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4–10 mg/kg, i.p.) dose-dependently decreased oxycodone self-administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4–4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4–10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2-015 or BAK4-54) provide new lead molecules for development. [ABSTRACT FROM AUTHOR]

The study objectives were to evaluate the efficacy, safety, tolerability, and pharmacokinetics of RP5063 versus placebo. The study was conducted in adults with acute exacerbation of schizophrenia or schizoaffective disorder. This 28-day, multicenter, placebo-controlled, double-blind study randomized 234 subjects to RP5063 15, 30, or 50mg; aripiprazole; or placebo (3:3:3:1:2) once daily. The aripiprazole arm was included solely to show assay sensitivity and was not powered to show efficacy. The primary endpoint was change from baseline to Day 28/EOT (End-of-Treatment) in Positive and Negative Syndrome Scale (PANSS) total score; secondary endpoints included PANSS subscales, improvement ≥1 point on the Clinical Global Impressions-Severity (CGI-S), depression and cognition scales. The primary analysis of PANSS Total showed improvement by a mean (SE) of -20.23 (2.65), -15.42 (2.04), and -19.21 (2.39) in the RP5063 15, 30, and 50mg arms, versus -11.41 (3.45) in the placebo arm. The difference between treatment and placebo reached statistical significance for the 15mg (p=0.021) and 50mg (p=0.016) arms. Improvement with RP5063 was also seen for multiple secondary efficacy outcomes. Discontinuation for any reason was much lower for RP5063 (14%, 25%, 12%) versus placebo (26%) and aripiprazole (35%). The most common treatment-emergent adverse events (TEAE) in the RP5063 groups were insomnia and agitation. There were no significant changes in body weight, electrocardiogram, or incidence of orthostatic hypotension; there was a decrease in blood glucose, lipid profiles, and prolactin levels. In conclusion, the novel dopamine serotonin stabilizer, RP5063 is an efficacious and well-tolerated treatment for acute exacerbation of schizophrenia or schizoaffective disorder. [ABSTRACT FROM AUTHOR]

Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson’s disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10 days with daily oral administration of PPI-1025 (10, 50 or 200 mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone. [ABSTRACT FROM AUTHOR]