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Sample records for dopamine synthesis capacity

  1. Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in ventral striatum

    PubMed Central

    Deserno, Lorenz; Beck, Anne; Huys, Quentin JM; Lorenz, Robert C.; Buchert, Ralph; Buchholz, Hans-Georg; Plotkin, Michail; Kumakara, Yoshitaka; Cumming, Paul; Heinze, Hans-Jochen; Grace, Anthony A.; Rapp, Michael A.; Schlagenhauf, Florian; Heinz, Andreas

    2015-01-01

    Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug related reward. Indeed, reactivity in dopaminergic target areas of patients with alcohol dependence is shifted from non-drug related stimuli towards drug-related stimuli. Such ‘hijacked‘ dopamine signals may impair flexible learning from non-drug related rewards and thus promote craving for the drug of abuse. Here, we used fMRI to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N=27). The same subjects also underwent FDOPA PET to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs, nor striatal dopamine synthesis capacity differed between patients and controls. However, the ventral striatal coding of RPEs was negatively correlated with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between RPE coding and dopamine synthesis capacity depended on the amount of chronic-habitual alcohol intake. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence and this is linked to long-term alcohol intake of patients. Drug intake may thus perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake. PMID:25546072

  2. Ventral Striatal Dopamine Synthesis Capacity Predicts Financial Extravagance in Parkinson’s Disease

    PubMed Central

    Lawrence, Andrew D.; Brooks, David J.; Whone, Alan L.

    2013-01-01

    Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders. PMID:23450713

  3. Ventral striatal dopamine synthesis capacity is associated with individual differences in behavioral disinhibition

    PubMed Central

    Lawrence, Andrew D.; Brooks, David J.

    2014-01-01

    Pathological gambling, alongside addictive and antisocial disorders, forms part of a broad psychopathological spectrum of externalizing disorders, which share an underlying genetic vulnerability. The shared externalizing propensity is a highly heritable, continuously varying trait. Disinhibitory personality traits such as impulsivity and novelty seeking (NS) function as indicators of this broad shared externalizing tendency, which may reflect, at the neurobiological level, variation in the reactivity of dopaminergic (DAergic) brain reward systems centered on the ventral striatum (VS). Here, we examined whether individual differences in ventral striatal dopamine (DA) synthesis capacity were associated with individual variation in disinhibitory personality traits. Twelve healthy male volunteers underwent 6-[18F]Fluoro-L-DOPA (FDOPA) positron emission tomography (PET) scanning to measure striatal DA synthesis capacity, and completed a measure of disinhibited personality (NS). We found that levels of ventral, but not dorsal, striatal DA synthesis capacity were significantly correlated with inter-individual variation in disinhibitory personality traits, particularly a propensity for financial extravagance and irresponsibility. Our results are consistent with preclinical models of behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of personality based vulnerability to pathological gambling and other externalizing disorders. PMID:24672449

  4. Aberrant Salience Is Related to Reduced Reinforcement Learning Signals and Elevated Dopamine Synthesis Capacity in Healthy Adults.

    PubMed

    Boehme, Rebecca; Deserno, Lorenz; Gleich, Tobias; Katthagen, Teresa; Pankow, Anne; Behr, Joachim; Buchert, Ralph; Roiser, Jonathan P; Heinz, Andreas; Schlagenhauf, Florian

    2015-07-15

    The striatum is known to play a key role in reinforcement learning, specifically in the encoding of teaching signals such as reward prediction errors (RPEs). It has been proposed that aberrant salience attribution is associated with impaired coding of RPE and heightened dopamine turnover in the striatum, and might be linked to the development of psychotic symptoms. However, the relationship of aberrant salience attribution, RPE coding, and dopamine synthesis capacity has not been directly investigated. Here we assessed the association between a behavioral measure of aberrant salience attribution, the salience attribution test, to neural correlates of RPEs measured via functional magnetic resonance imaging while healthy participants (n = 58) performed an instrumental learning task. A subset of participants (n = 27) also underwent positron emission tomography with the radiotracer [(18)F]fluoro-l-DOPA to quantify striatal presynaptic dopamine synthesis capacity. Individual variability in aberrant salience measures related negatively to ventral striatal and prefrontal RPE signals and in an exploratory analysis was found to be positively associated with ventral striatal presynaptic dopamine levels. These data provide the first evidence for a specific link between the constructs of aberrant salience attribution, reduced RPE processing, and potentially increased presynaptic dopamine function. PMID:26180188

  5. The vulnerability of nigral neurons to Parkinson's disease is unrelated to their intrinsic capacity for dopamine synthesis: an in situ hybridization study.

    PubMed

    Kingsbury, A E; Marsden, C D; Foster, O J

    1999-03-01

    The contribution of the dopamine-synthetic capacity of nigral neuronal subregions to their vulnerability to degeneration in idiopathic Parkinson's disease (IPD) was explored using semiquantitative in situ hybridization to study expression of mRNA encoding the rate-limiting dopamine synthetic enzyme, tyrosine hydroxylase (TH). Expression of mRNA, the structural protein, beta-tubulin, and the glycolytic enzyme, fructose-1,6, biphosphate aldolase (aldolase C) was studied in parallel in individual neurons of the substantia nigra pars compacta (SNc) in matched groups of IPD and control subjects. TH mRNA expression was found to be heterogeneously expressed in nigral neurons in control and IPD subjects. There was no significant difference in mean values for TH mRNA expression between control and IPD cases and none between nigral subregions, either in control subjects or in established IPD subjects in this study, but there was evidence for a selective upregulation of TH mRNA expression in non-melanized neurons in IPD. There was no relationship between TH mRNA expression disease duration or L-dopa dosage in the IPD group. Mean TH mRNA values for two additional 40-year-old control subjects fell within the range of values of the aged-control group. Aldolase C and beta-tubulin expression did not differ between control and IPD groups or between nigral subregions. These findings suggest that regulation of dopamine synthesis at the level of the cell body does not play a part in determining the pattern of nigral cell vulnerability in IPD. The heterogeneous pattern of TH synthesis was not age-dependent and may be of physiological significance in nigral function. There was no evidence for compensatory upregulation of TH synthesis in surviving melanized neurons in IPD but non-melanized neurons may be involved in this process. Surviving nigral neurons in IPD appear to retain the capacity for normal aldolase C and beta-tubulin peptide synthesis. Long-term L-dopa treatment does not

  6. Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

    PubMed Central

    Simpson, Eleanor H.; Morud, Julia; Winiger, Vanessa; Biezonski, Dominik; Zhu, Judy P.; Bach, Mary Elizabeth; Malleret, Gael; Polan, H. Jonathan; Ng-Evans, Scott; Phillips, Paul E.M.; Kellendonk, Christoph; Kandel, Eric R.

    2014-01-01

    A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val158 allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val158 allele, stimulus–response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans. PMID:24639487

  7. Dopamine autoreceptors and the effects of drugs on locomotion and dopamine synthesis.

    PubMed Central

    Brown, F.; Campbell, W.; Mitchell, P. J.; Randall, K.

    1985-01-01

    Criteria for distinguishing dopamine autoreceptor agonism from other mechanisms of inhibiting locomotion were examined, together with the relationship between inhibition of locomotion and dopamine synthesis. ED50 potencies to inhibit locomotion of mice were established for drugs from a number of categories. Spiperone 0.02 mg kg-1 significantly (P less than 0.05) reversed inhibition of locomotion by known dopamine agonists but not that by the other types of drug. Idazoxan antagonized inhibition of locomotion due to alpha 2-agonists but not dopamine agonists. RU 24926 (N-propyl-N,N-di[2-(3-hydroxyphenyl)ethyl]amine) was antagonized by both spiperone and idazoxan. Only for dopamine agonists was there good correlation (r = 0.97) between potencies to inhibit locomotion in mice and L-dihydroxyphenylalanine (L-DOPA) accumulation in the nucleus accumbens of rats treated with gamma-butyrolactone and 3-hydroxybenzylhydrazine. The specific dopamine D1-agonist, SK&F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine), was inactive in both tests at doses up to 10 mg kg-1. The mixed dopamine agonist/antagonist, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine, commonly known as (-)-3-PPP, acted as a dopamine agonist in both tests but inhibited locomotion more potently than L-DOPA accumulation. The inhibitory effects of dopamine agonists on locomotion were not prevented by alpha-methyl-p-tyrosine pretreatment. The data suggest that spiperone-reversible inhibition of locomotion in mice is a good criterion for dopamine autoreceptor agonists. The receptors involved are affected by low doses of both dopamine agonists and antagonists and seem similar to those involved in the autoreceptor mediated inhibition of dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:4005487

  8. Catecholamines up Integrates Dopamine Synthesis and Synaptic Trafficking

    PubMed Central

    Wang, Zhe; Ferdousy, Faiza; Lawal, Hakeem; Huang, Zhinong; Daigle, J. Gavin; Izevbaye, Iyare; Doherty, Olugbenga; Thomas, Jerrad; Stathakis, Dean G; O’Donnell, Janis M.

    2011-01-01

    The highly reactive nature of dopamine renders dopaminergic neurons vulnerable to oxidative damage. We recently demonstrated that loss-of-function mutations in the Drosophila gene Catecholamines up (Catsup) elevate dopamine pools but, paradoxically, also confer resistance to paraquat, an herbicide that induces oxidative stress-mediated toxicity in dopaminergic neurons. We now report a novel association of the membrane protein, Catsup, with GTP cyclohydrolase rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis and tyrosine hydroxylase, rate-limiting enzyme for dopamine biosynthesis, which requires BH4 as a cofactor. Loss-of-function Catsup mutations cause dominant hyperactivation of both enzymes. Elevated dopamine levels in Catsup mutants coincide with several distinct characteristics, including hypermobility, minimal basal levels of 3,4-Dihydroxy-Phenylacetic Acid, an oxidative metabolite of dopamine, and resistance to the Vesicular Monoamine Transporter inhibitor, reserpine, suggesting that excess dopamine is synaptically active and that Catsup functions in the regulation of synaptic vesicle loading and release of dopamine. We conclude that Catsup regulates and links the dopamine synthesis and transport networks. PMID:21985068

  9. Cell-free protein synthesis and purification of human dopamine D2 receptor long isoform.

    PubMed

    Basu, Dipannita; Castellano, Jessica M; Thomas, Nancy; Mishra, Ram K

    2013-01-01

    The human dopamine D2 receptor long isoform (D2L) has significant implications in neurological and neuropsychiatric disorders such as Parkinson's disease and schizophrenia. Detailed structural knowledge of this receptor is limited owing to its highly hydrophobic nature, which leads to protein aggregation and host toxicity when expressed in cellular systems. The newly emerging field of cell-free protein expression presents numerous advantages to overcome these challenges. This system utilizes protein synthesis machinery and exogenous DNA to synthesize functional proteins outside of intact cells. This study utilizes two different cell-free systems for the synthesis of human dopamine D2L receptor. These include the Escherichia coli lysate-based system and the wheat-germ lysate-based system. The bacterial cell-free method used pET 100/D-TOPO vector to synthesize hexa-histidine-tagged D2L receptor using a dialysis bag system; the resulting protein was purified using nickel-nitrilotriacetic acid affinity resin. The wheat germ system used pEU-glutathione-S-transferase (GST) vector to synthesize GST-tagged D2L receptor using a bilayer translation method; the resulting protein was purified using a GST affinity resin. The presence and binding capacity of the synthesized D2L receptor was confirmed by immunoblotting and radioligand competition assays, respectively. Additionally, in-gel protein sequencing via Nano LC-MS/MS was used to confirm protein synthesis via the wheat germ system. The results showed both systems to synthesize microgram quantities of the receptor. Improved expression of this highly challenging protein can improve research and understanding of the human dopamine D2L receptor. PMID:23424095

  10. Dopamine and cognitive control: sex-by-genotype interactions influence the capacity to switch attention.

    PubMed

    Gurvich, C; Rossell, S L

    2015-03-15

    Cognitive performance in healthy persons varies widely between individuals. Sex differences in cognition are well reported, and there is an emerging body of evidence suggesting that the relationship between dopaminergic neurotransmission, implicated in many cognitive functions, is modulated by sex. Here, we examine the influence of sex and genetic variations along the dopaminergic pathway on aspects of cognitive control. A total of 415 healthy individuals, selected from an international consortium linked to Brain Research and Integrative Neuroscience Network (BRAINnet), were genotyped for two common and functional genetic variations of dopamine regulating genes: the catechol-O-methyltransferase [COMT] gene (rs4680) and the dopamine receptor D2 [DRD2] gene (rs6277). Cognitive measures were selected to explore sustained attention (using a continuous performance task), switching of attention (using a Trails B adaptation) and working memory (a visual computerised adaptation of digit span). While there were no main effects for genotype across any tasks, analyses revealed significant sex by genotype interactions for the capacity to switch attention. In relation to COMT, superior performance was noted in females with the Val/Val genotype and for DRD2, superior performance was seen for TT females and CC males. These findings highlight the importance of considering genetic variation in baseline dopamine levels in addition to sex, when considering the impact of dopamine on cognition in healthy populations. These findings also have important implications for the many neuropsychiatric disorders that implicate dopamine, cognitive changes and sex differences. PMID:25510197

  11. Tyrosine administration enhances dopamine synthesis and release in light-activated rat retina

    NASA Technical Reports Server (NTRS)

    Gibson, C. J.; Watkins, C. J.; Wurtman, R. J.

    1983-01-01

    Exposure of dark-adapted albino rats to light (350 lux) significantly elevated retinal levels of the dopamine metabolite dihydroxyphenyl acetic acid during the next hour; their return to a dark environment caused dihydroxyphenyl acetic acid levels to fall. Retinal dopamine levels were increased slightly by light exposure, suggesting that the increase in dihydroxyphenyl acetic acid reflected accelerated dopamine synthesis. Administration of tyrosine (100 mg/kg, i.p.) further elevated retinal dihydroxyphenyl acetic acid among light-exposed animals, but failed to affect dopamine release among animals in the dark. These observations show that a physiological stimulus - light exposure - can cause catecholaminergic neurons to become tyrosine-dependent; they also suggest that food consumption may affect neurotransmitter release within the retina.

  12. Strontium vanadate nanoribbons: Synthesis, characterization and detection of dopamine

    SciTech Connect

    Zhou, Qing; Shao, Mingwang; Chen, Tao; Xu, Hongyan

    2010-09-15

    Large-scale, high-purity and uniform strontium vanadate (Sr{sub 2}V{sub 2}O{sub 7}) nanoribbons were easily synthesized via a hydrothermal process without any surfactants. The as-prepared products were up to hundreds of micrometers in length, 200-600 nm in width, and 20 nm in thickness. These nanomaterials were employed to modify glassy carbon electrode, which displayed excellent electrochemical sensitivity in detecting dopamine in the presence of ascorbic acid. A linear relationship between the concentrations of dopamine and its oxidation peak currents was obtained. The modified electrode exhibited high reproducibility and stability, which might be found potential application in the biosensors.

  13. Dopamine as a Carbon Source: The Controlled Synthesis of Hollow Carbon Spheres and Yolk-Structured Carbon Nanocomposites

    SciTech Connect

    Dai, Sheng; Liu, Rui; Mahurin, Shannon Mark; Li, Chen; Unocic, Raymond R; Idrobo Tapia, Juan C; Gao, Hongjun; Pennycook, Stephen J

    2011-01-01

    A facile and versatile synthesis using dopamine as a carbon source gives hollow carbon spheres and yolk-shell Au{at}Carbon nanocomposites. The uniform nature of dopamine coatings and their high carbon yield endow the products with high structural integrity. The Au{at}C nanocomposites are catalytically active.

  14. Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI☆

    PubMed Central

    Yokum, Sonja; Marti, C. Nathan; Smolen, Andrew; Stice, Eric

    2014-01-01

    Because food intake exerts its rewarding effect by increasing dopamine (DA) signaling in reward circuitry, it theoretically follows that individuals with a greater number of genotypes putatively associated with high DA signaling capacity are at increased risk for overeating and subsequent weight gain. We tested the association between the multilocus genetic composite risk score, defined by the total number of genotypes putatively associated with greater DA signaling capacity (i.e. TaqIA A2 allele, DRD2-141C Ins/Del and Del/Del genotypes, DRD4-S allele, DAT1-S allele, and COMT Val/Val genotype), and future increases in Body Mass Index (BMI) in three prospective studies. Participants in Study 1 (N = 30; M age = 15.2; M baseline BMI = 26.9), Study 2 (N = 34; M age = 20.9; M baseline BMI = 28.2), and Study 3 (N = 162; M age = 15.3, M baseline BMI = 20.8) provided saliva samples from which epithelial cells were collected, permitting DNA extraction. The multilocus genetic composite risk score was associated with future increases in BMI in all three studies (Study 1, r = 0.37; Study 2, r = 0.22; Study 3, r = 0.14) and the overall sample (r = 0.19). DRD4-S was associated with increases in BMI in Study 1 (r = 0.42), Study 2 (r = 0.27), and in the overall sample (r = 0.17). DAT1-S was associated with increases in BMI in Study 3 (r = 0.17) and in the overall sample (r = 0.12). There were no associations between the other genotypes (TaqIA, COMT, and DRD2-141C) and change in BMI over 2-year follow-up. Data suggest that individuals with a genetic propensity for greater DA signaling capacity are at risk for future weight gain and that combining alleles that theoretically have a similar function may provide a more reliable method of modeling genetic risk associated with future weight gain than individual genotypes. PMID:25523644

  15. A Research Synthesis of the Evaluation Capacity Building Literature

    ERIC Educational Resources Information Center

    Labin, Susan N.; Duffy, Jennifer L.; Meyers, Duncan C.; Wandersman, Abraham; Lesesne, Catherine A.

    2012-01-01

    The continuously growing demand for program results has produced an increased need for evaluation capacity building (ECB). The "Integrative ECB Model" was developed to integrate concepts from existing ECB theory literature and to structure a synthesis of the empirical ECB literature. The study used a broad-based research synthesis method with…

  16. MicroRNA-133 Inhibits Behavioral Aggregation by Controlling Dopamine Synthesis in Locusts

    PubMed Central

    Wang, Yanli; Guo, Xiaojiao; He, Jing; Kang, Le

    2014-01-01

    Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3′ untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts. PMID:24586212

  17. Chromatographic assay to study the activity of multiple enzymes involved in the synthesis and metabolism of dopamine and serotonin.

    PubMed

    Morgan, Lindsay D; Baker, Hannah; Yeoman, Mark S; Patel, Bhavik Anil

    2012-03-21

    Serotonin and dopamine are crucial regulators of signalling in the peripheral and central nervous systems. We present an ex-vivo, isocratic chromatographic method that allows for the measurement of tyrosine, L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), tryptophan, 5-hydroxytryptophan (5-HTP), serotonin and 5-hydroxy-3-indoleacetic acid (5-HIAA) in a model central nervous (CNS) system, to study the role of key enzymes involved in the synthesis and metabolism of serotonin and dopamine. By utilising a sample splitting technique, we could test a single CNS sample at multiple time points under various pharmacological treatments. In, addition, we were able to conduct this assay by utilising the endogenous biochemical components of the CNS to study the synthesis and metabolism of serotonin and dopamine, negating the requirement of additional enzyme activators or stabilisers in the biological matrix. Finally we utilised NSD-1015, an aromatic amino acid decarboxylase enzyme inhibitor used to study the synthesis of dopamine and serotonin to monitor alterations in levels of key neurochemicals. 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015) was able to reduce levels of serotonin and dopamine, whilst elevating precursors L-DOPA and 5-HTP. PMID:22290325

  18. Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

    PubMed

    Urbanek, Rebecca A; Xiong, Hui; Wu, Ye; Blackwell, William; Steelman, Gary; Rosamond, Jim; Wesolowski, Steven S; Campbell, James B; Zhang, Minli; Brockel, Becky; Widzowski, Daniel V

    2013-01-15

    Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model. PMID:23237836

  19. Genetic Variation in COMT Activity Impacts Learning and Dopamine Release Capacity in the Striatum

    ERIC Educational Resources Information Center

    Simpson, Eleanor H.; Morud, Julia; Winiger, Vanessa; Biezonski, Dominik; Zhu, Judy P.; Bach, Mary Elizabeth; Malleret, Gael; Polan, H. Jonathan; Ng-Evans, Scott; Phillips, Paul E. M.; Kellendonk, Christoph; Krandel, Eric R.

    2014-01-01

    A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the "COMT Val" [superscript 158] allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity…

  20. Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens.

    PubMed

    Aquino-Miranda, Guillermo; Escamilla-Sánchez, Juan; González-Pantoja, Raúl; Bueno-Nava, Antonio; Arias-Montaño, José-Antonio

    2016-07-01

    We studied the effect of activating histamine H3 receptors (H3Rs) on rat nucleus accumbens (rNAcc) dopaminergic transmission by analyzing [(3)H]-dopamine uptake by synaptosomes, and dopamine synthesis and depolarization-evoked [(3)H]-dopamine release in slices. The uptake of [(3)H]-dopamine by rNAcc synaptosomes was not affected by the H3R agonist RAMH (10(-10)-10(-6) M). In rNAcc slices perfusion with RAMH (1 μM) had no significant effect on [(3)H]-dopamine release evoked by depolarization with 30 mM K(+) (91.4 ± 4.5% of controls). The blockade of dopamine D2 autoreceptors with sulpiride (1 μM) enhanced K(+)-evoked [(3)H]-dopamine release (168.8 ± 15.5% of controls), but under this condition RAMH (1 μM) also failed to affect [(3)H]-dopamine release. Dopamine synthesis was evaluated in rNAcc slices incubated with the l-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor NSD-1015 (1 mM). Forskolin-induced DOPA accumulation (220.1 ± 10.4% of controls) was significantly reduced by RAMH (41.1 ± 6.5% and 43.5 ± 9.1% inhibition at 100 nM and 1 μM, respectively), and this effect was prevented by the H3R antagonist ciproxifan (10 μM). DOPA accumulation induced by preventing cAMP degradation with IBMX (iso-butyl-methylxantine, 1 mM) or by activating receptors for the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) with PACAP-27 (1 μM) was reduced (IBMX) or prevented (PACAP-27) by RAMH (100 nM). In contrast, DOPA accumulation induced by 8-Bromo-cAMP (1 mM) was not affected by RAMH (100 nM). These results indicate that in rNAcc H3Rs do not modulate dopamine uptake or release, but regulate dopamine synthesis by inhibiting cAMP formation and thus PKA activation. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26169221

  1. Synthesis and evaluation of 3-aryl piperidine analogs as potent and efficacious dopamine D4 receptor agonists.

    PubMed

    Wang, Xueqing; Bhatia, Pramila A; Daanen, Jerome F; Latsaw, Steve P; Rohde, Jeffrey; Kolasa, Teodozyi; Hakeem, Ahmed A; Matulenko, Mark A; Nakane, Masaki; Uchic, Marie E; Miller, Loan N; Chang, Renjie; Moreland, Robert B; Brioni, Jorge D; Stewart, Andrew O

    2005-08-01

    A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed. PMID:15896964

  2. A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

    PubMed Central

    Cartier, Etienne A.; Parra, Leonardo A.; Baust, Tracy B.; Quiroz, Marisol; Salazar, Gloria; Faundez, Victor; Egaña, Loreto; Torres, Gonzalo E.

    2010-01-01

    Synaptic transmission depends on neurotransmitter pools stored within vesicles that undergo regulated exocytosis. In the brain, the vesicular monoamine transporter-2 (VMAT2) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles. Prior to storage within vesicles, DA synthesis occurs at the synaptic terminal in a two-step enzymatic process. First, the rate-limiting enzyme tyrosine hydroxylase (TH) converts tyrosine to di-OH-phenylalanine. Aromatic amino acid decarboxylase (AADC) then converts di-OH-phenylalanine into DA. Here, we provide evidence that VMAT2 physically and functionally interacts with the enzymes responsible for DA synthesis. In rat striata, TH and AADC co-immunoprecipitate with VMAT2, whereas in PC 12 cells, TH co-immunoprecipitates with the closely related VMAT1 and with overexpressed VMAT2. GST pull-down assays further identified three cytosolic domains of VMAT2 involved in the interaction with TH and AADC. Furthermore, in vitro binding assays demonstrated that TH directly interacts with VMAT2. Additionally, using fractionation and immunoisolation approaches, we demonstrate that TH and AADC associate with VMAT2-containing synaptic vesicles from rat brain. These vesicles exhibited specific TH activity. Finally, the coupling between synthesis and transport of DA into vesicles was impaired in the presence of fragments involved in the VMAT2/TH/AADC interaction. Taken together, our results indicate that DA synthesis can occur at the synaptic vesicle membrane, where it is physically and functionally coupled to VMAT2-mediated transport into vesicles. PMID:19903816

  3. Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults.

    PubMed

    Smith, Christopher T; Wallace, Deanna L; Dang, Linh C; Aarts, Esther; Jagust, William J; D'Esposito, Mark; Boettiger, Charlotte A

    2016-03-01

    Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude. PMID:26683066

  4. Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library.

    PubMed

    Stucchi, Mattia; Gmeiner, Peter; Huebner, Harald; Rainoldi, Giulia; Sacchetti, Alessandro; Silvani, Alessandra; Lesma, Giordano

    2015-08-13

    A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating the effect of such diversity on the dopamine receptor affinity, a small library of compounds was prepared, applying post-Ugi transformations. Ligand stimulated binding assays indicated that some compounds show a significant affinity, with K i values up to 53 nM for the D2 receptor. Molecular docking studies with the D2 and D3 receptor homology models were also performed on selected compounds. They highlighted key interactions at the indole head and at the piperazine moiety, which resulted in good agreement with the known pharmacophore models, thus helping to explain the observed structure-activity relationship data. Molecular insights from this study could enable a rational improvement of the split-Ugi primary scaffold, toward more selective ligands. PMID:26288260

  5. The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

    NASA Astrophysics Data System (ADS)

    Chen, Zhengming; Yang, Ji; Skolnick, Phil

    The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

  6. Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library

    PubMed Central

    2015-01-01

    A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating the effect of such diversity on the dopamine receptor affinity, a small library of compounds was prepared, applying post-Ugi transformations. Ligand stimulated binding assays indicated that some compounds show a significant affinity, with Ki values up to 53 nM for the D2 receptor. Molecular docking studies with the D2 and D3 receptor homology models were also performed on selected compounds. They highlighted key interactions at the indole head and at the piperazine moiety, which resulted in good agreement with the known pharmacophore models, thus helping to explain the observed structure–activity relationship data. Molecular insights from this study could enable a rational improvement of the split-Ugi primary scaffold, toward more selective ligands. PMID:26288260

  7. Synthesis and dopamine transporter imaging in rhesus monkeys with fluorine-18 labeled FECT

    SciTech Connect

    Keil, R.; Hoffman, J.M.; Eschima, D.

    1996-05-01

    Parkinson`s patients have been shown to suffer a 60-80% loss of dopamine transporters in the substantia nigra and striatum. Dopamine transporter ligands labeled with fluorine-18 (t {1/2}=110 min) are attractive probes for measuring the density of dopamine transporter sites n the striatum for the diagnosis and evaluation of Parkinson`s patients by PET. We have synthesized (Ki = 32 nM vs RTI-55), fluorine-18 labeled 2{beta}-carbomethoxy-3{beta}(4-chlorophenyl)-8-(3-fluoropropyl)nortropane (FECT), with favorable kinetics as a potential dopamine transporter PET imaging agent. Treatment of 2{beta}-carbomethoxy-3{beta}-(4-chlorophenyl)nortropane (1) with 1-bromo-2-fluoroethane (2) in CH3CN at 80{degrees}C gave FECT (3). [F-18]FECT (3) was prepared by treating 1,2-ditosyloxyethane (4) with NCA K[F-18]/K222 (365 mCi) for 5 min in CH3CN at 85{degrees}C to give [F-18] 1-fluoro-2-tosyloxyethane (5) (175 mCi)in 59% E.O.B. yield. Coupling of [F-18] 5 with 1 in DMF at 135 {degrees}C for 45 min gave [F-18]FECT (41 mCi) in 25% yield E.O.B. following HPLC purification in a total synthesis time of 122 min. [F-18] 5 was >99% radiochemically pure with a specific activity of 5 Ci/{mu}mole. Following intravenous administration to a rhesus monkey [F-18]FECT (8.13 mCi) showed a peak uptake at 30 min in the striatum (S) followed by a slow clearance and a rapid washout from the cerebellum to afford a high S/C ratio = 11.0 at 125 min. Radio-HPLC analysis of the ether extracts form plasma samples for radioactive metabolites detected only the presence of [F-18]FECT. These results suggest that FECT is an Research supported by DOE.

  8. Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

    PubMed Central

    Glavind, Emilie; Aagaard, Niels Kristian; Grønbæk, Henning; Møller, Holger Jon; Orntoft, Nikolaj Worm; Vilstrup, Hendrik; Thomsen, Karen Louise

    2016-01-01

    Background and Aim Data on quantitative metabolic liver functions in the life-threatening disease alcoholic hepatitis are scarce. Urea synthesis is an essential metabolic liver function that plays a key regulatory role in nitrogen homeostasis. The urea synthesis capacity decreases in patients with compromised liver function, whereas it increases in patients with inflammation. Alcoholic hepatitis involves both mechanisms, but how these opposite effects are balanced remains unclear. Our aim was to investigate how alcoholic hepatitis affects the capacity for urea synthesis. We related these findings to another measure of metabolic liver function, the galactose elimination capacity (GEC), as well as to clinical disease severity. Methods We included 20 patients with alcoholic hepatitis and 7 healthy controls. The urea synthesis capacity was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the blood α-amino nitrogen concentration and urea nitrogen synthesis rate during alanine infusion. The GEC was determined using blood concentration decay curves after intravenous bolus injection of galactose. Clinical disease severity was assessed by the Glasgow Alcoholic Hepatitis Score and Model for End-Stage Liver Disease (MELD) score. Results The FHNC was markedly decreased in the alcoholic hepatitis patients compared with the healthy controls (7.2±4.9 L/h vs. 37.4±6.8 L/h, P<0.01), and the largest decrease was observed in those with severe alcoholic hepatitis (4.9±3.6 L/h vs. 9.9±4.9 L/h, P<0.05). The GEC was less markedly reduced than the FHNC. A negative correlation was detected between the FHNC and MELD score (rho = -0.49, P<0.05). Conclusions Alcoholic hepatitis markedly decreases the urea synthesis capacity. This decrease is associated with an increase in clinical disease severity. Thus, the metabolic failure in alcoholic hepatitis prevails such that the liver cannot adequately perform the metabolic up

  9. Part 1: synthesis of irreversible inhibitors of aldose reductase with subsequent development of a carbon-13 NMR protein probe. Part 2: synthesis of selenium analogs of dopamine as potential dopamine receptor agonists

    SciTech Connect

    Ares, J.J.

    1986-01-01

    Aldose reductase converts glucose into sorbitol using NADPH as a cofactor. Sorbitol accumulation in various tissues is believed to play a major role in the development of debilitating complications of diabetes; thus, much effort has been directed toward the preparation of aldose reductase inhibitors. Of the compounds prepared, the most active are the isothiocyanate and azide analogs of the reversible aldose reductase inhibitor alrestatin. The potency of the alrestatin isothiocyanate prompted the authors to examine the possibility that isothiocyanates enriched with carbon-13 could be used as carbon-13 NMR protein probes. Toward this end, a synthesis of carbon-13 enriched phenylisothiocyanate has been developed. This reagent has been successfully utilized to study peptides via carbon-13 NMR spectroscopy. Research in their laboratory over the years has focused on answering two fundamental questions regarding the interaction of dopamine with its receptor. First, can the concept of bioisosterism be applied to dopamine agonists. Secondly, what is the actual molecular species of dopamine which interacts with the dopamine receptor. In an effort to answer these questions, methyl selenide and dimethyl selenonium analogs of dopamine have been synthesized.

  10. Sodium-dependence and ouabain-sensitivity of the synthesis of dopamine in renal tissues of the rat.

    PubMed Central

    Soares-da-Silva, P.; Fernandes, M. H.

    1992-01-01

    1. The present study has examined the influence of sodium chloride (0-160 mM) and ouabain (100 and 500 microM), an inhibitor of the enzyme Na(+)-K+ ATPase, on the synthesis of dopamine in slices of rat renal cortex loaded with exogenous L-dihydroxyphenylalanine (L-DOPA). The deamination of newly-formed dopamine into 3,4-dihydroxyphenylacetic acid (DOPAC) was also examined. The assay of L-DOPA, dopamine and DOPAC in kidney slices was performed by high performance liquid chromatography (h.p.l.c.) with electrochemical detection. 2. The accumulation of newly-formed dopamine and DOPAC in kidney slices loaded with L-DOPA (50 and 100 microM) was found to be dependent on the concentration of NaCl in the medium. A similar picture could be observed for DOPAC. The fractional rate of accumulation (k; mM NaCl-1) was at 50 and 100 microM L-DOPA, respectively, 0.00305 +/- 0.00036 and 0.00328 +/- 0.00029 for dopamine and 0.00672 +/- 0.00072 and 0.00641 +/- 0.00069 for DOPAC. The sodium-dependent formation of dopamine was completely abolished when the experiments were performed in the absence of oxygen. 3. In experiments performed in the presence of 120 mM NaCl, but not in conditions of low sodium (20 mM NaCl in the medium), ouabain (100 and 500 microM) was found to inhibit the accumulation of newly-formed dopamine and DOPAC (14-57% reduction; P less than 0.05); this effect was more marked at 50 and 100 microM L-DOPA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1504714

  11. Stimulation of dopamine synthesis and activation of tyrosine hydroxylase by phorbol diesters in rat striatum

    SciTech Connect

    Onali, P.; Olianas, M.C.

    1987-03-23

    In rat striatal synaptosomes, 4..beta..-phorbol 12-myristate 13-acetate (PMA) and 4 ..beta..-phorbol 12,13-dibutyrate (PDBu), two activators of Ca/sup 2 +/-phospholipid-dependent protein kinase (protein kinase C) increased dopamine (DA) synthesis measured by following the release of /sup 14/CO/sub 2/ from L-(1-/sup 14/C) tyrosine. Maximal stimulation (21-28% increase of basal rate) was produced by 0.5 ..mu..M PMA and 1 ..mu..M PDBu. 4 ..beta..-Phorbol and 4 ..beta..-phorbol 13-acetate, which are not activators of protein kinase C, were ineffective at 1 ..mu..M. PMA did not change the release of /sup 14/CO/sub 2/ from L-(1-/sup 14/C)DOPA. Addition of 1 mM EGTA to a Ca/sup 2 +/-free incubation medium failed to affect PMA stimulation. KCl (60 mM) enhanced DA synthesis by 25%. Exposure of synaptosomes to either PMA or PDBu prior to KCl addition resulted in a more than additive increase (80-100%) of DA synthesis. A similar synergistic effect was observed when the phorbol diesters were combined with either veratridine or d-amphetamine but not with forskolin and dibutyryl cyclic AMP. Pretreatment of striatal synaptosomes with phorbol diesters produced an activation of tyrosine hydroxylase (TH) associated with a 60% increase of the Vmax and a decrease of the Km for the pterine cofactor 6-methyl-5,6,7,8-tetrahydropterin. These results indicate that protein kinase C participates in the regulation of striatal TH in situ and that its activation may act synergistically with DA releasing agents in stimulating DA synthesis. 37 references, 3 figures, 3 tables.

  12. Stimulation of dopamine D₁ receptor improves learning capacity in cooperating cleaner fish.

    PubMed

    Messias, João P M; Santos, Teresa P; Pinto, Maria; Soares, Marta C

    2016-01-27

    Accurate contextual decision-making strategies are important in social environments. Specific areas in the brain are tasked to process these complex interactions and generate correct follow-up responses. The dorsolateral and dorsomedial parts of the telencephalon in the teleost fish brain are neural substrates modulated by the neurotransmitter dopamine (DA), and are part of an important neural circuitry that drives animal behaviour from the most basic actions such as learning to search for food, to properly choosing partners and managing decisions based on context. The Indo-Pacific cleaner wrasse Labroides dimidiatus is a highly social teleost fish species with a complex network of interactions with its 'client' reef fish. We asked if changes in DA signalling would affect individual learning ability by presenting cleaner fish two ecologically different tasks that simulated a natural situation requiring accurate decision-making. We demonstrate that there is an involvement of the DA system and D1 receptor pathways on cleaners' natural abilities to learn both tasks. Our results add significantly to the growing literature on the physiological mechanisms that underlie and facilitate the expression of cooperative abilities. PMID:26791613

  13. Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum.

    PubMed

    Mertens, Birgit; Vanderheyden, Patrick; Michotte, Yvette; Sarre, Sophie

    2010-06-01

    A relationship between the central renin angiotensin system and the dopaminergic system has been described in the striatum. However, the role of the angiotensin II type 2 (AT(2)) receptor in this interaction has not yet been established. The present study examined the outcome of direct AT(2) receptor stimulation on dopamine (DA) release and synthesis by means of the recently developed nonpeptide AT(2) receptor agonist, compound 21 (C21). The effects of AT(2) receptor agonism on the release of DA and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine biosynthesis, were investigated using in vivo microdialysis. Local administration of C21 (0.1 and 1 microM) resulted in a decrease of the extracellular DOPAC levels, whereas extracellular DA concentrations remained unaltered, suggesting a reduced synthesis of DA. This effect was mediated by the AT(2) receptor since it could be blocked by the AT(2) receptor antagonist PD123319 (1 microM). A similar effect was observed after local striatal (10 nM) as well as systemic (0.3 and 3 mg/kg i.p.) administration of the AT(1) receptor antagonist, candesartan. TH activity as assessed by accumulation of extracellular levels of L-DOPA after inhibition of amino acid decarboxylase with NSD1015, was also reduced after local administration of C21 (0.1 and 1 microM) and candesartan (10 nM). Together, these data suggest that AT(1) and AT(2) receptors in the striatum exert an opposite effect on the modulation of DA synthesis rather than DA release. PMID:20097214

  14. Mapping the Catechol Binding Site in Dopamine D1 Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

    PubMed Central

    Bonner, Lisa A.; Laban, Uros; Chemel, Benjamin R.; Juncosa, Jose I.; Lill, Markus A.; Watts, Val J.; Nichols, David E.

    2012-01-01

    A novel class of isochroman dopamine analogues, 1, originally reported by Abbott Laboratories, had greater than 100-fold selectivity for D1-like vs. D2-like receptors. We synthesized a parallel series of chroman compounds, 2, and showed that repositioning the oxygen in the heterocyclic ring reduced potency and conferred D2-like receptor selectivity to these compounds. In silico modeling supported the hypothesis that the altered pharmacology for 2 was due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxyl of the catechol moiety. This interaction realigns the catechol hydroxyl groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds, 3. Our results suggest that when the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity is restored. PMID:21538900

  15. Perturbations in dopamine synthesis lead to discrete physiological effects and impact oxidative stress response in Drosophila.

    PubMed

    Hanna, Marley E; Bednářová, Andrea; Rakshit, Kuntol; Chaudhuri, Anathbandhu; O'Donnell, Janis M; Krishnan, Natraj

    2015-02-01

    The impact of mutations in four essential genes involved in dopamine (DA) synthesis and transport on longevity, motor behavior, and resistance to oxidative stress was monitored in Drosophila melanogaster. The fly lines used for this study were: (i) a loss of function mutation in Catecholamines up (Catsup(26)), which is a negative regulator of the rate limiting enzyme for DA synthesis, (ii) a mutant for the gene pale (ple(2)) that encodes for the rate limiting enzyme tyrosine hydroxylase (TH), (iii) a mutant for the gene Punch (Pu(Z22)) that encodes guanosine triphosphate cyclohydrolase, required for TH activity, and (iv) a mutant in the vesicular monoamine transporter (VMAT(Δ14)), which is required for packaging of DA as vesicles inside DA neurons. Median lifespans of ple(2), Pu(Z22) and VMAT(Δ14) mutants were significantly decreased compared to Catsup(26) and wild type controls that did not significantly differ between each other. Catsup(26) flies survived longer when exposed to hydrogen peroxide (80 μM) or paraquat (10mM) compared to ple(2), Pu(Z22) or VMAT(Δ14) and controls. These flies also exhibited significantly higher negative geotaxis activity compared to ple(2), Pu(Z22), VMAT(Δ14) and controls. All mutant flies demonstrated rhythmic circadian locomotor activity in general, albeit Catsup(26) and VMAT(Δ14) flies had slightly weaker rhythms. Expression analysis of some key antioxidant genes revealed that glutathione S-transferase Omega-1 (GSTO1) expression was significantly up-regulated in all DA synthesis pathway mutants and especially in Catsup(26) and VMAT(Δ14) flies at both mRNA and protein levels. Taken together, we hypothesize that DA could directly influence GSTO1 transcription and thus play a significant role in the regulation of response to oxidative stress. Additionally, perturbations in DA synthesis do not appear to have a significant impact on circadian locomotor activity rhythms per se, but do have an influence on general locomotor

  16. Dopamine Polymerization in Liquid Marbles: A General Route to Janus Particle Synthesis.

    PubMed

    Sheng, Yifeng; Sun, Guanqing; Ngai, To

    2016-04-01

    Coating a liquid with a particle shell not only renders a droplet superhydrophobic but also isolates a well-confined microenvironment for miniaturized chemical processes. Previously, we have demonstrated that particles at the liquid marble interface provide an ideal platform for the site-selective modification of superhydrophobic particles. However, the need for a special chemical reaction limits their potential use for the fabrication of Janus particles with various properties. Herein, we combine the employment of liquid marbles as microreactors with the remarkable adhesive ability of polydopamine to develop a general route for the synthesis of Janus particles from micrometer-sized superhydrophobic particles. We demonstrate that dopamine polymerization and deposition inside liquid marbles could be used for the selective surface modification of microsized silica particles, resulting in the formation of Janus particles. Moreover, it is possible to manipulate the Janus balance of the particles via the addition of surfactants and/or organic solvents to tune the interfacial energy. More importantly, owing to the many functional groups in polydopamine, we show that versatile strategies could be introduced to use these partially polydopamine-coated silica particles as platforms for further modification, including nanoparticle immobilization, metal ion chelation and reduction, as well as for chemical reactions. Given the flexibility in the choice of cores and the modification strategies, this developed method is distinctive in its high universality, good controllability, and great practicability. PMID:26963571

  17. Controllable Synthesis of Functional Hollow Carbon Nanostructures with Dopamine As Precursor for Supercapacitors.

    PubMed

    Liu, Chao; Wang, Jing; Li, Jiansheng; Luo, Rui; Shen, Jinyou; Sun, Xiuyun; Han, Weiqing; Wang, Lianjun

    2015-08-26

    N-doped hollow carbon spheres (N-HCSs) are promising candidates as electrode material for supercapacitor application. In this work, we report a facile one-step synthesis of discrete and highly dispersible N-HCSs with dopamine (DA) as a carbon precursor and TEOS as a structure-assistant agent in a mixture containing water, ethanol, and ammonia. The architectures of resultant N-HCSs, including yolk-shell hollow carbon spheres (YS-HCSs), single-shell hollow carbon spheres (SS-HCSs), and double-shells hollow carbon spheres (DS-HCSs), can be efficiently controlled through the adjustment of the amount of ammonia. To explain the relation and formation mechanism of these hollow carbon structures, the samples during the different synthetic steps, including polymer/silica spheres, carbon/silica spheres and silica spheres by combustion in air, were characterized by TEM. Electrochemical measurements performed on YS-HCSs, SS-HCSs, and DS-HCSs showed high capacitance with 215, 280, and 381 F g(-1), respectively. Moreover, all the nitrogen-doped hollow carbon nanospheres showed a good cycling stability 97.0% capacitive retention after 3000 cycles. Notably, the highest capacitance of DS-HCSs up to 381 F g(-1) is higher than the capacitance reported so far for many carbon-based materials, which may be attributed to the high surface area, hollow structure, nitrogen functionalization, and double-shell architecture. These kinds of N-doped hollow-structured carbon spheres may show promising prospects as advanced energy storage materials and catalyst supports. PMID:26243663

  18. Dopamine and the cognitive downside of a promised bonus

    PubMed Central

    Aarts, Esther; Wallace, Deanna L.; Dang, Linh C.; Jagust, William; Cools, Roshan; D'Esposito, Mark

    2014-01-01

    It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine synthesis capacity in the striatum. These data demonstrate not only that appetitive motivation can have paradoxical detrimental effects for cognitive control, but also provide a mechanistic account of these effects. PMID:24525265

  19. Lesions of dopamine neurons in the medial prefrontal cortex: effects on self-administration of amphetamine and dopamine synthesis in the brain of the rat.

    PubMed

    Leccese, A P; Lyness, W H

    1987-09-01

    It has been suggested that dopamine (DA)-containing neurons within the medial prefrontal cortex subserve a role in the positive reinforcing effects of psychomotor stimulants. Injections of 6-hydroxydopamine (6-OHDA) into this region, which destroyed a major portion of the DA innervation, but maintained the integrity of noradrenergic and serotonergic neurons, failed to alter either the acquisition or maintenance of the intravenous self-administration of d-amphetamine in rats. Compared to vehicle-injected controls (sham lesions), the animals treated with 6-OHDA acquired the drug-abuse behaviour and maintained comparable, stable rates of self-injection. The lesions increased concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens septi but not in the striatum. The increased synthesis of DA in the nucleus accumbens septi [demonstrated by increased accumulation of dihydroxyphenylalanine (DOPA)] was abolished by the intravenous administration of d-amphetamine, in patterns mimicking those of animals trained in self-administration. PMID:3118232

  20. Synthesis, Pharmacological Evaluation and Molecular Modeling Studies of Triazole Containing Dopamine D3 Receptor Ligands

    PubMed Central

    Peng, Xin; Wang, Qi; Mishra, Yogesh; Xu, Jinbin; Reichert, David E.; Malik, Maninder; Taylor, Michelle; Luedtke, Robert R.; Mach, Robert H.

    2015-01-01

    A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors. PMID:25556097

  1. Synthesis and characterization of iodobenzamide analogues: Potential D-2 dopamine receptor imaging agents

    SciTech Connect

    Murphy, R.A.; Kung, H.F.; Kung, M.P.; Billings, J. )

    1990-01-01

    (S)-N-((1-Ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-3-iodo-6- methoxybenzamide (({sup 123}I)IBZM) is a central nervous system (CNS) D-2 dopamine receptor imaging agent. In order to investigate the versatility of this parent structure in specific dopamine receptor localization and the potential for developing new dopamine receptor imaging agents, a series of new iodinated benzamides with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was synthesized and radiolabeled, and the in vivo and in vitro biological properties were characterized. The best analogue of IBZM is IBF (21). The specific binding of ({sup 125}I)IBF (21) with rat striatal tissue preparation was found to be saturable and displayed a Kd of 0.106 {plus minus} 0.015 nM. Competition data of various receptor ligands for ({sup 125}I)IBF (21) binding show the following rank order of potency: spiperone greater than IBF (21) greater than IBZM greater than (+)-butaclamol greater than ({plus minus})-ADTN,6,7 greater than ketanserin greater than SCH-23390 much greater than propranolol. The in vivo biodistribution results confirm that ({sup 125}I)IBF (21) concentrated in the striatal area after iv injection into rats. The study demonstrates that ({sup 123}I)IBF (21) is a potential agent for imaging CNS D-2 dopamine receptors.

  2. Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

    NASA Technical Reports Server (NTRS)

    Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Mannisto, P. T.

    1992-01-01

    Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

  3. Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

    NASA Technical Reports Server (NTRS)

    Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Maennistoe, P. T.

    1991-01-01

    Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 microg/kg or about 2 percent of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5 percent and 1.5 percent, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33 percent and 16 percent, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine, and 3,4-dihydroxyphenvlacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However, dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceedimg 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

  4. Synthesis and carbonic anhydrase inhibitory properties of sulfamides structurally related to dopamine.

    PubMed

    Aksu, Kadir; Nar, Meryem; Tanc, Muhammet; Vullo, Daniela; Gülçin, Ilhami; Göksu, Süleyman; Tümer, Ferhan; Supuran, Claudiu T

    2013-06-01

    A series of novel sulfamides incorporating the dopamine scaffold were synthesized. Reaction of amines and tert-butyl-alcohol/benzyl alcohol in the presence of chlorosulfonyl isocyanate (CSI) afforded sulfamoyl carbamates, which were converted to the title compounds by treatment with trifluoroacetic acid or by palladium-catalyzed hydrogenolysis. Inhibition of six α-carbonic anhydrases (CAs, EC 4.2.1.1), that is, CA I, CA II, CA VA, CA IX, CA XII and CA XIV, and two β-CAs from Candida glabrata (CgCA) and Mycobacterium tuberculosis (Rv3588) with these sulfamides was investigated. All CA isozymes were inhibited in the low micromolar to nanomolar range by the dopamine sulfamide analogues. K(i)s were in the range of 0.061-1.822 μM for CA I, 1.47-2.94 nM for CA II, 2.25-3.34 μM for CA VA, 0.041-0.37 μM for CA IX, 0.021-1.52 μM for CA XII, 0.007-0.219 μM for CA XIV, 0.35-5.31 μM for CgCA and 0.465-4.29 μM for Rv3588. The synthesized sulfamides may lead to inhibitors targeting medicinally relevant CA isoforms with potential applications as antiepileptic, antiobesity antitumor agents or anti-infective. PMID:23623256

  5. Synthesis and characterization of selective dopamine D2 receptor ligands using aripiprazole as the lead compound

    PubMed Central

    Vangveravong, Suwanna; Zhang, Zhanbin; Taylor, Michelle; Bearden, Melissa; Xu, Jinbin; Cui, Jinquan; Wang, Wei; Luedtke, Robert R.; Mach, Robert H.

    2011-01-01

    A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D2-like dopamine receptors. These compounds also share structural elements with the classical D2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D2 receptor subtype with high affinity (Ki values <0.3 nM), (b) exhibit >50-fold D2 versus D3 receptor binding selectivity and (c) be partial agonists at both the D2 and D3 receptor subtype. PMID:21536445

  6. In vitro protein synthesis capacities in a cold stenothermal and a temperate eurythermal pectinid.

    PubMed

    Storch, D; Heilmayer, O; Hardewig, I; Pörtner, H-O

    2003-09-01

    The translational system was isolated from the gills of the Antarctic scallop Adamussium colbecki (Smith) and the European scallop Aequipecten opercularis (Linnaeus) for in vitro protein synthesis capacities microg protein mg FW(-1) day(-1)) and the translational capacities of RNA (k(RNA in vitro) mg protein mg RNA(-1) day(-1)). In vitro protein synthesis capacity in the cold-adapted pectinid at 0 degrees C was similar to the one found in the temperate scallop at 25 degrees C. These findings might reflect cold compensated rates in Adamussium colbecki, partly explainable by high tissue levels of RNA. Cold-compensated in vitro protein synthesis capacities may further result from increments in the translational capacity of RNA. The thermal sensitivity of the translation machinery was slightly different in the two species, with significantly lower levels of Arrhenius activation energies E(a) and Q(10) in Adamussium colbecki in the temperature range 0-15 degrees C. Reduced protein synthesis and translational capacities were found in vitro in gills of long-term aquarium-maintained Adamussium colbecki and were accounted for by a loss of protein synthesis machinery, i.e. a reduction in RNA levels, as well as a decrease in the amount of protein synthesized per milligram of RNA (RNA translational capacity, k(RNA in vitro)). Such changes may involve food uptake or mirror metabolic depression strategies, like those occurring during winter. Consequences of high in vitro RNA translational capacities found in the permanently cold-adapted species are discussed in the context of seasonal food availability and growth rates at high latitudes. PMID:12905006

  7. p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors.

    PubMed

    Sekine, Yusuke; Takagahara, Shuichi; Hatanaka, Ryo; Watanabe, Takeshi; Oguchi, Haruka; Noguchi, Takuya; Naguro, Isao; Kobayashi, Kazuto; Tsunoda, Makoto; Funatsu, Takashi; Nomura, Hiroshi; Toyoda, Takeshi; Matsuki, Norio; Kuranaga, Erina; Miura, Masayuki; Takeda, Kohsuke; Ichijo, Hidenori

    2011-09-01

    In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses. PMID:21878507

  8. Synthesis, Protein Levels, Activity and Phosphorylation State of Tyrosine Hydroxylase in Mesoaccumbens and Nigrostriatal Dopamine Pathways of Chronically Food-restricted Rats

    PubMed Central

    Pan, Yan; Berman, Yemiliya; Haberny, Sandra; Meller, Emanuel; Carr, Kenneth D.

    2006-01-01

    Chronic food restriction (FR) enhances the rewarding and motor-activating effects of abused drugs, and is accompanied by changes in dopamine (DA) dynamics and increased D-1 DA receptor-mediated cell signaling and transcriptional responses in nucleus accumbens (NAc). However, little is known about effects of FR on DA synthetic activity in the mesoaccumbens and nigrostriatal pathways. In Experiment 1 of the present study, tyrosine hydroxylase (TH) gene expression was measured in ventral tegmental area and substantia nigra, using real time RT-PCR and in situ hybridization; no differences were observed between FR and ad libitum fed (AL) rats. In Experiment 2, TH protein levels, determined by Western blot, were found to be elevated in NAc and caudate-putamen (CPu) of FR relative to AL rats. In the absence of increased transcription, this may reflect a slowing of TH degradation. In Experiments 3 and 4, DA synthetic activity was assessed by Western blot measurement of TH phosphorylation at Ser-40, and HPLC measurement of in vivo tyrosine hydroxylation rate, as reflected by DOPA accumulation following administration of a decarboxylase inhibitor (NSD-1015; 100 mg/kg, i.p.). Basal phospho-Ser(40)-TH levels did not differ between groups but DOPA accumulation was decreased by FR. Decreased DOPA synthesis, despite increased levels of TH protein, may reflect the inhibitory effect of increased DA binding to TH protein or decreased concentrations of cofactor tetrahydrobiopterin. Finally, in response to d-amphetamine (0.5 and 5.0 mg/kg, i.p.), phospho-Ser(40)-TH was selectively decreased in NAc of FR rats. This suggests increased feedback inhibition of DA synthesis - a possible consequence of postsynaptic receptor hypersensitivity, or increased extracellular DA concentration. These results indicate that FR increases TH protein levels, but may decrease the capacity for DA synthesis by decreasing TH activity. According to this scheme, the previously observed upregulation of striatal

  9. Phytosteryl sinapates and vanillates: chemoenzymatic synthesis and antioxidant capacity assessment.

    PubMed

    Tan, Zhuliang; Shahidi, Fereidoon

    2013-06-01

    Phytosterols and their derivatives have attracted much attention because of their health benefits to humans and are widely used in food, pharmaceuticals, and cosmetics in the past decades. While most of the research has focused on free phytosterols and phytosteryl esters of fatty acids, few researches reported on phytosteryl phenolates, the esters of phytosterols with phenolic acids. Two novel group phytosteryl phenolates, namely phytosteryl sinapates and vanillates, were successfully chemoenzymatically synthesised in this work and their structures confirmed. Fourier transform infrared (FTIR) and high performance chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) using atmospheric pressure chemical ionisation (APCI) under both positive and negative ion modes were employed for this purpose. High antioxidant capacity of phytosteryl sinapates was observed using both oxygen radical absorbance capacity (ORAC) assay and cooked ground meat model system. Although phytosteryl vanillates showed lower antioxidant capacity than phytosteryl sinapates, they were stronger antioxidants than vanillic acid and vinyl vanillate in both assays employed. Conjugation of phytosterols with sinapic or vanillic acid rendered higher antioxidant capacity. Further studies on health benefits of phytosteryl sinapates and vanillates are necessary. PMID:23411265

  10. Sensitivity of kinetic macro parameters to changes in dopamine synthesis, storage, and metabolism: a simulation study for [¹⁸F]FDOPA PET by a model with detailed dopamine pathway.

    PubMed

    Matsubara, Keisuke; Watabe, Hiroshi; Kumakura, Yoshitaka; Hayashi, Takuya; Endres, Christopher J; Minato, Kotaro; Iida, Hidehiro

    2011-08-01

    Quantitative interpretation of brain [¹⁸F]FDOPA PET data has been made possible by several kinetic modeling approaches, which are based on different assumptions about complex [¹⁸F]FDOPA metabolic pathways in brain tissue. Simple kinetic macro parameters are often utilized to quantitatively evaluate metabolic and physiological processes of interest, which may include DDC activity, vesicular storage, and catabolism from (18) F-labeled dopamine to DOPAC and HVA. A macro parameter most sensitive to the changes of these processes would be potentially beneficial to identify impaired processes in a neurodegenerative disorder such as Parkinson's disease. The purpose of this study is a systematic comparison of several [¹⁸F]FDOPA macro parameters in terms of sensitivities to process-specific changes in simulated time-activity curve (TAC) data of [¹⁸F]FDOPA PET. We introduced a multiple-compartment kinetic model to simulate PET TACs with physiological changes in the dopamine pathway. TACs in the alteration of dopamine synthesis, storage, and metabolism were simulated with a plasma input function obtained by a non-human primate [¹⁸F]FDOPA PET study. Kinetic macro parameters were calculated using three conventional linear approaches (Gjedde-Patlak, Logan, and Kumakura methods). For simulated changes in dopamine storage and metabolism, the slow clearance rate (k(loss) ) as calculated by the Kumakura method showed the highest sensitivity to these changes. Although k(loss) performed well at typical ROI noise levels, there was large bias at high noise level. In contrast, for simulated changes in DDC activity it was found that K(i) and V(T), estimated by Gjedde-Patlak and Logan method respectively, have better performance than k(loss). PMID:21190220

  11. Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter

    PubMed Central

    Qiao, Hongwen; Zhu, Lin; Lieberman, Brian P.; Zha, Zhihao; Plössl, Karl; Kung, Hank F.

    2012-01-01

    A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2β position was synthesized, labeled with the positron-emitter fluorine-18 (T1/2 = 109.8 min), and tested as potential in vivo dopamine transporter (DAT) imaging agents. The corresponding chlorinated analogs were prepared and employed as precursors for radiolabeling leading to the fluorine-18-labeled derivatives via a one-step nucleophilic aliphatic substitution reaction. In vitro binding results showed that the 2β-amino compounds 6b, 6d and 7b displayed moderately high affinities to DAT (Ki < 10 nM). Biodistribution studies of [18F]6b and [18F]6d showed that the brain uptakes in rats were low. This is likely due to their low lipophilicities. Further structural modifications of these tropane derivatives will be needed to improve their in vivo properties as DAT imaging agents. PMID:22658558

  12. Synthesis and radioiodination of ergoline derivatives: potential in-vivo dopamine receptor site mapping radiopharmaceuticals

    SciTech Connect

    Mikhail, E.A.

    1985-01-01

    The need of a dopamine-receptor based radiopharmaceutical for brain imaging is apparent. If such an agent is made available to physicians, it could provide means for detecting brain tumors, and diagnose such mental disorders as parkinsonism, schizophrenia and psychosis. Currently, such agents are yet to be discovered. Procedures were developed to synthesize and label four ergoline derivatives which could potentially exhibit affinity to dopamine receptors. Labelling with /sup 125/I was accomplished in some cases by displacing a suitably positioned leaving group with /sup 125/I-anion, while in other cases iodine exchange procedures were utilized. Formulations of the labeled derivatives were achieved via the formation of their water soluble tartarate salts. Biodistribution studies in mature Sprague-Dawley rats showed that of the four radioactive compounds injected, the highest uptake in the brain and adrenals was achieved with 8 ..beta..-(I-125)-iodomethyl-6-propylergoline. In addition, high target/nontarget ratios were obtained with the above mentioned compound. On the other hand, the least brain and adrenal uptake as well as the lowest target/nontarget ratios were exhibited by 8 ..beta..-(I-125)-(p-iodobenzenesulfonyl)-lysergol presumably due to its in-vivo instability. A comparative biodistribution study for ergoline derivatives and N-isopropyl-(I-123)-p-iodoamphetamine was conducted. The biodistribution studies showed that the brain to blood ratio for the ergoline derivative 8 ..beta..-(I-125)-iodomethyl-6-propylergoline to be very close to that for /sup 125/I-IMP at 1 minute after dose administration. However after 15 minutes the brain/blood ratio of compound XLVI was half the value of /sup 123/I-IMP. Different mechanisms of brain influx and efflux are known to occur with the amphetamine and ergoline derivatives.

  13. Influence of glutamate on the content and metabolism of dopamine in the nigrostriatal system of rats distinguished by capacity for learning.

    PubMed

    Karpova, I V; Yakimovskii, A F

    1994-01-01

    The effect of repeated (over the course of nine days) intrastriatal microinjections of glutamate (5 or 0.5 micrograms in 0.75 microliters of physiological solution daily) were investigated in 42 male Sprague-Dawley rats. Twenty-nine rats were preliminarily trained in a Skinner box using food reinforcement. It was demonstrated that the administration of glutamate to rats not subjected to training increases the content of homovanillic acid in the striatum. A similar influence in rats that are capable of learning leads to an increase in the content of dopamine and a decrease in the level of homovanillic acid in this nucleus, while it does not induce changes in the biochemical indicators under investigation in those rats that are incapable of learning. Microinjections of glutamate also do not alter the capacity for learning in any of the groups of animals. The possible causes for the different influence of intrastriatal microinjections of glutamate on the activity of the nigrostriatal system of rats differing by capacity for learning are discussed. PMID:7808643

  14. Facile synthesis of hexagonal-shaped polypyrrole self-assembled particles for the electrochemical detection of dopamine

    NASA Astrophysics Data System (ADS)

    Lee, Chung-Yi; Hsu, Di-Yao; Prasannan, Adhimoorthy; Kalaivani, Raman; Hong, Po-Da

    2016-02-01

    Nanomaterials have been used as an electroactive medium to enhance the efficiency of bio/chemical sensors, primarily when synergy is reached upon mixing different materials. In this study, we report on the facile synthesis of hexagonal-shaped plate-like polypyrrole (PPY-IC) prepared through inclusion polymerization of the host-guest pyrrole monomeric inclusion complex of β-cyclodextrin (β-CD) to be used in the detection of the neurotransmitter dopamine (DA). The amount of the monomer complex plays a crucial role in the fabrication of well-defined hexagonal-shaped PPY-IC through intermolecular interactions such as π-π interactions and hydrogen bonding between the β-CD and PPY. The microstructure and morphology of the PPY-IC were examined by using various analytical techniques and a tentative mechanism for the growth process proposed which elucidates the formation of the hierarchical structure of the PPY-IC. Cyclo-voltammetry was performed with a PPY-IC modified glassy carbon electrode (GCE) for the electrochemical detection of DA. The concepts behind the novel architecture of the PPY-IC modified electrodes have potential for the production of materials to be used in electrochemical sensors and biosensors.

  15. One-pot synthesis of magnetite nanorods/graphene composites and its catalytic activity toward electrochemical detection of dopamine.

    PubMed

    Salamon, J; Sathishkumar, Y; Ramachandran, K; Lee, Yang Soo; Yoo, Dong Jin; Kim, Ae Rhan; Gnana Kumar, G

    2015-02-15

    Magnetite (Fe3O4) nanorods anchored over reduced graphene oxide (rGO) were synthesized through a one-pot synthesis method, where the reduction of GO and in-situ generation of Fe3O4 nanorods occurred concurrently. The average head and tail diameter of Fe3O4 nanorods anchored over the rGO matrix are found to be 32 and 11 nm, respectively, and morphology, structure and diameter of bare Fe3O4 nanorods were not altered even after the composite formation with rGO. The increased structural disorders and decrement in the sp(2) domains stimulated the high electrical conductivity and extended catalytic active sites for the prepared rGO/Fe3O4 nanocomposite. The constructed rGO/Fe3O4/GCE sensor exhibited excellent electrocatalytic activity toward the electrooxidation of dopamine (DA) with a quick response time of 6s, a wide linear range between 0.01 and 100.55 µM, high sensitivity of 3.15 µA µM(-1) cm(-2) and a lower detection limit of 7 nM. Furthermore, the fabricated sensor exhibited a practical applicability in the quantification of DA in urine samples with an excellent recovery rate. The excellent electroanalytical performances and straight-forward, surfactant and template free preparation method construct the rGO/Fe3O4 composite as an extremely promising material for the diagnosis of DA related diseases in biomedical applications. PMID:25240127

  16. Synthesis of hybrid cellulose nanocomposite bonded with dopamine SiO2/TiO2 and its antimicrobial activity

    NASA Astrophysics Data System (ADS)

    Ramesh, Sivalingam; Kim, Gwang-Hoon; Kim, Jaehwan; Kim, Joo-Hyung

    2015-04-01

    Organic-inorganic hybrid material based cellulose was synthesized by the sol-gel approach. The explosion of activity in this area in the past decade has made tremendous progress in industry or academic both fundamental understanding of sol-gel process and applications of new functionalized hybrid materials. In this present research work, we focused on cellulose-dopamine functionalized SiO2/TiO2 hybrid nanocomposite by sol-gel process. The cellulose-dopamine hybrid nanocomposite was synthesized via γ-aminopropyltriethoxysilane (γ-APTES) coupling agent by in-situ sol-gel process. The chemical structure of cellulose-amine functionalized dopamine bonding to cellulose structure with covalent cross linking hybrids was confirmed by FTIR spectral analysis. The morphological analysis of cellulose-dopamine nanoSiO2/TiO2 hybrid nanocomposite materials was characterized by XRD, SEM and TEM. From this different analysis results indicate that the optical transparency, thermal stability, control morphology of cellulose-dopamine-SiO2/TiO2 hybrid nanocomposite. Furthermore cellulose-dopamine-SiO2/TiO2 hybrid nanocomposite was tested against pathogenic bacteria for antimicrobial activity.

  17. Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

    PubMed

    Lorenz, Robert C; Gleich, Tobias; Buchert, Ralph; Schlagenhauf, Florian; Kühn, Simone; Gallinat, Jürgen

    2015-10-01

    Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition. PMID:26177932

  18. In Situ Chemical Synthesis of Lithium Fluoride/Metal Nanocomposite for High Capacity Prelithiation of Cathodes.

    PubMed

    Sun, Yongming; Lee, Hyun-Wook; Zheng, Guangyuan; Seh, Zhi Wei; Sun, Jie; Li, Yanbin; Cui, Yi

    2016-02-10

    The initial lithium loss during the formation stage is a critical issue that significantly reduces the specific capacity and energy density of current rechargeable lithium-ion batteries (LIBs). An effective strategy to solve this problem is using electrode prelithiation additives that can work as a secondary lithium source and compensate the initial lithium loss. Herein we show that nanocomposites of lithium fluoride and metal (e.g., LiF/Co and LiF/Fe) can be efficient cathode prelithiation materials. The thorough mixing of ultrafine lithium fluoride and metal particles (∼5 nm) allows lithium to be easily extracted from the nanocomposites via an inverse conversion reaction. The LiF/Co nanocomposite exhibits an open circuit voltage (OCV, 1.5 V) with good compatibility with that of existing cathode materials and delivers a high first-cycle "donor" lithium-ion capacity (516 mA h g(-1)). When used as an additive to a LiFePO4 cathode, the LiF/Co nanocomposite provides high lithium compensation efficiency. Importantly, the as-formed LiF/metal nanocomposites possess high stability and good compatibility with the regular solvent, binder, and existing battery processing conditions, in contrast with the anode prelithiation materials that usually suffer from issues of high chemical reactivity and instability. The facile synthesis route, high stability in ambient and battery processing conditions, and high "donor" lithium-ion capacity make the LiF/metal nanocomposites ideal cathode prelithiation materials for LIBs. PMID:26784146

  19. Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo.

    PubMed

    Meyer, Andrew C; Neugebauer, Nichole M; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P; Bardo, Michael T

    2013-10-01

    Vesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg) on METH-induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward-relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ-793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum, medial prefrontal cortex and orbitofrontal cortex. In NAc shell, METH produced a time-dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ-793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ-793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH-induced increase in extracellular DA. Both LOB and GZ-793A enhanced the duration of the METH-induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and striatum, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. These results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ-793A to decrease METH reward. PMID:23875705

  20. Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures.

    PubMed

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-04-12

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

  1. Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis

    SciTech Connect

    Klein, I.; Samarel, A.M.; Welikson, R.; Hong, C. )

    1991-04-01

    Heterotopic cardiac isografts are vascularly perfused hearts that maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal location, the heart is hemodynamically unloaded and undergoes negative growth, leading to cardiac atrophy. At 7 and 14 days after transplantation, the transplanted heart was decreased in size compared with the in situ heart (p less than 0.001). To assess the possible mechanism(s) to account for this reduction in size we studied in vivo rates of total left ventricular (LV) protein synthesis, total LV RNA content, and 18S ribosomal RNA content by nucleic acid hybridization. The LV protein synthetic rate was 4.7 and 5.3 mg/day in the in situ heart and was significantly decreased to 2.9 and 2.7 mg/day in the transplanted hearts at 7 and 14 days, respectively. LV RNA content of the transplant declined to 53% and 48% of the in situ value at 7 and 14 days, respectively. Hybridization studies revealed that LV 18S ribosomal subunit content was reduced proportionately to total RNA in the heterotopic hearts. As a result of these changes, there was no significant difference in the efficiency of total LV protein synthesis between the in situ and transplanted hearts. The present studies demonstrate that the hemodynamic unloading and cardiac atrophy that is characteristic of heterotopic cardiac transplantation is accompanied by a decrease in LV total RNA content and 18S RNA, resulting in a decreased capacity for myocardial protein synthesis.

  2. Effective seed-assisted synthesis of gold nanoparticles anchored nitrogen-doped graphene for electrochemical detection of glucose and dopamine.

    PubMed

    Thanh, Tran Duy; Balamurugan, Jayaraman; Lee, Seung Hee; Kim, Nam Hoon; Lee, Joong Hee

    2016-07-15

    A novel gold nanoparticle-anchored nitrogen-doped graphene (AuNP/NG) nanohybrid was synthesized through a seed-assisted growth method, as an effective electrocatalyst for glucose and dopamine detection. The AuNP/NG nanohybrids exhibited high sensitivity and selectivity toward glucose and dopamine sensing applications. The as-synthesized nanohybrids exhibited excellent catalytic activity toward glucose, with a linear response throughout the concentration range from 40μM to 16.1mM, a detection limit of 12μM, and a short response time (∼ 10s). It also exhibited an excellent response toward DA, with a wide detection range from 30nM to 48μM, a low detection limit of 10nM, and a short response time (∼ 8s). Furthermore, it also showed long-term stability and high selectivity for the target analytes. These results imply that such nanohybrids show a great potential for electrochemical biosensing application. PMID:26967913

  3. Mutant huntingtin activates Nrf2-responsive genes and impairs dopamine synthesis in a PC12 model of Huntington's disease

    PubMed Central

    van Roon-Mom, Willeke MC; Pepers, Barry A; 't Hoen, Peter AC; Verwijmeren, Carola ACM; den Dunnen, Johan T; Dorsman, Josephine C; van Ommen, GertJan B

    2008-01-01

    Background Huntington's disease is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD or Huntington's disease gene. Although micro array studies on patient and animal tissue provide valuable information, the primary effect of mutant huntingtin will inevitably be masked by secondary processes in advanced stages of the disease. Thus, cell models are instrumental to study early, direct effects of mutant huntingtin. mRNA changes were studied in an inducible PC12 model of Huntington's disease, before and after aggregates became visible, to identify groups of genes that could play a role in the early pathology of Huntington's disease. Results Before aggregation, up-regulation of gene expression predominated, while after aggregates became visible, down-regulation and up-regulation occurred to the same extent. After aggregates became visible there was a down-regulation of dopamine biosynthesis genes accompanied by down-regulation of dopamine levels in culture, indicating the utility of this model to identify functionally relevant pathways. Furthermore, genes of the anti-oxidant Nrf2-ARE pathway were up-regulated, possibly as a protective mechanism. In parallel, we discovered alterations in genes which may result in increased oxidative stress and damage. Conclusion Up-regulation of gene expression may be more important in HD pathology than previously appreciated. In addition, given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway constitutes a new attractive therapeutic target for HD. PMID:18844975

  4. Synthesis of ROS scavenging microspheres from a dopamine containing poly(β-amino ester) for applications for neurodegenerative disorders.

    PubMed

    Newland, Ben; Wolff, Paul; Zhou, Dezhong; Wang, Wei; Zhang, Hong; Rosser, Anne; Wang, Wenxin; Werner, Carsten

    2016-02-23

    Parkinson's disease (PD) is a common neurodegenerative disease characterized by a substantial decrease of dopaminergic neurons in the substantia nigra pars compacta. The neurological deterioration during PD can be, in part, attributed to elevated levels of reactive oxygen species (ROS). Radical scavengers have previously been shown to protect dopaminergic cells from toxic effects in vitro. Hence, new approaches need to be investigated to improve the administration of antioxidants in order to provide neuroprotection. Polymers exhibiting catechol structures offer one such approach due to their interesting physicochemical properties. In the present study a photocrosslinkable dopamine-containing poly(β-amino ester) (DPAE) was synthesized from poly(ethylene glycol) diacrylate (PEGDA) and dopamine hydrochloride using Michael type addition. A water-in-oil emulsion technique was used to photo-crosslink the polymer into spherical microparticles. DPAE microspheres featured excellent scavenging properties towards 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radicals in a dose dependent manner and could even reduce the dissolved oxygen content of physiological solution. Furthermore, the concentrations required for radical scavenging were shown to be non-toxic towards dopaminergic SH-SY5Y cells as well as primary astrocytes and primary embryonic rat ventral midbrain cultures. PMID:26756041

  5. Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands.

    PubMed

    Cao, Yongkai; Min, Chengchun; Acharya, Srijan; Kim, Kyeong-Man; Cheon, Seung Hoon

    2016-01-15

    The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R. PMID:26707842

  6. The Role of De Novo Catecholamine Synthesis in Mediating Methylmercury-Induced Vesicular Dopamine Release From Rat Pheochromocytoma (PC12) Cells

    PubMed Central

    Atchison, William D.

    2013-01-01

    The purpose of this study was to characterize methylmercury (MeHg)–induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect. Because DA release induced by 5µM MeHg was associated with a significant percentage of cell death at 60 and 120min, 2µM MeHg was chosen for further characterization of release mechanisms. MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release. Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium. MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release. The tyrosine hydroxylase inhibitor α-methyltyrosine (300µM, 24h) completely abolished MeHg-induced DA release. MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10µM), revealing that MeHg increases tyrosine hydroxylase activity. Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis. PMID:23425605

  7. Levodopa Reverses Cytokine-Induced Reductions in Striatal Dopamine Release

    PubMed Central

    Hernandez, Carla R.; Miller, Andrew H.

    2015-01-01

    Background: Studies using neuroimaging and in vivo microdialysis in humans and nonhuman primates indicate that inflammatory cytokines such as interferon-alpha reduce dopamine release in the ventral striatum in association with depressive symptoms including anhedonia and psychomotor slowing. Methods: Herein, we examined whether reduced striatal dopamine release in rhesus monkeys chronically treated with interferon-alpha can be restored by administration of the dopamine precursor levodopa via reverse in vivo microdialysis. Results: Levodopa completely reversed interferon-alpha–induced reductions in striatal dopamine release. No changes were found in the 3,4-dihydroxyphenylacetic acid to dopamine ratio, which increases when unpackaged dopamine is metabolized via monoamine oxidase. Conclusions: These findings suggest that inflammatory cytokines reduce the availability of dopamine precursors without affecting end-product synthesis or vesicular packaging and/or release and provide the foundation for future studies investigating therapeutic strategies that facilitate availability of dopamine precursors to improve depressive symptoms in patient populations with increased inflammation. PMID:25638816

  8. Synthesis and evaluation of novel N-fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter

    PubMed Central

    Liu, Jingying; Zhu, Lin; Plössl, Karl; Lieberman, Brian P.; Kung, Hank F.

    2011-01-01

    A series of novel N-fluoropyridyl-containing tropane derivatives were synthesized and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine (NET) were determined via competitive radioligand binding assays. Among these derivatives, compound 6d showed the highest binding affinity to DAT (Ki = 4.1 nM), and selectivity for DAT over SERT (5 fold) and NET (16 fold). Compound 6d was radiolabeled with Fluorine-18 in two steps. Regional brain distribution and ex vivo autoradiography studies of [18F]6d demonstrated that the ligand was selectively localized in the striatum region, where DAT binding sites are highly expressed. [18F]6d may be useful as a potential radioligand for imaging DATs with PET. PMID:21458259

  9. Hemolytic activity and solubilizing capacity of raffinose and melezitose fatty acid monoesters prepared by enzymatic synthesis.

    PubMed

    Carvalho, Luis; Morales, Juan C; Pérez-Victoria, José M; Pérez-Victoria, Ignacio

    2015-05-01

    The hemolytic activity and solubilizing capacity of two families of non-reducing trisaccharide fatty acid monoesters have been studied to assess their usefulness as surfactants for pharmaceutical applications. The carbohydrate-based surfactants investigated included homologous series of raffinose and melezitose monoesters bearing C10 to C18 acyl chains prepared by lipase-catalyzed synthesis in organic media. The hemolytic activity was determined in vitro using a static method based on the addition of the surfactants to an erythrocyte suspension and subsequent spectrophotometric determination of the released hemoglobin. The effect of the carbohydrate head group, the acyl chain length and the regioisomeric purity was investigated. In all cases, the carbohydrate monoester surfactants decreased their hemolytic activity (with respect to their critical micelle concentration) when increasing the length of the acyl chain. A very similar behaviour was observed either the carbohydrate head-group (raffinose and melezitose) or regardless of the regioisomeric purity. Interestingly, decanoyl (C10) and lauroyl (C12) monoesters were just marginally hemolytic at their critical micelle concentrations while the longer palmitoyl (C16) and (C18) stearoyl monoesters become hemolytic at concentrations much higher than their respective cmc. The palmitoyl and stearoyl monoesters also displayed higher solubilization capacity than the shorter acyl chain monoesters in a solubilization assay of a hydrophobic dye as a model drug mimic. These results suggest that raffinose and melezitose monoesters with long-chain fatty acids (C16 to C18) are promising surfactants for pharmaceutical applications and could be an alternative to the use of current commercial nonionic polyoxyethylene-based surfactants in parenteral formulations. PMID:25753196

  10. Interfacial Polymerization of Dopamine in a Pickering Emulsion: Synthesis of Cross-Linkable Colloidosomes and Enzyme Immobilization at Oil/Water Interfaces.

    PubMed

    Qu, Yanning; Huang, Renliang; Qi, Wei; Su, Rongxin; He, Zhimin

    2015-07-15

    Colloidosomes are promising carriers for immobilizing enzyme for catalytic purposes in aqueous/organic media. However, they often suffer from one or more problems regarding catalytic performance, stability, and recyclability. Here, we report a novel approach for the synthesis of cross-linkable colloidosomes by the selective polymerization of dopamine at oil/water interfaces in a Pickering emulsion. An efficient enzyme immobilization method was further developed by covalently bonding enzymes to the polydopamine (PDA) layer along with the formation of such colloidosomes with lipase as a model enzyme. In this enzyme system, the PDA layer served as a cross-linking layer and enzyme support for simultaneously enhancing the colloidosomes' stability and improving surface availability of the enzymes for catalytic reaction. It was found that the specific activity of lipases immobilized on the colloidosome shells was 8 and 1.4 times higher than that of free lipase and encapsulated lipase positioned in the aqueous cores of colloidosomes, respectively. Moreover, the immobilized lipases demonstrated excellent operational stability and recyclability, retaining 86.6% of enzyme activity after 15 cycles. It is therefore reasonable to expect that this novel approach for enzyme immobilization has great potential to serve as an important technique for the construction of biocatalytic systems. PMID:26104042

  11. Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.

    PubMed

    Pham-Huu, Duy-Phong; Deschamps, Jeffrey R; Liu, Shanghao; Madras, Bertha K; Meltzer, Peter C

    2007-01-15

    Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers. PMID:17070057

  12. Synthesis of 3beta-(4-[18F]fluoromethylphenyl)- and 3beta-(2-[18F] fluoromethylphenyl)tropane-2beta-carboxylic acid methyl esters: new ligands for mapping brain dopamine transporter with positron emission tomography.

    PubMed

    Petric, A; Barrio, J R; Namavari, M; Huang, S C; Satyamurthy, N

    1999-07-01

    The synthesis of two new dopamine transporter ligands, 3beta-(4-fluoromethylphenyl)tropane-2beta-carboxylic acid methyl ester and 3beta-(2-fluoromethylphenyl)tropane-2beta-carboxylic acid methyl ester, and their spectral characterization are described. The precursors for these ligands were prepared by TiCl4 catalyzed chloromethylation of 3beta-phenyltropane-2beta-carboxylic acid methyl ester followed by separation of the isomeric product mixture of 2- and 4-chloromethylphenyltropane derivatives. Reaction of the chloromethyl analogs with no-carrier-added [18F]fluoride ion followed by high performance liquid chromatography purification provided the corresponding [18F]fluoromethyltropanes, in good radiochemical yields, useful for imaging the brain dopamine transporter system in vivo with positron emission tomography. PMID:10473191

  13. Neurons expressing individual enzymes of dopamine synthesis in the mediobasal hypothalamus of adult rats: functional significance and topographic interrelations.

    PubMed

    Ugrumov, M; Taxi, J; Pronina, T; Kurina, A; Sorokin, A; Sapronova, A; Calas, A

    2014-09-26

    Besides dopaminergic (DA-ergic) neurons having all enzymes of DA synthesis, tyrosine hydroxylase (TH) and aromatic l-amino acid decarboxylase (AADC), "monoenzymatic" neurons expressing only one of them were found in the brain, mostly in the mediobasal hypothalamus (MBH). The aim of this study was to test our hypothesis that DA is synthesized by monoenzymatic neurons, i.e. l-3,4-dihydroxyphenylalanine (l-DOPA), which produced in the monoenzymatic TH neurons is transported in the monoenzymatic AADC neurons for DA synthesis. Incubation of MBH in Krebs-Ringer solution with l-leucine, a competitive inhibitor of l-DOPA uptake, was used to prevent a hypothetical l-DOPA capture into AADC-containing neurons. Incubation of the substantia nigra containing DA-ergic neurons under the same conditions served as the control. According to our data, the l-leucine administration provoked a decrease of DA concentration in MBH and in the incubation medium but not in the substantia nigra and respective incubation medium, showing a decrease of cooperative synthesis of DA in MBH. This conclusion was supported by an observation of higher concentration of l-DOPA in the incubation medium under perfusion of MBH with Krebs-Ringer solution containing tolcapone, an inhibitor of catechol-O-methyltransferase, and l-leucine than under perfusion with the same solution, but without l-leucine. Functional interaction between monoenzymatic TH and AADC neurons was indirectly confirmed by finding in electron microscopy their close relations in MBH. Besides monoenzymatic AADC neurons, any AADC-possessing neurons, catecholaminergic and serotoninergic, apparently, could participate in DA synthesis together with monoenzymatic TH neurons. This idea was confirmed by the observation of close topographic relations between monoenzymatic TH neurons and those containing both enzymes, i.e. DA-ergic, noradrenergic or adrenergic. Thus, monoenzymatic neurons possessing TH or AADC and being in close topographic relations

  14. Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.

    PubMed

    Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R; McIntosh, J Michael; Brunzell, Darlene H; Cannon, Jason R; Drenan, Ryan M

    2014-04-01

    α6β2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

  15. Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs

    PubMed Central

    Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R.; McIntosh, J. Michael; Brunzell, Darlene H.; Cannon, Jason R.; Drenan, Ryan M.

    2014-01-01

    α6β2* nAChRs in the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9’S mice) that are hypersensitive to nicotine and endogenous acetylcholine (ACh). Evoked extracellular dopamine (DA) levels were enhanced in α6L9’S NAc slices compared to control, non-transgenic (nonTg) slices. Extracellular DA levels in both nonTg and α6L9’S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by ACh plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9’S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9’S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) compared to nonTg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE) were unchanged in α6L9’S compared to nonTg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9’S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

  16. A facile one-pot synthesis of carbon nitride dots-reduced graphene oxide nanocomposites for simultaneous enhanced detecting of dopamine and uric acid.

    PubMed

    Yang, Ziyin; Zheng, Xiaohui; Li, Zhi; Zheng, Jianbin

    2016-08-01

    In this study, we described the facile synthesis of carbon nitride dots-reduced graphene oxide nanocomposites (CNDs-rGO) and their application for the enhanced electrochemical determination of dopamine (DA) and uric acid (UA). CNDs-rGO were synthesized for the first time through a green and facile one-step approach, carried out by hydrothermal heat-treatment of an aqueous solution containing GO and chitosan without introduction of other reducing agents or surface modifier. Then, the morphology and composition of CNDs-rGO nanocomposites were characterized by transmission electron microscopy (TEM), Raman spectroscopy, X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. TEM observations revealed that CNDs with a size of about 5.0 nm were homogeneously and densely distributed on the surface of rGO. Electrochemical investigations indicated that CNDs-rGO nanocomposites exhibited an excellent performance toward DA and UA. The linear range for DA was estimated to be from 80 nM to 227 μM with a sensitivity of 154.3 μA mM(-1) cm(-2) and a low detection limit of 0.03 μM. Meanwhile, the linear range for UA was estimated to be from 80 nM to 328 μM with a high sensitivity of 178.1 μA mM(-1) cm(-2) and a low detection limit of 0.05 μM. Therefore, CNDs-rGO nanocomposites showed great application potential for constructing electrochemical sensors for the detection of DA and UA. PMID:27284588

  17. Sunlight assisted synthesis of silver nanoparticles in zeolite matrix and study of its application on electrochemical detection of dopamine and uric acid in urine samples.

    PubMed

    Meenakshi, S; Devi, S; Pandian, K; Devendiran, R; Selvaraj, M

    2016-12-01

    Sunlight assisted reduction of silver ions were accomplished for the synthesis of silver nanoparticles incorporated within the mesoporous silicate framework of zeolite Y. The zeolite-Y and AgNP/Zeo-Y were characterized by field emission scanning electron microscopy, transmission electron microscopy, N2 adsorption-desorption BET isotherm and X-ray diffraction techniques. The incorporation of silver nanoparticles within the porous framework was further confirmed by cyclic voltammetry and electrochemical impedance spectroscopy. An enhanced electrocatalytic oxidation of biologically important molecules like dopamine and uric acid using AgNP/Zeo-Y modified glassy carbon electrode has been developed. A simultaneous oxidation of DA and UA peaks were obtained at +0.31V and +0.43V (vs. Ag/AgCl) using AgNP/Zeo-Y/GCE under the optimum experimental condition. A well-resolved peak potential window (~120mV) for the oxidation of both DA and UA were observed at AgNP/Zeo-Y/GCE system. The calibration curves for DA and UA were obtained within the dynamic linear range of 0.02×10(-6) to 0.18×10(-6)M (R(2)=0.9899) and 0.05×10(-6) to 0.7×10(-6)M (R(2)=0.9996) and the detection limits were found to be 1.6×10(-8)M and 2.51×10(-8)M by using differential pulse voltammetry (DPV) method. The proposed method was successfully applied for the determination of both DA and UA in human urine samples with a related standard deviation was <3%, and n=5 using the standard addition method. PMID:27612692

  18. Increased local dopamine secretion has growth promoting effects in cholangiocarcinoma

    PubMed Central

    Coufal, Monique; Invernizzi, Pietro; Gaudio, Eugenio; Bernuzzi, Francesca; Frampton, Gabriel A.; Onori, Paolo; Franchitto, Antonio; Carpino, Guido; Ramirez, Jonathan C.; Alvaro, Domenico; Marzioni, Marco; Battisti, Guido; Benedetti, Antonio; DeMorrow, Sharon

    2009-01-01

    Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We have previously shown that serotonin metabolism is dysregulated in cholangiocarcinoma leading to an increased secretion of serotonin, which has growth-promoting effects. Because serotonin and dopamine share the degradation machinery, we evaluated the secretion of dopamine from cholangiocarcinoma and its effects on cell proliferation. Using 4 cholangiocarcinoma cell lines and human biopsy samples, we demonstrated that there was an increase in mRNA and protein expression of the dopamine synthesis enzymes tyrosine hydroxylase and dopa decarboxylase in cholangiocarcinoma. There was increased dopamine secretion from cholangiocarcinoma cell lines compared to H69 and HIBEC cholangiocytes and increased dopamine immunoreactivity in human biopsy samples. Furthermore, administration of dopamine to all cholangiocarcinoma cell lines studied increased proliferation by up to 30% which could be blocked by the pretreatment of the D2 and D4 dopamine receptor antagonists, whereas blocking dopamine production by α-methyldopa administration suppressed growth by up to 25%. Administration of α-methyldopa to nude mice also suppressed cholangiocarcinoma tumor growth. The data presented here represent the first evidence that dopamine metabolism is dysregulated in cholangiocarcinoma and that modulation of dopamine synthesis may represent an alternative target for the development of therapeutic strategies. PMID:19795457

  19. An improved implementable process for the synthesis of zeolite 4A from bauxite tailings and its Cr3+ removal capacity

    NASA Astrophysics Data System (ADS)

    Lei, Peng-cheng; Shen, Xian-jiang; Li, Yang; Guo, Min; Zhang, Mei

    2016-07-01

    A simple and practical method for the synthesis of zeolite 4A from bauxite tailings is presented in this paper. Systematic investigations were carried out regarding the capacity of zeolite 4A to remove Cr(III) from aqueous solutions with relatively low initial concentrations of Cr(III) (5-100 mg·L-1). It is found that the new method is extremely cost-effective and can significantly contribute in decreasing environmental pollution caused by the dumping of bauxite tailings. The Cr(III) removal capacity highly depends on the initial pH value and concentration of Cr(III) in the solution. The maximum removal capacity of Cr(III) was evaluated to be 85.1 mg·g-1 for zeolite 4A, measured at an initial pH value of 4 and an initial Cr(III) concentration of 5 mg·L-1. This approach enables a higher removal capacity at lower concentrations of Cr(III), which is a clear advantage over the chemical precipitation method. The removal mechanism of Cr(III) by zeolite 4A was examined. The results suggest that both ion exchange and the surface adsorption-crystallization reaction are critical steps. These two steps collectively resulted in the high removal capacity of zeolite 4A to remove Cr(III).

  20. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission.

    PubMed

    Ford, C P

    2014-12-12

    Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These Gi/o-coupled inhibitory receptors play a major part in shaping dopamine transmission. Found at both somatodendritic and axonal sites, autoreceptors regulate the firing patterns of dopamine neurons and control the timing and amount of dopamine released from their terminals in target regions. Alterations in the expression and activity of autoreceptors are thought to contribute to Parkinson's disease as well as schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD), which emphasizes the importance of D2-autoreceptors in regulating the dopamine system. This review will summarize the cellular actions of dopamine autoreceptors and discuss recent advances that have furthered our understanding of the mechanisms by which D2-receptors control dopamine transmission. PMID:24463000

  1. Synthesis and Evaluation of the Anti-Oxidant Capacity of Curcumin Glucuronides, the Major Curcumin Metabolites

    PubMed Central

    Choudhury, Ambar K.; Raja, Suganya; Mahapatra, Sanjata; Nagabhushanam, Kalyanam; Majeed, Muhammed

    2015-01-01

    Curcumin metabolites namely curcumin monoglucuronide and curcumin diglucuronide were synthesized using an alternative synthetic approach. The anti-oxidant potential of these curcumin glucuronides was compared with that of curcumin using DPPH scavenging method and Oxygen Radical Absorbance Capacity (ORAC) assay. The results show that curcumin monoglucuronide exhibits 10 fold less anti-oxidant activity (DPPH method) and the anti-oxidant capacity of curcumin diglucuronide is highly attenuated compared to the anti-oxidant activity of curcumin. PMID:26783957

  2. Enzymic Capacities of Purified Cauliflower Bud Plastids for Lipid Synthesis and Carbohydrate Metabolism 1

    PubMed Central

    Journet, Etienne-Pascal; Douce, Roland

    1985-01-01

    Isolated cauliflower (Brassica oleracea) bud plastids, purified by isopycnic centrifugation in density gradients of Percoll, were found to be highly intact, to be practically devoid of extraplastidial contaminations, and to retain all the enzymes involved in fatty acid, phosphatidic acid, and monogalactosyldiacylglycerol synthesis. Purified plastids possess all the enzymes needed to convert triose phosphate to starch and vice versa, and are capable of conversion of glycerate 3-phosphate to pyruvate for fatty acid synthesis. They are also capable of oxidation of hexose phosphate and conversion to triose phosphate via the oxidative pentosephosphate pathway. Cauliflower bud plastids prove to be, therefore, biochemically very flexible organelles. Images Fig. 1 PMID:16664432

  3. Upregulation of capacity for glutathione synthesis in response to amino acid deprivation: regulation of glutamate-cysteine ligase subunits

    PubMed Central

    Sikalidis, Angelos K.; Mazor, Kevin M.; Lee, Jeong-In; Roman, Heather B.; Hirschberger, Lawrence L.; Stipanuk, Martha H.

    2014-01-01

    Using HepG2/C3A cells and MEFs, we investigated whether induction of GSH synthesis in response to sulfur amino acid deficiency is mediated by the decrease in cysteine levels or whether it requires a decrease in GSH levels per se. Both the glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunit mRNA levels were upregulated in response to a lack of cysteine or other essential amino acids, independent of GSH levels. This upregulation did not occur in MEFs lacking GCN2 (general control non-derepressible 2, also known as eIF2α kinase 4) or in cells expressing mutant eIF2α lacking the eIF2α kinase Ser51 phosphorylation site, indicating that expression of both GCLC and GCLM was mediated by the GCN2/ATF4 stress response pathway. Only the increase in GCLM mRNA level, however, was accompanied by a parallel increase in protein expression, suggesting that the enhanced capacity for GSH synthesis depended largely on increased association of GCLC with its regulatory subunit. Upregulation of both GCLC and GLCM mRNA levels in response to cysteine deprivation was dependent on new protein synthesis, which is consistent with expression of GCLC and GCLM being mediated by proteins whose synthesis depends on activation of the GCN2/ATF4 pathway. Our data suggest that the regulation of GCLC expression may be mediated by changes in the abundance of transcriptional regulators, whereas the regulation of GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent. PMID:24557597

  4. Upregulation of capacity for glutathione synthesis in response to amino acid deprivation: regulation of glutamate-cysteine ligase subunits.

    PubMed

    Sikalidis, Angelos K; Mazor, Kevin M; Lee, Jeong-In; Roman, Heather B; Hirschberger, Lawrence L; Stipanuk, Martha H

    2014-05-01

    Using HepG2/C3A cells and MEFs, we investigated whether induction of GSH synthesis in response to sulfur amino acid deficiency is mediated by the decrease in cysteine levels or whether it requires a decrease in GSH levels per se. Both the glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunit mRNA levels were upregulated in response to a lack of cysteine or other essential amino acids, independent of GSH levels. This upregulation did not occur in MEFs lacking GCN2 (general control non-derepressible 2, also known as eIF2α kinase 4) or in cells expressing mutant eIF2α lacking the eIF2α kinase Ser(51) phosphorylation site, indicating that expression of both GCLC and GCLM was mediated by the GCN2/ATF4 stress response pathway. Only the increase in GCLM mRNA level, however, was accompanied by a parallel increase in protein expression, suggesting that the enhanced capacity for GSH synthesis depended largely on increased association of GCLC with its regulatory subunit. Upregulation of both GCLC and GLCM mRNA levels in response to cysteine deprivation was dependent on new protein synthesis, which is consistent with expression of GCLC and GCLM being mediated by proteins whose synthesis depends on activation of the GCN2/ATF4 pathway. Our data suggest that the regulation of GCLC expression may be mediated by changes in the abundance of transcriptional regulators, whereas the regulation of GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent. PMID:24557597

  5. Synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro- 1H-3- benzazepine (TISCH): A high affinity and selective iodinated ligand for CNS D1 dopamine receptor

    SciTech Connect

    Chumpradit, S.; Kung, M.P.; Billings, J.J.; Kung, H.F. )

    1991-03-01

    The synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1 H-3- benzazepine, (+/-)-TISCH (8) has been achieved by resolution of intermediate 4, the O-methoxyl, 3'-bromo derivative, as the diastereomeric camphor sulfonate salt. The final products, R-(+)-8 and S-(-)-8, were prepared by treatment of R-(+)- or S-(-)-7, the 3'-tributyltin intermediates, with iodine in chloroform, followed by O-demethylation. By using HPLC with a chiral column, the optical purity (greater than 99%) of the intermediates and the final compounds was determined. Radioiodination was achieved by an iodo-destannylation reaction with sodium (125I)iodide and hydrogen peroxide. As expected, the R-(+)-(125I)-8 (the active isomer) displayed high affinity and selectivity to the CNS D-1 receptor in rat striatum tissue preparation (Kd = 0.205 nM). The rank order of potency was as follows: SCH-23390 (1a) greater than (+/-)-8 greater than (+)-butaclamol greater than spiperone, WB4101 greater than dopamine, 5-HT. After an iv injection, the R-(+)-(125I)-8 penetrated the blood-brain barrier with ease and displayed specific regional distribution corresponding to the D-1 receptor density, while the S-(-)-(125I)-8 showed no specific uptake. The data suggest that the ligand may be useful as a pharmacological tool for characterizing the D-1 dopamine receptor. When labeled with I-123, this ligand is a potential agent for in vivo imaging of CNS D-1 dopamine receptor.

  6. Tonic Dopamine Modulates Exploitation of Reward Learning

    PubMed Central

    Beeler, Jeff A.; Daw, Nathaniel; Frazier, Cristianne R. M.; Zhuang, Xiaoxi

    2010-01-01

    The impact of dopamine on adaptive behavior in a naturalistic environment is largely unexamined. Experimental work suggests that phasic dopamine is central to reinforcement learning whereas tonic dopamine may modulate performance without altering learning per se; however, this idea has not been developed formally or integrated with computational models of dopamine function. We quantitatively evaluate the role of tonic dopamine in these functions by studying the behavior of hyperdopaminergic DAT knockdown mice in an instrumental task in a semi-naturalistic homecage environment. In this “closed economy” paradigm, subjects earn all of their food by pressing either of two levers, but the relative cost for food on each lever shifts frequently. Compared to wild-type mice, hyperdopaminergic mice allocate more lever presses on high-cost levers, thus working harder to earn a given amount of food and maintain their body weight. However, both groups show a similarly quick reaction to shifts in lever cost, suggesting that the hyperdominergic mice are not slower at detecting changes, as with a learning deficit. We fit the lever choice data using reinforcement learning models to assess the distinction between acquisition and expression the models formalize. In these analyses, hyperdopaminergic mice displayed normal learning from recent reward history but diminished capacity to exploit this learning: a reduced coupling between choice and reward history. These data suggest that dopamine modulates the degree to which prior learning biases action selection and consequently alters the expression of learned, motivated behavior. PMID:21120145

  7. Dopamine: the rewarding years

    PubMed Central

    Marsden, Charles A

    2006-01-01

    Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine. PMID:16402097

  8. Synthesis of metal-adeninate frameworks with high separation capacity on C2/C1 hydrocarbons

    NASA Astrophysics Data System (ADS)

    He, Yan-Ping; Zhou, Nan; Tan, Yan-Xi; Wang, Fei; Zhang, Jian

    2016-06-01

    By introducing isophthalic acid or 2,5-thiophenedicarboxylic acid to assemble with adenine and cadmium salt, two isostructural and anionic porous metal-organic frameworks (1 and 2) possessing the novel (4,8)-connected sqc topology are presented here. 1 shows permanent porosity with Langmuir surface area of 770.1 m2/g and exhibits high separation capacity on C2/C1 hydrocarbons.

  9. Technical Assistance to Enhance Prevention Capacity: a Research Synthesis of the Evidence Base.

    PubMed

    Katz, Jason; Wandersman, Abraham

    2016-05-01

    Despite the availability of many evidence-based prevention interventions (EBIs), gaps exist in bringing these programs into widespread practice. Technical assistance (TA) is a strategy for enhancing the readiness of practitioners to implement EBIs. Although many millions of dollars are spent on TA each year, there is little consensus about what the essential features of TA are and how to provide TA with quality. A broad-based research synthesis methodology was used for analyzing the current evidence base for TA using three frames: (1) applying the Getting To Outcomes (GTO) model for categorizing evidence on TA that specifies tasks for planning, implementing, and evaluating TA; (2) understanding the relevance of a successful relationship between the TA provider and TA recipient; and (3) considering the extent to which TA fits the life cycle needs of the preventive intervention. Results indicated that an explicit model or organizing framework is rarely used to plan, implement, and/or evaluate TA; specific TA tasks performed vary widely across studies; TA is rarely delivered to recipients who are seeking to sustain innovations subsequent to adoption and implementation; however, there is systematic attention to relationships and relationship-building. Overall, this synthesis indicates that the extent to which TA is being delivered systematically is limited. We suggest that funders and other stakeholders develop and implement standards for TA quality in order to ensure that many of these limitations are addressed. PMID:26858179

  10. Restoration of the Dopamine Transporter through Cell Therapy Improves Dyskinesia in a Rat Model of Parkinson’s Disease

    PubMed Central

    Tomas, D.; Stanic, D.; Chua, H. K.; White, K.; Boon, W. C.; Horne, M.

    2016-01-01

    The dyskinesia of Parkinson's Disease is most likely due to excess levels of dopamine in the striatum. The mechanism may be due to aberrant synthesis but also, a deficiency or absence of the Dopamine Transporter. In this study we have examined the proposition that reinstating Dopamine Transporter expression in the striatum would reduce dyskinesia. We transplanted c17.2 cells that stably expressed the Dopamine Transporter into dyskinetic rats. There was a reduction in dyskinesia in rats that received grafts expressing the Dopamine Transporter. Strategies designed to increase Dopamine Transporter in the striatum may be useful in treating the dyskinesia associated with human Parkinson's Disease. PMID:27077649

  11. Influence of fatty acid on lipase-catalyzed synthesis of ascorbyl esters and their free radical scavenging capacity.

    PubMed

    Stojanović, Marija; Carević, Milica; Mihailović, Mladen; Veličković, Dušan; Dimitrijević, Aleksandra; Milosavić, Nenad; Bezbradica, Dejan

    2015-01-01

    Fatty acid (FA) ascorbyl esters are recently emerging food, cosmetic, and pharmaceutical additives, which can be prepared in an eco-friendly way by using lipases as catalysts. Because they are amphiphilic molecules, which possess high free radical scavenging capacity, they can be applied as liposoluble antioxidants as well as emulsifiers and biosurfactants. In this study, the influence of a wide range of acyl donors on ester yield in lipase-catalyzed synthesis and ester antioxidant activity was examined. Among saturated acyl donors, higher yields and antioxidant activities of esters were achieved when short-chain FAs were used. Oleic acid gave the highest yield overall and its ester exhibited a high antioxidant activity. Optimization of experimental factors showed that the highest conversion (60.5%) in acetone was achieved with 5 g L(-1) of lipase, 50 mM of vitamin C, 10-fold molar excess of oleic acid, and 0.7 mL L(-1) of initial water. Obtained results showed that even short- and medium-chain ascorbyl esters could be synthesized with high yields and retained (or even exceeded) free radical scavenging capacity of l-ascorbic acid, indicating prospects of broadening their application in emulsions and liposomes. PMID:25224149

  12. Design and Synthesis of Photoaffinity Labeling Ligands of the l-Prolyl-l-leucyl-glycinmide Binding Site Involved in the Allosteric Modulation of the Dopamine Receptor

    PubMed Central

    Fisher, Abigail; Mann, Amandeep; Verma, Vaneeta; Thomas, Nancy; Mishra, Ram K.; Johnson, Rodney L.

    2008-01-01

    Pro-Leu-Gly-NH2 (PLG), in addition to its endocrine effects, possesses the ability to modulate dopamine D2 receptors within the CNS. However, the precise binding site of PLG is unknown. Potential photoaffinity labeling ligands of the PLG binding site were designed as tools to be used in the identification of the macromolecule that possesses this binding site. Six different photoaffinity labeling ligands were designed and synthesized based upon γ-lactam PLG peptidomimetic 1. The 4-azido-benzoyl and 4-azido-2-hydroxy-benzoyl photoaffinity labeling moieties were placed at opposite ends of PLG peptidomimetic 1 to generate a series of ligands that potentially could be used to map the PLG binding site. All of the compounds that were synthesized possessed activity comparable to or better than PLG in enhancing [3H]N-propylnorapomorphine agonist binding to dopamine receptors. Photoaffinity ligands that were cross-linked to the receptor preparation produced a modulatory effect that was either comparable to or greater than the increase in agonist binding produced by the respective ligands that were not cross-linked to the dopamine receptor. The results indicate that these photoaffinity labeling agents are binding at the same site as PLG and PLG peptidomimetic 1. PMID:16392815

  13. Transition-metal-ion-mediated polymerization of dopamine: mussel-inspired approach for the facile synthesis of robust transition-metal nanoparticle-graphene hybrids.

    PubMed

    Yang, Liping; Kong, Junhua; Zhou, Dan; Ang, Jia Ming; Phua, Si Lei; Yee, Wu Aik; Liu, Hai; Huang, Yizhong; Lu, Xuehong

    2014-06-16

    Inspired by the high transition-metal-ion content in mussel glues, and the cross-linking and mechanical reinforcement effects of some transition-metal ions in mussel threads, high concentrations of nickel(II), cobalt(II), and manganese(II) ions have been purposely introduced into the reaction system for dopamine polymerization. Kinetics studies were conducted for the Ni(2+)-dopamine system to investigate the polymerization mechanism. The results show that the Ni(2+) ions could accelerate the assembly of dopamine oligomers in the polymerization process. Spectroscopic and electron microscopic studies reveal that the Ni(2+) ions are chelated with polydopamine (PDA) units, forming homogeneous Ni(2+)-PDA complexes. This facile one-pot approach is utilized to construct transition-metal-ion-PDA complex thin coatings on graphene oxide, which can be carbonized to produce robust hybrid nanosheets with well-dispersed metallic nickel/metallic cobalt/manganese(II) oxide nanoparticles embedded in PDA-derived thin graphitic carbon layers. The nickel-graphene hybrid prepared by using this approach shows good catalytic properties and recyclability for the reduction of p-nitrophenol. PMID:24862644

  14. Synthesis, fine structural characterization, and CO2 adsorption capacity of metal organic frameworks-74.

    PubMed

    Adhikari, Abhijit Krishna; Lin, Kuen-Song

    2014-04-01

    Two metal organic frameworks of MOF-74 group (zinc and copper-based) were successfully synthesized, characterized, and evaluated for CO2 adsorption. The both samples such as MOF-74(Zn) and MOF-74(Cu) were characterized with FE-SEM for morphology and particle size, XRD patterns for phase structure, FTIR for organic functional groups, nitrogen adsorption for pore textural properties, and X-ray absorption spectroscopy for fine structural parameters and oxidation states of central metal atoms. CO2 adsorption isotherms of MOF-74 samples were measured in a volumetric adsorption unit at 273 K and pressure up to 1.1 bar. The MOF-74(Zn) and MOF-74(Cu) adsorbents have the pore widths of 8.58 and 8.04 angstroms with the BET specific surface areas of 1,474 and 1,345 m2 g(-1), respectively. CO2 adsorption capacities of MOF-74(Zn) and MOF-74(Cu) were 4.10 and 3.38 mmol x g(-1), respectively measured at 273 K and 1.1 bar. The oxidation state of central atoms in MOF-74(Zn) was Zn(II) confirmed by XANES spectra while MOF-74(Cu) was composed of Cu(I) and Cu(II) central atoms. The bond distances of Zn--O and Cu--O were 1.98 and 1.94 angstroms, respectively. PMID:24734683

  15. A review and synthesis of recreation ecology research supporting carrying capacity and visitor use management decisionmaking

    USGS Publications Warehouse

    Marion, Jeff

    2016-01-01

    Resource and experiential impacts associated with visitation to wilderness and other similar backcountry settings have long been addressed by land managers under the context of “carrying capacity” decisionmaking. Determining a maximum level of allowable use, below which high-quality resource and experiential conditions would be sustained, was an early focus in the 1960s and 1970s. However, decades of recreation ecology research have shown that the severity and areal extent of visitor impact problems are influenced by an interrelated array of use-related, environmental, and managerial factors. This complexity, with similar findings from social science research, prompted scientists and managers to develop more comprehensive carrying capacity frameworks, including a new Visitor Use Management framework. These frameworks rely on a diverse array of management strategies and actions, often termed a “management toolbox,” for resolving visitor impact problems. This article reviews the most recent and relevant recreation ecology studies that have been applied in wildland settings to avoid or minimize resource impacts. The key findings and their management implications are highlighted to support the professional management of common trail, recreation site, and wildlife impact problems. These studies illustrate the need to select from a more diverse array of impact management strategies and actions based on an evaluation of problems to identify the most influential factors that can be manipulated.

  16. The relationship of nitric oxide synthesis capacity, oxidative stress, and albumin-to-creatinine ratio in black and white men: the SABPA study.

    PubMed

    Mels, Catharina M C; Huisman, Hugo W; Smith, Wayne; Schutte, Rudolph; Schwedhelm, Edzard; Atzler, Dorothee; Böger, Rainer H; Ware, Lisa J; Schutte, Aletta E

    2016-02-01

    Inadequate substrate availability and increased nitric oxide synthase inhibitor levels attenuate nitric oxide (NO) synthesis, whereas increased vascular oxidative stress may lead to inactivation of NO. We compared markers of NO synthesis capacity and oxidative stress in a bi-ethnic male population. Inter-relationships of ambulatory blood pressure and urinary albumin-to-creatinine ratio with NO synthesis capacity and oxidative stress markers were investigated. NO synthesis capacity markers (L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)) and oxidative stress markers (serum peroxides, total glutathione, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase) were measured. Black men displayed higher blood pressure and albumin-to-creatinine ratio (all p < 0.001), while NO synthesis capacity was more favorable (higher L-arginine and lower ADMA (p ≤ 0.003)). Antioxidant enzyme activities were similar except for the redox status markers (GR activity and GR/GPx ratio), which were upregulated in black men (p < 0.001). In black men, ADMA was inversely related to GPx activity (R (2) = 0.15; β = -0.20; p = 0.050) and GPx/SOD ratio (R (2) = 0.24; β = -0.37; p < 0.001), but none of these markers related to blood pressure or albumin-to-creatinine ratio. In white men, albumin-to-creatinine ratio was positively associated with ADMA (R (2) = 0.18; β = 0.39; p < 0.001) while ADMA was inversely related to GR activity (R (2) = 0.26; β = -0.29; p = 0.002) and GR/GPx ratio (R (2) = 0.25; β = -0.28; p = 0.003). Black men with elevated blood pressure and albumin-to-creatinine ratio displayed a favorable NO synthesis capacity. This may be counteracted by increased inactivation of NO, although it was not linked to vascular or renal phenotypes. In white men, reduced NO synthesis capacity may lower NO bio-availability, thereby influencing the albumin

  17. QUANTIFICATION OF RESERVE POOL DOPAMINE IN METHIONINE SULFOXIDE REDUCTASE A NULL MICE

    PubMed Central

    Ortiz, Andrea N.; Oien, Derek B.; Moskovitz, Jackob; Johnson, Michael A.

    2012-01-01

    Methionine sulfoxide reductase A knockout (MsrA−/−) mice, which serve as a potential model for neurodegeneration, suffer from increased oxidative stress and have previously been found to have chronically elevated brain dopamine content levels relative to control mice. Additionally, these high levels parallel increased presynaptic dopamine release. In this work, fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used to quantify striatal reserve pool dopamine in knockout mice and wild-type control mice. Reserve pool dopamine efflux, induced by amphetamine, was measured in brain slices from knockout and wild type mice in the presence of α-methyl-p-tyrosine, a dopamine synthesis inhibitor. Additionally, the stimulated release of reserve pool dopamine, mobilized by cocaine, was measured. Both efflux and stimulated release measurements were enhanced in slices from knockout mice, suggesting that these mice have greater reserve pool dopamine stores than wild-type and that these stores are effectively mobilized. Moreover, dopamine transporter labeling data indicate that the difference in measured dopamine efflux was likely not caused by altered dopamine transporter protein expression. Additionally, slices from MsrA−/− and wild-type mice were equally responsive to increasing extracellular calcium concentrations, suggesting that potential differences in either calcium entry or intracellular calcium handling are not responsible for increased reserve pool dopamine release. Collectively, these results demonstrate that MsrA−/− knockout mice maintain a larger dopamine reserve pool than wild-type control mice, and that this pool is readily mobilized. PMID:21219974

  18. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise.

    PubMed

    Felger, Jennifer C; Miller, Andrew H

    2012-08-01

    Data suggest that cytokines released during the inflammatory response target subcortical structures including the basal ganglia as well as dopamine function to acutely induce behavioral changes that support fighting infection and wound healing. However, chronic inflammation and exposure to inflammatory cytokines appears to lead to persisting alterations in the basal ganglia and dopamine function reflected by anhedonia, fatigue, and psychomotor slowing. Moreover, reduced neural responses to hedonic reward, decreased dopamine metabolites in the cerebrospinal fluid and increased presynaptic dopamine uptake and decreased turnover have been described. This multiplicity of changes in the basal ganglia and dopamine function suggest fundamental effects of inflammatory cytokines on dopamine synthesis, packaging, release and/or reuptake, which may sabotage and circumvent the efficacy of current treatment approaches. Thus, examination of the mechanisms by which cytokines alter the basal ganglia and dopamine function will yield novel insights into the treatment of cytokine-induced behavioral changes and inflammatory malaise. PMID:23000204

  19. Cytokine Effects on the Basal Ganglia and Dopamine Function: the Subcortical Source of Inflammatory Malaise

    PubMed Central

    Felger, Jennifer C.; Miller, Andrew H.

    2012-01-01

    Data suggest that cytokines released during the inflammatory response target subcortical structures including the basal ganglia as well as dopamine function to acutely induce behavioral changes that support fighting infection and wound healing. However, chronic inflammation and exposure to inflammatory cytokines appears to lead to persisting alterations in the basal ganglia and dopamine function reflected by anhedonia, fatigue, and psychomotor slowing. Moreover, reduced neural responses to hedonic reward, decreased dopamine metabolites in the cerebrospinal fluid and increased presynaptic dopamine uptake and decreased turnover have been described. This multiplicity of changes in the basal ganglia and dopamine function suggest fundamental effects of inflammatory cytokines on dopamine synthesis, packaging, release and/or reuptake, which may sabotage and circumvent the efficacy of current treatment approaches. Thus, examination of the mechanisms by which cytokines alter the basal ganglia and dopamine function will yield novel insights into the treatment of cytokine-induced behavioral changes and inflammatory malaise. PMID:23000204

  20. Gd-DTPA-Dopamine-Bisphytanyl Amphiphile: Synthesis, Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents.

    PubMed

    Gupta, Abhishek; Willis, Scott A; Waddington, Lynne J; Stait-Gardner, Tim; de Campo, Liliana; Hwang, Dennis W; Kirby, Nigel; Price, William S; Moghaddam, Minoo J

    2015-09-28

    Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd(III)-chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd-DTPA-dopamine-bisphytanyl (Gd-DTPA-Dop-Phy), which is readily capable of self-assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature (17)O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by (1)H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari-Szabo "model-free" approach. High payloads of Gd(III) ions in the liposomal nanoassemblies made solely from the Gd-DTPA-Dop-Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent. PMID:26376329

  1. Synthesis and characterization of extremely small gold nanoshells, and comparison of their photothermal conversion capacity with gold nanorods

    NASA Astrophysics Data System (ADS)

    Durán-Meza, A. L.; Moreno-Gutiérrez, D. S.; Ruiz-Robles, J. F.; Bañuelos-Frías, A.; Segovia-González, X. F.; Longoria-Hernández, A. M.; Gomez, E.; Ruiz-García, J.

    2016-05-01

    The current methods for preparing gold nanoshells (AuNSs) produce shells with a diameter of approximately 40 nm or larger, with a relatively large polydispersity. However, AuNSs with smaller diameters and more monodispersity are better suited for biomedical applications. In this work, we present a modified method for the preparation of AuNSs, based on the use of sacrificial silver nanoparticles (AgNPs). We customized the Lee-Meisel method to prepare small and monodisperse AgNPs that were used as sacrificial nanoparticles to prepare extremely small monodispersed AuNSs with an average diameter from 17 to 25 +/- 4 nm. We found that these AuNSs are faceted, and that the oxidized silver likely dissolves out of the nanoparticles through some of the facets on the AuNSs. This leads to a silver oxide plug on the surface of the AuNSs, which has not been reported before. The smaller AuNSs, prepared under the best conditions, absorb in the near infrared region (NIR) that is appropriate for applications, such as photothermal therapy or medical imaging. The AuNSs showed absorption peaks in the NIR similar to those of gold nanorods (AuNRs) but with better photothermal capacity. In addition, because of their negative charge, these AuNSs are more biocompatible than the positively charged AuNRs. The synthesis of small, monodisperse, stable and biocompatible nanoparticles, like the ones presented in this work, is of prime importance in biomedical applications.The current methods for preparing gold nanoshells (AuNSs) produce shells with a diameter of approximately 40 nm or larger, with a relatively large polydispersity. However, AuNSs with smaller diameters and more monodispersity are better suited for biomedical applications. In this work, we present a modified method for the preparation of AuNSs, based on the use of sacrificial silver nanoparticles (AgNPs). We customized the Lee-Meisel method to prepare small and monodisperse AgNPs that were used as sacrificial nanoparticles to

  2. Synthesis and characterization of extremely small gold nanoshells, and comparison of their photothermal conversion capacity with gold nanorods.

    PubMed

    Durán-Meza, A L; Moreno-Gutiérrez, D S; Ruiz-Robles, J F; Bañuelos-Frías, A; Segovia-González, X F; Longoria-Hernández, A M; Gomez, E; Ruiz-García, J

    2016-06-01

    The current methods for preparing gold nanoshells (AuNSs) produce shells with a diameter of approximately 40 nm or larger, with a relatively large polydispersity. However, AuNSs with smaller diameters and more monodispersity are better suited for biomedical applications. In this work, we present a modified method for the preparation of AuNSs, based on the use of sacrificial silver nanoparticles (AgNPs). We customized the Lee-Meisel method to prepare small and monodisperse AgNPs that were used as sacrificial nanoparticles to prepare extremely small monodispersed AuNSs with an average diameter from 17 to 25 ± 4 nm. We found that these AuNSs are faceted, and that the oxidized silver likely dissolves out of the nanoparticles through some of the facets on the AuNSs. This leads to a silver oxide plug on the surface of the AuNSs, which has not been reported before. The smaller AuNSs, prepared under the best conditions, absorb in the near infrared region (NIR) that is appropriate for applications, such as photothermal therapy or medical imaging. The AuNSs showed absorption peaks in the NIR similar to those of gold nanorods (AuNRs) but with better photothermal capacity. In addition, because of their negative charge, these AuNSs are more biocompatible than the positively charged AuNRs. The synthesis of small, monodisperse, stable and biocompatible nanoparticles, like the ones presented in this work, is of prime importance in biomedical applications. PMID:27227737

  3. Dopamine D1 and D2 Receptor Immunoreactivities in the Arcuate-Median Eminence Complex and their Link to the Tubero-Infundibular Dopamine Neurons

    PubMed Central

    Romero-Fernandez, W.; Borroto-Escuela, D.O.; Vargas-Barroso, V.; Narváez, M.; Di Palma, M.; Agnati, L.F.; Sahd, J. Larriva

    2014-01-01

    modulate the activity and/or Dopamine synthesis of substantial numbers of tubero-infundibular dopamine neurons at the somatic and terminal level. The immunohistochemical work also gives support to the view that dopamine D1 receptors and/or dopamine D2 receptors in the lateral palisade zone by mediating dopamine volume transmission may contribute to the inhibition of luteinizing hormone releasing hormone release from nerve terminals in this region. PMID:25308843

  4. The Neurotropic Parasite Toxoplasma Gondii Increases Dopamine Metabolism

    PubMed Central

    Prandovszky, Emese; Gaskell, Elizabeth; Martin, Heather; Dubey, J. P.; Webster, Joanne P.; McConkey, Glenn A.

    2011-01-01

    The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase the likelihood that the parasite will be transmitted back to its definitive cat host, an essential step in completion of the parasite's life cycle. The mechanism(s) responsible for behavioral changes in the host is unknown but two lines of published evidence suggest that the parasite alters neurotransmitter signal transduction: the disruption of the parasite-induced behavioral changes with medications used to treat psychiatric disease (specifically dopamine antagonists) and identification of a tyrosine hydroxylase encoded in the parasite genome. In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released. Immunostaining brain sections of infected mice with dopamine antibody showed intense staining of encysted parasites. Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells. Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, was also found in intracellular tissue cysts in brain tissue with antibodies specific for the parasite-encoded tyrosine hydroxylase. These observations provide a mechanism for parasite-induced behavioral changes. The observed effects on dopamine metabolism could also be relevant in interpreting reports of psychobehavioral changes in toxoplasmosis-infected humans. PMID:21957440

  5. The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity.

    PubMed

    Ferrero, G O; Velazquez, F N; Caputto, B L

    2012-07-12

    Our previous work showed that in T98G cells, a human glioblastoma multiforme-derived cell line, the association of c-Fos to the endoplasmic reticulum (ER) and consequently, the capacity of c-Fos to activate phospholipid synthesis, is regulated by the phosphorylation state of tyrosine (tyr) residues #10 and #30 of c-Fos. The small amount of c-Fos present in quiescent cells is tyr-phosphorylated, is dissociated from the ER membranes and does not activate phospholipid synthesis. However, on induction of the cell to re-enter growth, c-Fos expression is rapidly induced, it is found dephosphorylated, associated to ER membranes and activating phospholipid synthesis (Portal et al., 2007). Herein, using in vivo and in vitro experimental strategies, we show that the kinase c-Src is capable of phosphorylating tyr residues of c-Fos whereas the phosphatase TC45 T-cell protein-tyr phosphatase (TC-PTP) dephosphorylates them, thus enabling c-Fos/ER association and activation of phospholipid synthesis. Results also suggest that the regulation of the phosphorylation/dephosphorylation cycle of c-Fos occurs at the TC-PTP level: induction of cells to re-enter growth promotes the translocation of TC45 from a nuclear to a cytoplasmic location concomitant with its activation. Activated TC45 in its turn promotes dephosphorylation of pre-formed c-Fos, enabling cells to rapidly activate phospholipid synthesis to respond to its growth demands. PMID:22105363

  6. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity.

    PubMed

    Izumi, Yasuhiko; Sawada, Hideyuki; Yamamoto, Noriyuki; Kume, Toshiaki; Katsuki, Hiroshi; Shimohama, Shun; Akaike, Akinori

    2007-02-28

    Parkinson disease is characterized by selective degeneration of mesencephalic dopaminergic neurons, and endogenous dopamine may play a pivotal role in the degenerative processes. Using primary cultured mesencephalic neurons, we found that glutamate, an excitotoxin, caused selective dopaminergic neuronal death depending on endogenous dopamine content. Pramipexole, a dopamine D2/D3 receptor agonist used clinically in the treatment of Parkinson disease, did not affect glutamate-induced calcium influx but blocked dopaminergic neuronal death induced by glutamate. Pramipexole reduced dopamine content but did not change the levels of total or phosphorylated tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis. The neuroprotective effect of pramipexole was independent of dopamine receptor stimulation because it was not abrogated by domperidone, a dopamine D2-type receptor antagonist. Moreover, both active S(-)- and inactive R(+)-enantiomers of pramipexole as a dopamine D2-like receptor agonist equally suppressed dopaminergic neuronal death. These results suggest that pramipexole protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D2-like receptor activation. PMID:17161393

  7. Metaphit inhibits dopamine transport and binding of ( sup 3 H)methylphenidate, a proposed marker for the dopamine transport complex

    SciTech Connect

    Schweri, M.M. ); Jacobson, A.E.; Rice, K.C. ); Lessor, R.A.

    1989-01-01

    Metaphit, an acylating derivative of phencyclidine, was shown to interact with components of the dopamine nerve terminal in rat striatal tissue. This compound, previously demonstrated to be an irreversible inhibitor at the phencyclidine receptor, was shown in these experiments to irreversibly inhibit synaptosomal ({sup 3}H)dopamine uptake. It also inhibited binding of ({sup 3}H)methylphenidate to its recognition site, which is thought to be a subunit of the dopamine transporter. Although the inhibition was due primarily to a reduction in the binding and transport capacity of the systems studied, increases in the apparent K{sub D} of ({sup 3}H)methylphenidate and the K{sub m} of ({sup 3}H)dopamine were also observed. Differences in the behavior of Metaphit and phencylidine in these dopaminergic systems compared to their effects on the NMDA receptor-linked phencyclidine receptor suggest that Metaphit may be interacting with two distinct molecular sites in the rat striatum.

  8. Electrochemical Co-Reduction Synthesis of AuPt Bimetallic Nanoparticles-Graphene Nanocomposites for Selective Detection of Dopamine in the Presence of Ascorbic Acid and Uric Acid

    PubMed Central

    Zhao, Zongya; Zhang, Mingming; Chen, Xiang; Li, Youjun; Wang, Jue

    2015-01-01

    In this paper, AuPt bimetallic nanoparticles-graphene nanocomposites were obtained by electrochemical co-reduction of graphene oxide (GO), HAuCl4 and H2PtCl6. The as-prepared AuPt bimetallic nanoparticles-graphene nanocomposites were characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and other electrochemical methods. The morphology and composition of the nanocomposite could be easily controlled by adjusting the HAuCl4/H2PtCl6 concentration ratio. The electrochemical experiments showed that when the concentration ratio of HAuCl4/H2PtCl6 was 1:1, the obtained AuPt bimetallic nanoparticles-graphene nanocomposite (denoted as Au1Pt1NPs-GR) possessed the highest electrocatalytic activity toward dopamine (DA). As such, Au1Pt1NPs-GR nanocomposites were used to detect DA in the presence of ascorbic acid (AA) and uric acid (UA) using the differential pulse voltammetry (DPV) technique and on the modified electrode, there were three separate DPV oxidation peaks with the peak potential separations of 177 mV, 130 mV and 307 mV for DA and AA, DA and UA, AA and UA, respectively. The linear range of the constructed DA sensor was from 1.6 μM to 39.7 μM with a detection limit of 0.1 μM (S/N = 3). The obtained DA sensor with good stability, high reproducibility and excellent selectivity made it possible to detect DA in human urine samples. PMID:26184200

  9. Regulation of bat echolocation pulse acoustics by striatal dopamine

    PubMed Central

    Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

    2011-01-01

    SUMMARY The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg–1) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D1- and D2-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D2-type dopamine receptor agonist (Quinpirole) but not by a D1-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D2-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats. PMID:21900471

  10. Preparation of hybrid organic-inorganic mesoporous silicas applied to mercury removal from aqueous media: Influence of the synthesis route on adsorption capacity and efficiency.

    PubMed

    Pérez-Quintanilla, Damián; Sánchez, Alfredo; Sierra, Isabel

    2016-06-15

    New hybrid organic-inorganic mesoporous silicas were prepared by employing three different synthesis routes and mercury adsorption studies were done in aqueous media using the batch technique. The organic ligands employed for the functionalization were derivatives of 2-mercaptopyrimidine or 2-mercaptothiazoline, and the synthesis pathways used were post-synthesis, post-synthesis with surface ion-imprinting and co-condensation with ion-imprinting. The incorporation of functional groups and the presence of ordered mesopores in the organosilicas was confirmed by XRD, TEM and SEM, nitrogen adsorption-desorption isotherms, (13)C MAS-NMR, (29)Si MAS-NMR, elemental and thermogravimetric analysis. The highest adsorption capacity and selectivity observed was for the material functionalized with 2-mercaptothiazoline ligand by means the co-condensation with ion-imprinting route (1.03mmolg(-1) at pH 6). The prepared material could be potential sorbent for the extraction of this heavy metal from environmental and drinking waters. PMID:27023632

  11. Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.

    PubMed

    Daberkow, D P; Brown, H D; Bunner, K D; Kraniotis, S A; Doellman, M A; Ragozzino, M E; Garris, P A; Roitman, M F

    2013-01-01

    Drugs of abuse hijack brain-reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting nonexocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties, which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to 2 h. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration, and frequency of spontaneous dopamine transients, the naturally occurring, nonelectrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sugar reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sugar-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

  12. Age-dependent capacity to accelerate protein synthesis dictates the extent of compensatory growth in skeletal muscle following undernutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In both humans and animals, impaired growth during early life compromises adult lean body mass and muscle strength despite skeletal muscle’s large regenerative capacity. To identify the significance of developmental age on skeletal muscle’s capacity for catch-up growth following an episode of under ...

  13. One step solvothermal synthesis of functional hybrid γ-Fe2O3/carbon hollow spheres with superior capacities for heavy metal removal.

    PubMed

    Cui, Hao-Jie; Cai, Jie-Kui; Zhao, Huan; Yuan, Baoling; Ai, Cuiling; Fu, Ming-Lai

    2014-07-01

    One-step hydrothermal method was developed to prepare hybrid γ-Fe2O3/carbon hollow spheres with a predominant orientation (111) plane of γ-Fe2O3 and rich oxygen-containing functional groups on carbon. The resulting functional hybrid exhibited extremely high adsorption capacities for toxic Pb(II) and Cr(VI) ions in solutions with easy magnetic separation. The ease of synthesis and low cost, coupled with the efficient and rapid removal of toxic heavy metal ions, make hybrid γ-Fe2O3/carbon hollow spheres an attractive adsorbent for the purification of waste and contaminated water. PMID:24776674

  14. Dopamine and anorexia nervosa.

    PubMed

    Södersten, P; Bergh, C; Leon, M; Zandian, M

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. PMID:26608248

  15. Effects of activated carbon characteristics on the electrosorption capacity of titanium dioxide/activated carbon composite electrode materials prepared by a microwave-assisted ionothermal synthesis method.

    PubMed

    Liu, Po-I; Chung, Li-Ching; Ho, Chia-Hua; Shao, Hsin; Liang, Teh-Ming; Horng, Ren-Yang; Chang, Min-Chao; Ma, Chen-Chi M

    2015-05-15

    Titanium dioxide (TiO2)/ activated carbon (AC) composite materials, as capacitive deionization electrodes, were prepared by a two-step microwave-assisted ionothermal synthesis method. The electrosorption capacity of the composite electrodes was studied and the effects of AC characteristics were explored. These effects were investigated by multiple analytical techniques, including X-ray photoelectron spectroscopy, thermogravimetry analysis and electrochemical impedance spectroscopy, etc. The experimental results indicated that the electrosorption capacity of the TiO2/AC composite electrode is dependent on the characteristics of AC including the pore structure and the surface property. An enhancement in electrosorption capacity was observed for the TiO2/AC composite electrode prepared from the AC with higher mesopore content and less hydrophilic surface. This enhancement is due to the deposition of anatase TiO2 with suitable amount of Ti-OH. On the other hand, a decline in electrosorption capacity was observed for the TiO2/AC composite electrode prepared from the AC with higher micropore content and highly hydrophilic surface. High content of hydrogen bond complex formed between the functional group on hydrophilic surface with H2O, which will slow down the TiO2 precursor-H2O reaction. In such situation, the effect of TiO2 becomes unfavorable as the loading amount of TiO2 is less and the micropore can also be blocked. PMID:25576198

  16. Dopamine and binge eating behaviors

    PubMed Central

    Bello, Nicholas T.; Hajnal, Andras

    2010-01-01

    Central dopaminergic mechanisms are involved in the motivational aspects of eating and food choices. This review focuses on human and animal data examining the importance of dopamine on binge eating behaviors. Early works examining dopamine metabolites in the cerebrospinal fluid and plasma of bulimic individuals suggested decreased dopamine turnover during the active phase of the illness. While neuroimaging studies of dopamine mechanisms in bulimia nervosa (BN) and binge eating disorder (BED) are limited, genetic studies in humans have implicated an increased frequency of dopamine transporter and associated D2 receptor polymorphisms with binge pathology. Recent examinations of rodent models of dietary-induced binge eating (DIBE) have investigated plausible dopamine mechanisms involved in sustaining binge eating behaviors. In DIBE models, highly palatable foods (fats, sugars and their combination), as well as restricted access conditions appear to promote ingestive responses and result in sustained dopamine stimulation within the nucleus accumbens. Taken together with studies examining the comorbidity of illicit drug use and eating disorders, the data reviewed here support a role for dopamine in perpetuating the compulsive feeding patterns of BN and BED. As such, we propose that sustained stimulation of the dopamine systems by bingeing promoted by preexisting conditions (e.g., genetic traits, dietary restraint, stress, etc.) results in progressive impairments of dopamine signaling. To disrupt this vicious cycle, novel research-based treatment options aiming at the neural substrates of compulsive eating patterns are necessary. PMID:20417658

  17. Facile and cost effective synthesis of mesoporous spinel NiCo2O4 as an anode for high lithium storage capacity

    NASA Astrophysics Data System (ADS)

    Jadhav, Harsharaj S.; Kalubarme, Ramchandra S.; Park, Choong-Nyeon; Kim, Jaekook; Park, Chan-Jin

    2014-08-01

    To fulfill the high power and high energy density demands for Li-ion batteries (LIBs) new anode materials need to be explored to replace conventional graphite. Herein, we report the urea assisted facile co-precipitation synthesis of spinel NiCo2O4 and its application as an anode material for LIBs. The synthesized NiCo2O4 exhibited an urchin-like microstructure and polycrystalline and mesoporous nature. In addition, the mesoporous NiCo2O4 electrode exhibited an initial discharge capacity of 1095 mA h g-1 and maintained a reversible capacity of 1000 mA h g-1 for 400 cycles at 0.5 C-rate. The reversible capacity of NiCo2O4 could still be maintained at 718 mA h g-1, even at 10 C. The mesoporous NiCo2O4 exhibits great potential as an anode material for LIBs with the advantages of unique performance and facile preparation.To fulfill the high power and high energy density demands for Li-ion batteries (LIBs) new anode materials need to be explored to replace conventional graphite. Herein, we report the urea assisted facile co-precipitation synthesis of spinel NiCo2O4 and its application as an anode material for LIBs. The synthesized NiCo2O4 exhibited an urchin-like microstructure and polycrystalline and mesoporous nature. In addition, the mesoporous NiCo2O4 electrode exhibited an initial discharge capacity of 1095 mA h g-1 and maintained a reversible capacity of 1000 mA h g-1 for 400 cycles at 0.5 C-rate. The reversible capacity of NiCo2O4 could still be maintained at 718 mA h g-1, even at 10 C. The mesoporous NiCo2O4 exhibits great potential as an anode material for LIBs with the advantages of unique performance and facile preparation. Electronic supplementary information (ESI) available: Experimental details and additional experimental results. See DOI: 10.1039/c4nr02183e

  18. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo.

    PubMed

    Lohr, Kelly M; Bernstein, Alison I; Stout, Kristen A; Dunn, Amy R; Lazo, Carlos R; Alter, Shawn P; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J; Yi, Hong; Vecchio, Laura M; Goldstein, David S; Guillot, Thomas S; Salahpour, Ali; Miller, Gary W

    2014-07-01

    Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

  19. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

    PubMed Central

    Lohr, Kelly M.; Bernstein, Alison I.; Stout, Kristen A.; Dunn, Amy R.; Lazo, Carlos R.; Alter, Shawn P.; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J.; Yi, Hong; Vecchio, Laura M.; Goldstein, David S.; Guillot, Thomas S.; Salahpour, Ali; Miller, Gary W.

    2014-01-01

    Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

  20. N-Octanoyl Dopamine, a Non-Hemodyanic Dopamine Derivative, for Cell Protection during Hypothermic Organ Preservation

    PubMed Central

    Beck, Grietje; Schnuelle, Peter; Höger, Simone; Wehling, Martin; Yard, Benito A.

    2010-01-01

    Background Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects. Methodology/Principal Findings To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects. Conclusions/Significance In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors. PMID:20300525

  1. Growth of dopamine crystals

    NASA Astrophysics Data System (ADS)

    Patil, Vidya; Patki, Mugdha

    2016-05-01

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  2. Dopamine receptors - IUPHAR Review 13.

    PubMed

    Beaulieu, Jean-Martin; Espinoza, Stefano; Gainetdinov, Raul R

    2015-01-01

    The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors. PMID:25671228

  3. Dorsal Striatal Dopamine, Food Preference and Health Perception in Humans

    PubMed Central

    Wallace, Deanna L.; Aarts, Esther; Dang, Linh C.; Greer, Stephanie M.; Jagust, William J.; D′Esposito, Mark

    2014-01-01

    To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [18F]fluorometatyrosine (FMT), correlates with food-related decision-making, as well as body mass index (BMI) in 16 healthy-weight to moderately obese individuals. We find that lower PET FMT dopamine synthesis binding potential correlates with higher BMI, greater preference for perceived “healthy” foods, but also greater healthiness ratings for food items. These findings further substantiate the role of dorsal striatal dopamine in food-related behaviors and shed light on the complexity of individual differences in food preference. PMID:24806534

  4. Synthesis and Characterization of the Lithium-Rich Core-Shell Cathodes with Low Irreversible Capacity and Mitigated Voltage Fade

    SciTech Connect

    Li, Jing; Camardese, John; Shunmugasundaram, Ramesh; Glazier, Stephen; Lu, Zhonghua; Dahn, J.R.

    2015-05-12

    Lithium-rich layered Ni–Mn–Co oxide materials have been intensely studied in the past decade. Mn-rich materials have serious voltage fade issues, and the Ni-rich materials have poor thermal stability and readily oxidize the organic carbonate electrolyte. Core–shell (CS) strategies that use Ni-rich material as the core and Mn-rich materials as the shell can balance the pros and cons of these materials in a hybrid system. The lithium-rich CS materials introduced here show much improved overall electrochemical performance compared to the core-only and shell-only samples. Energy dispersive spectroscopy results show that there was diffusion of transition metals between the core and shell phases after sintering at 900 °C compared to the prepared hydroxide precursors. A Mn-rich shell was still maintained whereas the Co which was only in the shell in the precursor was approximately homogeneous throughout the particles. The CS samples with optimal lithium content showed low irreversible capacity (IRC), as well as high capacity and excellent capacity retention. Sample CS2-3 (the third sample in the 0.67Li1+x(Ni₀.₆₇Mn₀.₃₃)1–xO₂·0.33Li1+y(Ni₀.₄Mn₀.₅Co₀.₁)1–yO₂ CS2 series) had a reversible capacity of ~218 mAh/g with 12.3% (~30 mAh/g) irreversible capacity (IRC) and 98% capacity retention after 40 cycles to 4.6 V at 30 °C at a rate of ~C/20. Differential capacity versus potential (dQ/dV versus V) analysis confirmed that cells of the CS samples had stable impedance as well as a very stable average voltage. Apparently, the Mn-rich shell can effectively protect the Ni-rich core from reactions with the electrolyte while the Ni-rich core renders a high and stable average voltage.

  5. Soil infiltration capacity categorisation based on a geo-information synthesis of the valuated soil-ecological units data

    NASA Astrophysics Data System (ADS)

    Janglova, R.; Kvitek, T.

    2003-04-01

    After destructive floods that hit the Czech Republic in 1997 and 2002, water resources managers become more interested in the spatial distribution of hydrological, hydrogeological and environmental indicators, among which the soil infiltration capacity is one of the most important. The poster summarises a methodology for interpretation of the Valuated Soil-Ecological Units (BPEJ) data in terms of the infiltration capacity of agricultural soils, in order to delineate areas within which the soil infiltration capacity is homogeneous. The methodology was developed as a partial result within a broader project in which the process of infiltration and various ways of soil infiltration capacity estimation are studied. The task is accomplished with the help of ARC/INFO 8.0.2 geographic information system. The starting point is a vectorised layer of BPEJ polygons the attributes of which are BPEJ codes. The BPEJ code is a five-digit number which contains information about the climatic zone, the main soil unit (HPJ), the soil depth, the content of stones and the terrain slope and exposition. However, the terrain slope information is not accurate enough. It was therefore derived from a digital elevation model, generated from contour lines of a digital map 1:25 000 (DMÚ-25). Each partial criterion derivable from the BPEJ codes (HPJ, depth, stoneness, slope, exposition) was categorised into six classes according to their assumed influence on the soil infiltration capacity. Appropriate weights (from 0 to 5, where 0 denotes non-agricultural lands, 1 means the highest soil infiltration capacity and 5 the lowest) were assigned to each class. Then the coverages defined by particular criteria were overlaid. The output is an ARC/INFO coverage defining relatively homogeneous spatial units. The polygon attribute table of these units contains information about the soil infiltration capacity. The infiltration capacity itself was calculated from the weights assigned to partial criteria. The

  6. Reduced cardiolipin content decreases respiratory chain capacities and increases ATP synthesis yield in the human HepaRG cells.

    PubMed

    Peyta, Laure; Jarnouen, Kathleen; Pinault, Michelle; Guimaraes, Cyrille; Pais de Barros, Jean-Paul; Chevalier, Stephan; Dumas, Jean-François; Maillot, François; Hatch, Grant M; Loyer, Pascal; Servais, Stephane

    2016-04-01

    Cardiolipin (CL) is a unique mitochondrial phospholipid potentially affecting many aspects of mitochondrial function/processes, i.e. energy production through oxidative phosphorylation. Most data focusing on implication of CL content and mitochondrial bioenergetics were performed in yeast or in cellular models of Barth syndrome. Previous work reported that increase in CL content leads to decrease in liver mitochondrial ATP synthesis yield. Therefore the aim of this study was to determine the effects of moderate decrease in CL content on mitochondrial bioenergetics in human hepatocytes. For this purpose, we generated a cardiolipin synthase knockdown (shCLS) in HepaRG hepatoma cells showing bioenergetics features similar to primary human hepatocytes. shCLS cells exhibited a 55% reduction in CLS gene and a 40% decrease in protein expression resulting in a 45% lower content in CL compared to control (shCTL) cells. Oxygen consumption was significantly reduced in shCLS cells compared to shCTL regardless of substrate used and energy state analyzed. Mitochondrial low molecular weight supercomplex content was higher in shCLS cells (+60%) compared to shCTL. Significant fragmentation of the mitochondrial network was observed in shCLS cells compared to shCTL cells. Surprisingly, mitochondrial ATP synthesis was unchanged in shCLS compared to shCTL cells but exhibited a higher ATP:O ratio (+46%) in shCLS cells. Our results suggest that lowered respiratory chain activity induced by moderate reduction in CL content may be due to both destabilization of supercomplexes and mitochondrial network fragmentation. In addition, CL content may regulate mitochondrial ATP synthesis yield. PMID:26768115

  7. Dopamine D-2 receptor imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N- ((1-ethyl-2-pyrrolidinyl)methyl)benzamide

    SciTech Connect

    Kung, H.F.; Kasliwal, R.; Pan, S.G.; Kung, M.P.; Mach, R.H.; Guo, Y.Z.

    1988-05-01

    In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-(/sup 125/I)iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2- pyrrolidinyl)methyl)benzamide, (/sup 125/I)IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-(/sup 125/I)IBZM showed high specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone greater than (S)-(-)-IBZM greater than (+)-butaclamol much greater than (R)-(+)-IBZM greater than (S)-(-)-BZM greater than dopamine greater than ketanserin greater than SCH23390 much greater than propanolol. The results indicate that (/sup 125/I)IBZM binds specifically to the dopamine D-2-receptor with stereospecificity. The (/sup 125/I)IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.

  8. A heterocyclic compound CE-103 inhibits dopamine reuptake and modulates dopamine transporter and dopamine D1-D3 containing receptor complexes.

    PubMed

    Sase, Ajinkya; Aher, Yogesh D; Saroja, Sivaprakasam R; Ganesan, Minu Karthika; Sase, Sunetra; Holy, Marion; Höger, Harald; Bakulev, Vasiliy; Ecker, Gerhard F; Langer, Thierry; Sitte, Harald H; Leban, Johann; Lubec, Gert

    2016-03-01

    A series of compounds have been reported to enhance memory via the DA system and herein a heterocyclic compound was tested for working memory (WM) enhancement. 2-((benzhydrylsulfinyl)methyl)thiazole (CE-103) was synthesized in a six-step synthesis. Binding of CE-103 to the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters and dopamine reuptake inhibition was tested as well as blood brain permeation and a screen for GPCR targets. 60 male Sprague Dawley rats were divided into six groups: CE-103 treated 1-10 mg/kg body weight, trained (TDI) and yoked (YDI) and vehicle treated, trained (TVI) and yoked (YVI) rats. Daily single intraperitoneal injections for a period of 10 days were administered and rats were tested in a radial arm maze (RAM). Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT) and complexes containing the D1-3 dopamine receptor subunits were determined. CE-103 was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 14.73 μM). From day eight the compound was decreasing WM errors in the RAM significantly at both doses tested as compared to the vehicle controls. In the trained CE-103-treated group levels of the complex containing the phosphorylated dopamine transporter (pDAT) as well as D1R were decreased while levels of complexes containing D2R and D3R were significantly increased. CE-103 was shown to enhance spatial WM and DA reuptake inhibition with subsequent modulation of D1-3 receptors is proposed as a possible mechanism of action. PMID:26407764

  9. Hydrothermal synthesis and potential applicability of rhombohedral siderite as a high-capacity anode material for lithium ion batteries

    NASA Astrophysics Data System (ADS)

    Zhao, Shiqiang; Yu, Yue; Wei, Shanshan; Wang, Yuxi; Zhao, Chenhao; Liu, Rui; Shen, Qiang

    2014-05-01

    Natural siderite is a valuable iron mineral composed of ferrous carbonate (FeCO3), which is commonly found in hydrothermal veins and contains no sulfur or phosphorus. In this paper, micro-sized FeCO3 crystallites are synthesized via a facile hydrothermal route, and almost all of them possess a rhombohedral shape similar to that of natural products. When applied as an anode material for lithium ion batteries, the synthetic siderite can deliver an initial specific discharge capacity of ∼1587 mAh g-1 with a coulombic efficiency of 68% at 200 mA g-1, remaining a reversible value of 1018 mAh g-1 over 120 cycles. Even at a high current density of 1000 mA g-1, after 120 cycles the residual specific capacity (812 mAh g-1) is still higher than the theoretical capacity of FeCO3 (463 mAh g-1). Moreover, a novel reversible conversion mechanism accounts for the excellent electrochemical performances of rhombohedral FeCO3 to a great extent, implying the potential applicability of synthetic siderite as lithium ion battery anodes.

  10. Dopamine- and Tyrosine Hydroxylase-Immunoreactive Neurons in the Brain of the American Cockroach, Periplaneta americana.

    PubMed

    Hamanaka, Yoshitaka; Minoura, Run; Nishino, Hiroshi; Miura, Toru; Mizunami, Makoto

    2016-01-01

    The catecholamine dopamine plays several vital roles in the central nervous system of many species, but its neural mechanisms remain elusive. Detailed neuroanatomical characterization of dopamine neurons is a prerequisite for elucidating dopamine's actions in the brain. In the present study, we investigated the distribution of dopaminergic neurons in the brain of the American cockroach, Periplaneta americana, using two antisera: 1) an antiserum against dopamine, and 2) an antiserum against tyrosine hydroxylase (TH, an enzyme required for dopamine synthesis), and identified about 250 putatively dopaminergic neurons. The patterns of dopamine- and TH-immunoreactive neurons were strikingly similar, suggesting that both antisera recognize the same sets of "dopaminergic" neurons. The dopamine and TH antibodies intensively or moderately immunolabeled prominent brain neuropils, e.g. the mushroom body (memory center), antennal lobe (first-order olfactory center) and central complex (motor coordination center). All subdivisions of the mushroom body exhibit both dopamine and TH immunoreactivity. Comparison of immunolabeled neurons with those filled by dye injection revealed that a group of immunolabeled neurons with cell bodies near the calyx projects into a distal region of the vertical lobe, which is a plausible site for olfactory memory formation in insects. In the antennal lobe, ordinary glomeruli as well as macroglomeruli exhibit both dopamine and TH immunoreactivity. It is noteworthy that the dopamine antiserum labeled tiny granular structures inside the glomeruli whereas the TH antiserum labeled processes in the marginal regions of the glomeruli, suggesting a different origin. In the central complex, all subdivisions excluding part of the noduli and protocerebral bridge exhibit both dopamine and TH immunoreactivity. These anatomical findings will accelerate our understanding of dopaminergic systems, specifically in neural circuits underlying aversive memory formation

  11. Iron Storage within Dopamine Neurovesicles Revealed by Chemical Nano-Imaging

    PubMed Central

    Ortega, Richard; Cloetens, Peter; Devès, Guillaume; Carmona, Asunción; Bohic, Sylvain

    2007-01-01

    Altered homeostasis of metal ions is suspected to play a critical role in neurodegeneration. However, the lack of analytical technique with sufficient spatial resolution prevents the investigation of metals distribution in neurons. An original experimental setup was developed to perform chemical element imaging with a 90 nm spatial resolution using synchrotron-based X-ray fluorescence. This unique spatial resolution, combined to a high brightness, enables chemical element imaging in subcellular compartments. We investigated the distribution of iron in dopamine producing neurons because iron-dopamine compounds are suspected to be formed but have yet never been observed in cells. The study shows that iron accumulates into dopamine neurovesicles. In addition, the inhibition of dopamine synthesis results in a decreased vesicular storage of iron. These results indicate a new physiological role for dopamine in iron buffering within normal dopamine producing cells. This system could be at fault in Parkinson's disease which is characterized by an increased level of iron in the substancia nigra pars compacta and an impaired storage of dopamine due to the disruption of vesicular trafficking. The re-distribution of highly reactive dopamine-iron complexes outside neurovesicles would result in an enhanced death of dopaminergic neurons. PMID:17895967

  12. Synthesis of fungus-like MoS2 nanosheets with ultrafast adsorption capacities toward organic dyes

    NASA Astrophysics Data System (ADS)

    Song, HaoJie; You, Shengsheng; Jia, XiaoHua

    2015-11-01

    Fungus-like molybdenum disulfide (MoS2) nanosheets with a thickness of a few nanometers have been successfully synthesized via one-pot hydrothermal method. The as-prepared MoS2 nanosheets with a high surface area of 106.989 m2 g-1 exhibited excellent wastewater treatment performance with high removal capacities toward organic dyes. In addition, the fungus-like MoS2 nanosheets can absorb Congo red completely within 2 min. Successful access to high quality fungus-like MoS2 nanosheets will make it possible for their potential application in catalysis and other fields.

  13. One-step synthesis of a novel N-doped microporous biochar derived from crop straws with high dye adsorption capacity.

    PubMed

    Lian, Fei; Cui, Guannan; Liu, Zhongqi; Duo, Lian; Zhang, Guilong; Xing, Baoshan

    2016-07-01

    N-doping is one of the most promising strategies to improve the adsorption capacity and selectivity of carbon adsorbents. Herein, synthesis, characterization and dye adsorption of a novel N-doped microporous biochar derived from direct annealing of crop straws under NH3 is presented. The resultant products exhibit high microporosity (71.5%), atomic percentage of nitrogen (8.81%), and adsorption capacity to dyes, which is about 15-20 times higher than that of original biochar. Specifically, for the sample NBC800-3 pyrolyzed at 800 °C in NH3 for 3 h, its adsorption for acid orange 7 (AO7, anionic) and methyl blue (MB, cationic) is up to 292 mg g(-1) and 436 mg g(-1), respectively, which is among the highest ever reported for carbonaceous adsorbents. The influences of N-doping and porous structure on dye adsorption of the synthesized carbons are also discussed, where electrostatic attraction, π-π electron donor-accepter interaction, and Lewis acid-base interaction mainly contribute to AO7 adsorption, and surface area (especially pore-filling) dominates MB adsorption. The N-doped biochar can be effectively regenerated and reused through direct combustion and desorption approaches. PMID:27039365

  14. Facile synthesis of nickel-foam-based nano-architectural composites as binder-free anodes for high capacity Li-ion batteries

    NASA Astrophysics Data System (ADS)

    Min, Shudi; Zhao, Chongjun; Ju, Peiwen; Zhou, Tengfei; Gao, Hong; Zheng, Yang; Wang, Hongqiang; Chen, Guorong; Qian, Xiuzhen; Guo, Zaiping

    2016-02-01

    A series of nickel foam (NF)-based composites of MxOy/RGO/Ni(OH)2 [MxOy = Co3O4, MnO2, and Ni(OH)2] with diverse multilayer nano-architectures were designed and grown in situ on NF through a one-pot hydrothermal process. Based on the redox reaction between the active NF substrate and graphene oxide (GO), along with electrostatic forces between the Mn+ ions and GO in the solution, strong interactions take place at the interfaces of MxOy/RGO, RGO/Ni(OH)2, and Ni(OH)2/Ni, and thus, there is good contact for electron transfer. These MxOy/RGO/Ni(OH)2 samples were directly used as conductive-agent- and binder-free anodes for lithium ion batteries (LIBs), and the Ni(OH)2/RGO/Ni(OH)2/NF composite electrode showed a high specific capacity, good rate capability, and excellent cycling stability, especially, it had a high reversible capacity of about 1330 mAh g-1 even after 200 cycles at 100 mA g-1. This general strategy presents a promising route for the design and synthesis of various multilayer nano-architectural transition metal oxides (hydroxide)/RGO composites on NF as energy storage materials.

  15. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

    PubMed

    Berridge, K C; Robinson, T E

    1998-12-01

    What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is 'no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the 'taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary

  16. Complexity of dopamine metabolism

    PubMed Central

    2013-01-01

    Parkinson’s disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability. In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD. PMID:23683503

  17. Enzymatic synthesis, structural characterization and antioxidant capacity assessment of a new lipophilic malvidin-3-glucoside-oleic acid conjugate.

    PubMed

    Cruz, Luis; Fernandes, Iva; Guimarães, Marta; de Freitas, Victor; Mateus, Nuno

    2016-06-15

    The chemical modification of anthocyanins (water-soluble pigments) into more lipophilic compounds is very important to expand their application in the food, medical and cosmetic industries. In this work, the synthesis of a pure malvidin-3-glucoside-oleic acid ester derivative was achieved by enzymatic catalysis. This approach allowed us to synthesize a novel compound, malvidin-3-O-(6''-oleoyl)glucoside (Mv3glc-OA), which was structurally characterized by mass spectrometry and for the first time by NMR spectroscopy. The enzymatic reaction revealed to be regioselective giving only one ester product. Antioxidant features of the malvidin-3-glucoside lipophilic derivative by means of DPPH, FRAP and lipid peroxidation assays were assessed, which confirmed that the structural modification of the genuine malvidin-3-glucoside into a more lipophilic compound did not compromise its antioxidant potential and protected more effectively a lipidic substrate from oxidation, which is an important insight for future technological applications. PMID:27220831

  18. Synthesis of bilayer MoS{sub 2} nanosheets by a facile hydrothermal method and their methyl orange adsorption capacity

    SciTech Connect

    Ye, Lijuan; Xu, Haiyan; Zhang, Dingke; Chen, Shijian

    2014-07-01

    Highlights: • Hexagonal phase of MoS{sub 2} nanosheets was synthesized by a facile hydrothermal method. • FE-SEM and TEM images show the sheets-like morphology of MoS{sub 2}. • Bilayer MoS{sub 2} can be grown under the optimized mole ratio of 2:1 of S:Mo at 180 °C for 50 h. • The MoS{sub 2} nanosheets possess high methyl orange adsorption capacity due to the large surface area. - Abstract: Molybdenum disulfide (MoS{sub 2}) nanosheets have received significant attention recently due to the potential applications for exciting physics and technology. Here we show that MoS{sub 2} nanosheets can be prepared by a facile hydrothermal method. The study of the properties of the MoS{sub 2} nanosheets prepared at different conditions suggests that the mole ratio of precursors and hydrothermal time significantly influences the purity, crystalline quality and thermal stability of MoS{sub 2}. X-ray diffraction, Raman spectra and transmission electron microscopy results indicate that bilayer MoS{sub 2} can be grown under an optimized mole ratio of 2:1 of S:Mo at 180 °C for 50 h. Moreover, such ultrathin nanosheets exhibit a prominent photoluminescence and possess high methyl orange adsorption capacity due to the large surface area, which can be potentially used in photodevice and photochemical catalyst.

  19. Theory and practice: bulk synthesis of C3B and its H2- and Li-storage capacity.

    PubMed

    King, Timothy C; Matthews, Peter D; Glass, Hugh; Cormack, Jonathan A; Holgado, Juan Pedro; Leskes, Michal; Griffin, John M; Scherman, Oren A; Barker, Paul D; Grey, Clare P; Dutton, Siân E; Lambert, Richard M; Tustin, Gary; Alavi, Ali; Wright, Dominic S

    2015-05-11

    Previous theoretical studies of C3B have suggested that boron-doped graphite is a promising H2- and Li-storage material, with large maximum capacities. These characteristics could lead to exciting applications as a lightweight H2-storage material for automotive engines and as an anode in a new generation of batteries. However, for these applications to be realized a synthetic route to bulk C3B must be developed. Here we show the thermolysis of a single-source precursor (1,3-(BBr2)2C6H4) to produce graphitic C3B, thus allowing the characteristics of this elusive material to be tested for the first time. C3B was found to be compositionally uniform but turbostratically disordered. Contrary to theoretical expectations, the H2- and Li-storage capacities are lower than anticipated, results that can partially be explained by the disordered nature of the material. This work suggests that to model the properties of graphitic materials more realistically, the possibility of disorder must be considered. PMID:25810151

  20. p58IPK is an inhibitor of the eIF2α kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity.

    PubMed

    Roobol, Anne; Roobol, Jo; Bastide, Amandine; Knight, John R P; Willis, Anne E; Smales, C Mark

    2015-01-15

    One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2α (eukaryotic translation initiation factor 2α). This is mediated by four eIF2α kinases and it has been suggested that each kinase is specific to the cellular stress imposed. In the present study, we show that both PERK (PKR-like endoplasmic reticulum kinase/eIF2α kinase 3) and GCN2 (general control non-derepressible 2/eIF2α kinase 4) are required for the stress responses associated with conditions encountered by cells overexpressing secreted recombinant protein. Importantly, whereas GCN2 is the kinase that is activated following cold-shock/hypothermic culturing of mammalian cells, PERK and GCN2 have overlapping functions since knockdown of one of these at the mRNA level is compensated for by the cell by up-regulating levels of the other. The protein p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2α kinases PKR (dsRNA-dependent protein kinase/eIF2α kinase 2) and PERK and hence prevent or delay eIF2α phosphorylation and consequent inhibition of translation. However, we show that p58IPK is a general inhibitor of the eIF2α kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2α phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis under endoplasmic reticulum (ER), hypothermic and prolonged culture stress conditions. Taken together, our data suggest that there is considerable cross talk between the eIF2α kinases to ensure that protein synthesis is tightly regulated. Their activation is controlled by p58 and the expression levels and localization of this protein are crucial in the capacity the cells to respond to cellular stress via control of protein synthesis rates and subsequent folding in the ER. PMID:25329545

  1. A scalable graphene sulfur composite synthesis for rechargeable lithium batteries with good capacity and excellent columbic efficiency.

    PubMed

    Gao, Xianfeng; Li, Jianyang; Guan, Dongsheng; Yuan, Chris

    2014-03-26

    Sulfur nanoparticles wrapped with a conductive graphene framework was synthesized with a high sulfur loading through a scalable one-step process. The graphene-coated sulfur nanostructured composite, when used as cathode for lithium sulfur battery, shows a reversible capacity of 808 mAh g(-1) at a rate of 210 mA g(-1) and an average columbic efficiency of ∼98.3% over 100 cycles. It is found that graphene oxide (GO) with a porous structure offers flexible confinement function that helps prevent the loss of active materials, thus extending the cycling life of the electrode. Moreover, reduced graphene oxide provides a conductive network surrounding the sulfur particles, which facilitates both electron transport and ion transportation. This novel one-step, all-solution-based process is scalable and provides a promising approach for potential industrial applications. PMID:24555988

  2. Radiolabeled2{beta}-carbo-2{prime}(S)-fluoroisopropoxy-3{beta}-(4-iodophenyl)-tropane (FIPIT): Synthesis, characterization and primate imaging of a radioligand for mapping dopamine transporter sites by both PET and SPECT

    SciTech Connect

    Keil, R.; Shi, B.; Hoffman, J.M.

    1996-05-01

    Highly potent and selective dopamine transporter ligands containing both iodine and fluorine are versatile probes for in vivo mapping of dopamine transporter sites in the striatum by PET and SPECT when labeled with fluorine-18 and iodine-123, respectively. Dual labeled biochemical probes are attractive agents since only one set of toxicity and pharmacokinetic analysis may be required for ligand validation for both imaging modalities. Recently, we reported that replacement of the methyl ester of 2{beta}-carbomethoxy-3{beta}-(4-chlorophenyl)tropane with a 2{prime}(R,S)-[F-18]fluoroisopropyl ester affords a highly potent and selective dopamine transporter ligand, 2{beta}-carbo-2{prime}(R,S)- fluoroisopropoxy-3{beta}-(4-chlorophenyl)tropane (FIPCT). FIPCT showed high uptake and retention in the striatum (S) resulting in good S/cerebellum = 3.5 at 125 min post injection in a rhesus monkey. These findings prompted us to synthesize and evaluate the 4-iodo analog, 2{beta}-carbo-2{prime}-(S)-fluoroisopropoxy-3{beta}-(4-iodophenyl)tropane (1) with 1-fluoropropan-2-ol (2) and POC13. These results suggest that [F-18]S-FIPIT is an excellent candidate for mapping of dopamine transporter sites.

  3. Dopamine, Working Memory, and Training Induced Plasticity: Implications for Developmental Research

    ERIC Educational Resources Information Center

    Soderqvist, Stina; Bergman Nutley, Sissela; Peyrard-Janvid, Myriam; Matsson, Hans; Humphreys, Keith; Kere, Juha; Klingberg, Torkel

    2012-01-01

    Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also…

  4. Neuropharmacology of dopamine receptors:

    PubMed Central

    Tarazi, Frank I.

    2001-01-01

    There has been an extraordinary recent accumulation of information concerning the neurobiology and neuropharmacology of dopamine (DA) receptors in the mammalian central nervous system. Many new DA molecular entities have been cloned, their gene, peptide sequences and structures have been identified, their anatomical distributions in the mammalian brain described, and their pharmacology characterized. Progress has been made toward developing selective ligands and drug-candidates for different DA receptors. The new discoveries have greatly stimulated preclinical and clinical studies to explore the neuropharmacology of DA receptors and their implications in the neuropathophysiology of different neuropsychiatric diseases including schizophrenia, Parkinson’s disease and attention-deficit hyperactivity disorder. Accordingly, it seems timely to review the salient aspects of this specialized area of preclinical neuropharmacology and its relevance to clinical neuropsychiatry. PMID:24019715

  5. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

    PubMed

    Kim, D S; Szczypka, M S; Palmiter, R D

    2000-06-15

    Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons. PMID:10844009

  6. Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux

    PubMed Central

    da Luz, Marcio H. M.; Peres, Italo T.; Santos, Tiago G.; Martins, Vilma R.; Icimoto, Marcelo Y.; Lee, Kil S.

    2015-01-01

    Accumulation of protein aggregates is a histopathological hallmark of several neurodegenerative diseases, but in most cases the aggregation occurs without defined mutations or clinical histories, suggesting that certain endogenous metabolites can promote aggregation of specific proteins. One example that supports this hypothesis is dopamine and its metabolites. Dopamine metabolism generates several oxidative metabolites that induce aggregation of α-synuclein, and represents the main etiology of Parkinson's diseases. Because dopamine and its metabolites are unstable and can be highly reactive, we investigated whether these molecules can also affect other proteins that are prone to aggregate, such as cellular prion protein (PrPC). In this study, we showed that dopamine treatment of neuronal cells reduced the number of viable cells and increased the production of reactive oxygen species (ROS) as demonstrated in previous studies. Overall PrPC expression level was not altered by dopamine treatment, but its unglycosylated form was consistently reduced at 100 μM of dopamine. At the same concentration, the level of phosphorylated mTOR and 4EBP1 was also reduced. Moreover, dopamine treatment decreased the solubility of PrPC, and increased its accumulation in autophagosomal compartments with concomitant induction of LC3-II and p62/SQSTM1 levels. In vitro oxidation of dopamine promoted formation of high-order oligomers of recombinant prion protein. These results suggest that dopamine metabolites alter the conformation of PrPC, which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrPC aggregates is an important feature of prion diseases. Thus, this study brings new insight into the dopamine metabolism as a source of endogenous metabolites capable of altering PrPC solubility and its subcellular localization. PMID:25698927

  7. Dopamine- and Tyrosine Hydroxylase-Immunoreactive Neurons in the Brain of the American Cockroach, Periplaneta americana

    PubMed Central

    Hamanaka, Yoshitaka; Minoura, Run; Nishino, Hiroshi; Miura, Toru; Mizunami, Makoto

    2016-01-01

    The catecholamine dopamine plays several vital roles in the central nervous system of many species, but its neural mechanisms remain elusive. Detailed neuroanatomical characterization of dopamine neurons is a prerequisite for elucidating dopamine’s actions in the brain. In the present study, we investigated the distribution of dopaminergic neurons in the brain of the American cockroach, Periplaneta americana, using two antisera: 1) an antiserum against dopamine, and 2) an antiserum against tyrosine hydroxylase (TH, an enzyme required for dopamine synthesis), and identified about 250 putatively dopaminergic neurons. The patterns of dopamine- and TH-immunoreactive neurons were strikingly similar, suggesting that both antisera recognize the same sets of “dopaminergic” neurons. The dopamine and TH antibodies intensively or moderately immunolabeled prominent brain neuropils, e.g. the mushroom body (memory center), antennal lobe (first-order olfactory center) and central complex (motor coordination center). All subdivisions of the mushroom body exhibit both dopamine and TH immunoreactivity. Comparison of immunolabeled neurons with those filled by dye injection revealed that a group of immunolabeled neurons with cell bodies near the calyx projects into a distal region of the vertical lobe, which is a plausible site for olfactory memory formation in insects. In the antennal lobe, ordinary glomeruli as well as macroglomeruli exhibit both dopamine and TH immunoreactivity. It is noteworthy that the dopamine antiserum labeled tiny granular structures inside the glomeruli whereas the TH antiserum labeled processes in the marginal regions of the glomeruli, suggesting a different origin. In the central complex, all subdivisions excluding part of the noduli and protocerebral bridge exhibit both dopamine and TH immunoreactivity. These anatomical findings will accelerate our understanding of dopaminergic systems, specifically in neural circuits underlying aversive memory

  8. Low Temperature Vacuum Synthesis of Triangular CoO Nanocrystal/Graphene Nanosheets Composites with Enhanced Lithium Storage Capacity

    PubMed Central

    Guan, Qun; Cheng, Jianli; Li, Xiaodong; Wang, Bin; Huang, Ling; Nie, Fude; Ni, Wei

    2015-01-01

    CoO nanocrystal/graphene nanosheets (GNS) composites, consisting of a triangular CoO nanocrystal of 2~20 nm on the surface of GNS, are synthesized by a mild synthetic method. First, cobalt acetate tetrahydrate is recrystallized in the alcohol solution at a low temperature. Then, graphene oxide mixed with cobalt-precursor followed by high vacuum annealing to form the CoO nanocrystal/GNS composites. The CoO nanocrystal/GNS composites exhibit a high reversible capacity of 1481.9 m Ah g−1 after 30 cycles with a high Coulombic efficiency of over 96% when used as anode materials for lithium ion battery. The excellent electrochemical performances may be attributed to the special structure of the composites. The well-dispersed triangular CoO nanocrystal on the substrate of conductive graphene can not only have a shorter diffusion length for lithium ions, better stress accommodation capability during the charge-discharge processes and more accessible active sites for lithium-ion storage and electrolyte wetting, but also possess a good conductive network, which can significantly improve the whole electrochemical performance. PMID:25961670

  9. Low Temperature Vacuum Synthesis of Triangular CoO Nanocrystal/Graphene Nanosheets Composites with Enhanced Lithium Storage Capacity

    NASA Astrophysics Data System (ADS)

    Guan, Qun; Cheng, Jianli; Li, Xiaodong; Wang, Bin; Huang, Ling; Nie, Fude; Ni, Wei

    2015-05-01

    CoO nanocrystal/graphene nanosheets (GNS) composites, consisting of a triangular CoO nanocrystal of 2~20 nm on the surface of GNS, are synthesized by a mild synthetic method. First, cobalt acetate tetrahydrate is recrystallized in the alcohol solution at a low temperature. Then, graphene oxide mixed with cobalt-precursor followed by high vacuum annealing to form the CoO nanocrystal/GNS composites. The CoO nanocrystal/GNS composites exhibit a high reversible capacity of 1481.9 m Ah g-1 after 30 cycles with a high Coulombic efficiency of over 96% when used as anode materials for lithium ion battery. The excellent electrochemical performances may be attributed to the special structure of the composites. The well-dispersed triangular CoO nanocrystal on the substrate of conductive graphene can not only have a shorter diffusion length for lithium ions, better stress accommodation capability during the charge-discharge processes and more accessible active sites for lithium-ion storage and electrolyte wetting, but also possess a good conductive network, which can significantly improve the whole electrochemical performance.

  10. Dopamine reward prediction error coding

    PubMed Central

    Schultz, Wolfram

    2016-01-01

    Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

  11. Ca-rich Ca-Al-oxide, high-temperature-stable sorbents prepared from hydrotalcite precursors: synthesis, characterization, and CO2 capture capacity.

    PubMed

    Chang, Po-Hsueh; Chang, Yen-Po; Chen, San-Yuan; Yu, Ching-Tsung; Chyou, Yau-Pin

    2011-12-16

    We present the design and synthesis of Ca-rich Ca-Al-O oxides, with Ca(2+)/Al(3+) ratios of 1:1, 3:1, 5:1, and 7:1, which were prepared by hydrothermal decomposition of coprecipitated hydrotalcite-like Ca-Al-CO(3) precursors, for high-temperature CO(2) adsorption at 500-700 °C. In situ X-ray diffraction measurements indicate that the coprecipitated, Ca-rich, hydrotalcite-like powders with Ca(2+)/Al(3+) ratios of 5:1 and 7:1 contained Ca(OH)(2) and layered double hydroxide (LDH) phases. Upon annealing, LDH was first destroyed at approximately 200 °C to form an amorphous matrix, and then at 450-550 °C, the Ca(OH)(2) phase was converted into a CaO matrix with incorporated Al(3+) to form a homogeneous solid solution without a disrupted lattice structure. CaO nanocrystals were grown by thermal treatment of the weakly crystalline Ca-Al-O oxide matrix. Thermogravimetric analysis indicates that a CO(2) adsorption capacity of approximately 51 wt. % can be obtained from Ca-rich Ca-Al-O oxides prepared by calcination of 7:1 Ca-Al-CO(3) LDH phases at 600-700 °C. Furthermore, a relatively high CO(2) capture capability can be achieved, even with gas flows containing very low CO(2) concentrations (CO(2)/N(2) = 10 %). Approximately 95.6 % of the initial CO(2) adsorption capacity of the adsorbent is retained after 30 cycles of carbonation-calcination. TEM analysis indicates that carbonation-promoted CaCO(3) formation in the Ca-Al-O oxide matrix at 600 °C, but a subsequent desorption in N(2) at 700 °C, caused the formation CaO nanocrystals of approximately 10 nm. The CaO nanocrystals are widely distributed in the weakly crystalline Ca-Al-O oxide matrix and are present during the carbonation-calcination cycles. This demonstrates that Ca-Al-O sorbents that developed through the synthesis and calcination of Ca-rich Ca-Al LDH phases are suitable for long-term cyclic operation in severe temperature environments. PMID:22072595

  12. Synthesis on accumulation of putative neurotransmitters by cultured neural crest cells

    SciTech Connect

    Maxwell, G.D.; Sietz, P.D.; Rafford, C.E.

    1982-07-01

    The events mediating the differentiation of embryonic neural crest cells into several types of neurons are incompletely understood. In order to probe one aspect of this differentiation, we have examined the capacity of cultured quail trunk neural crest cells to synthesize, from radioactive precursors, and store several putative neurotransmitter compounds. These neural crest cultures develop the capacity to synthesize and accumulate acetylcholine and the catecholamines norepinephrine and dopamine. In contrast, detectable but relatively little synthesis and accumulation of 5-hydroxytryptamine gamma-aminobutyric acid, or octopamine from the appropriate radiolabeled precursors were observed. The capacity for synthesis and accumulation of radiolabeled acetylcholine and catecholamines is very low or absent at 2 days in vitro. Between 3 and 7 days in vitro, there is a marked rise in both catecholamine and acetylcholine accumulation in the cultures. These findings suggest that, under the particular conditions used in these experiments, the development of neurotransmitter biosynthesis in trunk neural crest cells ijs restricted and resembles, at least partially, the pattern observed in vivo. The development of this capacity to synthesize and store radiolabeled acetylcholine and catecholamines from the appropriate radioactive precursors coincides closely with the development of the activities of the synthetic enzymes choline acetyltransferase and dopamine beta-hydroxylase reported by others.

  13. Indicators for tracking programmes to strengthen health research capacity in lower- and middle-income countries: a qualitative synthesis

    PubMed Central

    2014-01-01

    Background The monitoring and evaluation of health research capacity strengthening (health RCS) commonly involves documenting activities and outputs using indicators or metrics. We sought to catalogue the types of indicators being used to evaluate health RCS and to assess potential gaps in quality and coverage. Methods We purposively selected twelve evaluations to maximize diversity in health RCS, funders, countries, and approaches to evaluation. We explored the quality of the indicators and extracted them into a matrix across individual, institutional, and national/regional/network levels, based on a matrix in the ESSENCE Planning, Monitoring and Evaluation framework. We synthesized across potential impact pathways (activities to outputs to outcomes) and iteratively checked our findings with key health RCS evaluation stakeholders. Results Evaluations varied remarkably in the strengths of their evaluation designs. The validity of indicators and potential biases were documented in a minority of reports. Indicators were primarily of activities, outputs, or outcomes, with little on their inter-relationships. Individual level indicators tended to be more quantitative, comparable, and attentive to equity considerations. Institutional and national–international level indicators were extremely diverse. Although linkage of activities through outputs to outcomes within evaluations was limited, across the evaluations we were able to construct potential pathways of change and assemble corresponding indicators. Conclusions Opportunities for improving health RCS evaluations include work on indicator measurement properties and development of indicators which better encompass relationships with knowledge users. Greater attention to evaluation design, prospective indicator measurement, and systematic linkage of indicators in keeping with theories of change could provide more robust evidence on outcomes of health RCS. PMID:24725961

  14. Mesolimbic dopamine signals the value of work.

    PubMed

    Hamid, Arif A; Pettibone, Jeffrey R; Mabrouk, Omar S; Hetrick, Vaughn L; Schmidt, Robert; Vander Weele, Caitlin M; Kennedy, Robert T; Aragona, Brandon J; Berke, Joshua D

    2016-01-01

    Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (phasic) dopamine fluctuations support learning, whereas much slower (tonic) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We found that minute-by-minute dopamine levels covaried with reward rate and motivational vigor. Second-by-second dopamine release encoded an estimate of temporally discounted future reward (a value function). Changing dopamine immediately altered willingness to work and reinforced preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly evolving decision variable, the available reward for investment of effort, which is employed for both learning and motivational functions. PMID:26595651

  15. Cocaine induction of dopamine transporter trafficking to the plasma membrane.

    PubMed

    Little, Karley Y; Elmer, Lawrence W; Zhong, Huailing; Scheys, Joshua O; Zhang, Lian

    2002-02-01

    Several previous human postmortem experiments have detected an increase in striatal [(3)H]WIN 35428 binding to the dopamine transporter (DAT) in chronic cocaine users. However, animal experiments have found considerable variability in DAT radioligand binding levels in brain after cocaine administration, perhaps caused by length and dose of treatment and type of radioligand used. The present experiments tested the hypothesis that [(3)H]WIN 35428 binding and [(3)H]dopamine uptake would be increased by exposure to cocaine through alterations in DAT cellular trafficking, rather than increased protein synthesis. Experiments were conducted in stably hDAT-transfected N2A cells and assessed the dose response and time course of cocaine effects on [(3)H]WIN 35428 binding to the DAT, [(3)H]dopamine uptake, measures of DAT protein and mRNA, as well as DAT subcellular location. Cocaine doses of 10(-6) M caused statistically significant increases in [(3)H]WIN 35428 binding and [(3)H]dopamine uptake after 12 and 3 h, respectively. Despite these increases in DAT function, there was no change in DAT total protein or mRNA. Immunofluorescence and biotinylation experiments indicated that cocaine treatment induced increases in plasma membrane DAT immunoreactivity and intracellular decreases. The present model system may further our understanding of regulatory alterations in DAT radioligand binding and function caused by cocaine exposure. PMID:11809869

  16. Renal dopamine excretion in healthy volunteers after oral ingestion of L-dopa.

    PubMed

    Barthelmebs, M; Mbou, P; Stephan, D; Grima, M; Imbs, J L

    1993-01-01

    L-Dopa is converted to dopamine by aromatic-L-amino acid decarboxylase (AADC). In the kidney, proximal tubular epithelial cells are rich in AADC and urinary free dopamine excretion is a marker for endorenal extraneuronal dopamine synthesis. The urinary free dopamine excretion was analysed in a double-blind cross-over study after oral ingestion of L-Dopa or a placebo in five healthy volunteers. The drug ingestions were separated by one week's wash-out. Since in a preliminary study, two volunteers ingesting a single L-Dopa dose of 500 mg with breakfast experienced nausea, the five volunteers of the present study were given 300 mg L-Dopa (50 mg at 9 am with breakfast, 100 mg before lunch and 150 mg before dinner) without any adverse effects. L-Dopa induced an increase in 24-h urinary dopamine excretion (HPLC with electrochemical detection). Free urinary dopamine (1900 micrograms/24 h) accounted for 0.8% of the daily oral L-Dopa dose and represented 10% of total urinary dopamine excretion. L-Dopa treatment had no significant effect on mean ambulatory arterial blood pressure and heart rate measured from 9 am to 6 pm (Spacelabs) or on 24 h urinary water and sodium excretion. PMID:8458598

  17. The role of counter ions in nano-hematite synthesis: Implications for surface area and selenium adsorption capacity.

    PubMed

    Lounsbury, Amanda W; Yamani, Jamila S; Johnston, Chad P; Larese-Casanova, Philip; Zimmerman, Julie B

    2016-06-01

    Nano metal oxides are of interest for aqueous selenium (Se) remediation, and as such, nano-hematite (nα-Fe2O3) was examined for use as a Se adsorbent. The effect of surface area on adsorption was also studied. nα-Fe2O3 particles were synthesized from Fe(NO3)3 and FeCl3 via forced hydrolysis. The resulting particles have similar sizes, morphologies, aggregate size, pore size, and PZC. The nα-Fe2O3 from FeCl3 (nα-Fe2O3-C) differs from the nα-Fe2O3 from Fe(NO3)3 (nα-Fe2O3-N) with a ∼25±2m(2)/g greater surface area. Selenite Se(IV) adsorption capacity on nα-Fe2O3 has a qmax ∼17mg/g for the freeze-dried and re-suspended nα-Fe2O3. The Δqmax for nα-Fe2O3 from Fe(NO3)3 and FeCl3 that remained in suspension was 4.6mg/g. For selenate Se(VI), the freeze-dried and re-suspended particles realize a Δqmax= 1.5mg/g for nα-Fe2O3 from Fe(NO3)3 and FeCl3. The nα-Fe2O3 from Fe(NO3)3 and FeCl3 that remained in suspension demonstrated Se(VI) Δqmax=5.4mg/g. In situ ATR-FTIR isotherm measurements completed for Se(VI) at a pH 6 suggest that Se(VI) forms primarily outer-sphere complexes with nα-Fe2O3 synthesized from both salts. PMID:26905609

  18. Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity

    PubMed Central

    2015-01-01

    Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands. PMID:25126833

  19. Depression of brain dopamine and its metabolite after mating in European honeybee (Apis mellifera) queens

    NASA Astrophysics Data System (ADS)

    Harano, Ken-Ichi; Sasaki, Ken; Nagao, Takashi

    2005-07-01

    To explore neuro-endocrinal changes in the brain of European honeybee (Apis mellifera) queens before and after mating, we measured the amount of several biogenic amines, including dopamine and its metabolite in the brain of 6- and 12-day-old virgins and 12-day-old mated queens. Twelve-day-old mated queens showed significantly lower amounts of dopamine and its metabolite (N-acetyldopamine) than both 6- and 12-day-old virgin queens, whereas significant differences in the amounts of these amines were not detected between 6- and 12-day-old virgin queens. These results are explained by down-regulation of both synthesis and secretion of brain dopamine after mating. It is speculated that higher amounts of brain dopamine in virgin queens might be involved in activation of ovarian follicles arrested in previtellogenic stages, as well as regulation of their characteristic behaviors.

  20. The capacity of interleukin-4 to induce in vitro IgE synthesis by B cells of patients with common variable immunodeficiency.

    PubMed Central

    Pastorelli, G; Roncarolo, M G; Peronne, C; Tovo, P A; de Vries, J E

    1990-01-01

    Interleukin-4 (IL-4) has been shown to induce IgE synthesis by peripheral blood mononuclear cells (PBMC) of normal donors in vitro. However, induction of PBMC of patients with common variable immunodeficiency (CVI) with IL-4 resulted in IgE production in only two out of eight cases tested. PBMC of the first patient that produced IgE in response to IL-4 also secreted normal levels of IL-4 upon activation. PBMC of the second patient secreted very low levels of IL-4 in vitro which may account for the very low serum IgE levels in this patient. Of the other six patients who had very low serum IgE levels and whose PBMC failed to produce IgE in response to IL-4 in vitro, five did not secrete IL-4 upon in vitro activation. The capacity of the T cells to produce IL-4 was intact in the sixth patient. Collectively our data indicate that PBMC of the majority of patients with CVI are defective since they failed to respond appropriately to IL-4 and they failed to produce IL-4, contributing to the view that CVI is a heterogeneous disorder in which a variety of T and B cell defects occur. PMID:2119918

  1. Increased lead and cadmium tolerance of Typha angustifolia from Huaihe River is associated with enhanced phytochelatin synthesis and improved antioxidative capacity.

    PubMed

    Liu, Yunlei; Chen, Jian; Lu, Shaonan; Yang, Libo; Qian, Jiazhong; Cao, Shuqing

    2016-11-01

    Heavy metal contamination of water is an increasing environmental problem worldwide, and the use of aquatic plants for phytoremediation of heavy metal pollution has become an important subject of research. One key to successful phytoremediation is the identification of plants that are efficient at sequestering heavy metals. In this study, we examined the growth and heavy metal accumulation of Typha angustifolia and compared growth characteristics and tolerance mechanisms in plants from the Huaihe and Chaohu Rivers irrigated with different concentrations of lead (Pb) and cadmium (Cd). T. angustifolia from Huaihe River showed enhanced tolerance and accumulation of Pb and Cd and had greater biomass and more vigorous growth than the ecotype from Chaohu River. In addition, higher phytochelatin (PC) content and significantly higher superoxide dismutase and catalase activities were detected in T. angustifolia from Huaihe River than in T. angustifolia from Chaohu River. These findings suggest that high Pb and Cd accumulation and tolerance in T. angustifolia from Chaohu River is associated with its higher PC synthesis and better antioxidative capacity, and that the Huaihe ecotype of T. angustifolia might also be an efficient species for phytoremediation of Pb and Cd in water contaminated by heavy metals. PMID:26959972

  2. Dopamine Receptors and Neurodegeneration

    PubMed Central

    Rangel-Barajas, Claudia; Coronel, Israel; Florán, Benjamín

    2015-01-01

    Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases. PMID:26425390

  3. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

    PubMed Central

    Hansen, Freja H.; Skjørringe, Tina; Yasmeen, Saiqa; Arends, Natascha V.; Sahai, Michelle A.; Erreger, Kevin; Andreassen, Thorvald F.; Holy, Marion; Hamilton, Peter J.; Neergheen, Viruna; Karlsborg, Merete; Newman, Amy H.; Pope, Simon; Heales, Simon J.R.; Friberg, Lars; Law, Ian; Pinborg, Lars H.; Sitte, Harald H.; Loland, Claus; Shi, Lei; Weinstein, Harel; Galli, Aurelio; Hjermind, Lena E.; Møller, Lisbeth B.; Gether, Ulrik

    2014-01-01

    Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies. PMID:24911152

  4. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats.

    PubMed

    McDougall, Sanders A; Mohd-Yusof, Alena; Kaplan, Graham J; Abdulla, Zuhair I; Lee, Ryan J; Crawford, Cynthia A

    2013-04-15

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  5. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

    PubMed Central

    McDougall, Sanders A.; Mohd-Yusof, Alena; Kaplan, Graham J.; Abdulla, Zuhair I.; Lee, Ryan J.; Crawford, Cynthia A.

    2013-01-01

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  6. Dopamine Modulates Insulin Release and Is Involved in the Survival of Rat Pancreatic Beta Cells

    PubMed Central

    Iglesias Osma, Maria Carmen; Blanco, Enrique J.; Carretero Hernández, Marta; Sánchez Robledo, Virginia; Catalano Iniesta, Leonardo; Carrero, Sixto

    2015-01-01

    The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen), and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01), by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01) after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01) following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets. PMID:25886074

  7. Dopamine regulates body size in Caenorhabditis elegans.

    PubMed

    Nagashima, Takashi; Oami, Eitaro; Kutsuna, Natsumaro; Ishiura, Shoichi; Suo, Satoshi

    2016-04-01

    The nervous system plays a critical role in the regulation of animal body sizes. In Caenorhabditis elegans, an amine neurotransmitter, dopamine, is required for the tactile perception of food and food-dependent behavioral changes, while its role in development is unknown. In this study, we show that dopamine negatively regulates body size through a D2-like dopamine receptor, DOP-3, in C. elegans. Dopamine alters body size without affecting food intake or developmental rate. We also found that dopamine promotes egg-laying, although the regulation of body size by dopamine was not solely caused by this effect. Furthermore, dopamine negatively regulates body size through the suppression of signaling by octopamine and Gq-coupled octopamine receptors, SER-3 and SER-6. Our results demonstrate that dopamine and octopamine regulate the body size of C. elegans and suggest a potential role for perception in addition to ingestion of food for growth. PMID:26921458

  8. Dopamine, reward learning, and active inference

    PubMed Central

    FitzGerald, Thomas H. B.; Dolan, Raymond J.; Friston, Karl

    2015-01-01

    Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings. PMID:26581305

  9. An updated view on the role of dopamine in myopia.

    PubMed

    Feldkaemper, Marita; Schaeffel, Frank

    2013-09-01

    retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies. PMID:23434455

  10. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  11. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU)

    PubMed Central

    Harding, Cary O.; Winn, Shelley R.; Gibson, K. Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-01-01

    Summary Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  12. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    PubMed

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  13. Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia.

    PubMed

    Jarraya, Béchir; Boulet, Sabrina; Ralph, G Scott; Jan, Caroline; Bonvento, Gilles; Azzouz, Mimoun; Miskin, James E; Shin, Masahiro; Delzescaux, Thierry; Drouot, Xavier; Hérard, Anne-Sophie; Day, Denise M; Brouillet, Emmanuel; Kingsman, Susan M; Hantraye, Philippe; Mitrophanous, Kyriacos A; Mazarakis, Nicholas D; Palfi, Stéphane

    2009-10-14

    In Parkinson's disease, degeneration of specific neurons in the midbrain can cause severe motor deficits, including tremors and the inability to initiate movement. The standard treatment is administration of pharmacological agents that transiently increase concentrations of brain dopamine and thereby discontinuously modulate neuronal activity in the striatum, the primary target of dopaminergic neurons. The resulting intermittent dopamine alleviates parkinsonian symptoms but is also thought to cause abnormal involuntary movements, called dyskinesias. To investigate gene therapy for Parkinson's disease, we simulated the disease in macaque monkeys by treating them with the complex I mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces selective degeneration of dopamine-producing neurons. In this model, we demonstrated that injection of a tricistronic lentiviral vector encoding the critical genes for dopamine synthesis (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and guanosine 5'-triphosphate cyclohydrolase 1) into the striatum safely restored extracellular concentrations of dopamine and corrected the motor deficits for 12 months without associated dyskinesias. Gene therapy-mediated dopamine replacement may be able to correct Parkinsonism in patients without the complications of dyskinesias. PMID:20368163

  14. DOPAMINE DEPLETION SLOWS RETINAL TRANSMISSION

    EPA Science Inventory

    In male hooded rats, depletion of norepinephrine and dopamine by a-methyl-paratyrosine (AMT) significantly increased the latencies of early peaks in flash-evoked potentials recorded from the visual cortex, lateral geniculate nucleus, and optic tract. These effects were not produc...

  15. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

    PubMed

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-10-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  16. Rapid determination of dopamine in human plasma using a gold nanoparticle-based dual-mode sensing system.

    PubMed

    Zhang, Yali; Qi, Suijian; Liu, Zhonggang; Shi, Yupeng; Yue, Wanqing; Yi, Changqing

    2016-04-01

    Dopamine plays a very important role in biological systems and has a direct relationship with the ability of learning and cognition, human desires, feelings and mental state, as well as motor functions. Traditional methods for the detection of dopamine are complicated and time-consuming, therefore it is necessary to explore rapid and accurate detection of dopamine with high sensitivity and specificity. Herein we report a dual-mode system of colorimetric and fluorometric analyses based on gold nanoparticles (AuNPs) and aptamers specifically targeting dopamine. Aptamers modified with the fluorophore were used as dopamine specific recognition probe and the sensing mechanism is based on the color change of AuNPs and the fluorescence recovery of fluorophore conjugated on the aptamers in the presence of dopamine. The addition of aptamers into AuNPs colloid solution would prevent the AuNPs from aggregation in the high-salt solution. The close distance between AuNPs and fluorophore conjugated on the aptamers would lead to the quenching of fluorescence signal. In the presence of dopamine, the conformation of the aptamers and the inter-particle distance would be changed, leading to the aggregation of AuNPs, which subsequently results in color change from red to blue and fluorescence signal recovery. The dual-mode sensing system demonstrated high specificity towards dopamine with the detection limit as low as 78.7 nM. The sensing system reflects on its simplicity as no surface functionalization is required for the nanoparticles, leading to less laborious and more cost-effective synthesis. The reaction time is only 6 min, demonstrating a simple approach for rapid analysis of dopamine. More importantly, the sensing system allows the detection of dopamine in both aqueous solution and complicated biological sample with sensitive response, illustrating the feasibility and reliability for the potential applications in clinical and biomedical analysis in the future. PMID:26838842

  17. [Effect of aluminum on the non-enzymatic oxidation of dopamine].

    PubMed

    Marinho, C R; Manso, C F

    1994-11-01

    The effect of different concentrations of aluminum sulphate on the nonenzymatic oxidation of dopamine was studied in order to evaluate the action of this metal on neuromelanin synthesis. Data shows that under the studied conditions, aluminum partially inhibits dopamine self-oxidation, decreasing the formation of some intermediate compounds, namely dopaminequinone and dopaminochrome. If neuromelanins have a cytoprotective function in the central nervous system, possibly acting as intracellular scavengers of free radicals and redox metal ions, their decrease due to aluminum could be responsible for serious damage to neuronal tissues. PMID:7717100

  18. Increased brain dopamine and dopamine receptors in schizophrenia

    SciTech Connect

    Mackay, A.V.; Iversen, L.L.; Rossor, M.; Spokes, E.; Bird, E.; Arregui, A.; Creese, I.; Synder, S.H.

    1982-09-01

    In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients.

  19. Dopamine-dependent periadolescent maturation of corticostriatal functional connectivity in mouse

    PubMed Central

    Galiñanes, Gregorio L.; Taravini, Irene R.E.; Murer, M. Gustavo

    2009-01-01

    Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined pre- and post-adolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase-locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals irrespective of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional

  20. Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling

    PubMed Central

    Chuhma, Nao; Mingote, Susana; Moore, Holly; Rayport, Stephen

    2014-01-01

    Summary Midbrain dopamine neurons fire in bursts conveying salient information. Bursts are associated with pauses in tonic firing of striatal cholinergic interneurons. While the reciprocal balance of dopamine and acetylcholine in the striatum is well known, how dopamine neurons control cholinergic neurons has not been elucidated. Here we show that dopamine neurons make direct fast dopaminergic and glutamatergic connections with cholinergic interneurons, with regional heterogeneity. Dopamine neurons drive a burst-pause firing sequence in cholinergic interneurons in the medial shell of the nucleus accumbens, mixed actions in the accumbens core, and a pause in the dorsal striatum. This heterogeneity is due mainly to regional variation in dopamine-neuron glutamate cotransmission. A single dose of amphetamine attenuates dopamine neuron connections to cholinergic interneurons with dose-dependent regional specificity. Overall, the present data indicate that dopamine neurons control striatal circuit function via discrete, plastic connections with cholinergic interneurons. PMID:24559678

  1. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    PubMed Central

    España, Rodrigo A.; Jones, Sara R.

    2013-01-01

    The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

  2. Mesolimbic Dopamine Signals the Value of Work

    PubMed Central

    Hamid, Arif A.; Pettibone, Jeffrey R.; Mabrouk, Omar S.; Hetrick, Vaughn L.; Schmidt, Robert; Vander Weele, Caitlin M.; Kennedy, Robert T.; Aragona, Brandon J.; Berke, Joshua D.

    2015-01-01

    Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions. PMID:26595651

  3. Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology.

    PubMed

    Strömberg, Ingrid; Bickford, Paula; Gerhardt, Greg A

    2010-02-01

    Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease. PMID:19853009

  4. Imaging dopamine transmission parameters in cannabis dependence.

    PubMed

    Ghazzaoui, Rassil; Abi-Dargham, Anissa

    2014-07-01

    Low striatal dopamine D2/3 receptor (D2/3) availability and low ventrostriatal dopamine release have been observed in alcoholism, cocaine and heroin dependence. Multiple studies to date have examined D2 availability in cannabis dependence and have consistently failed to demonstrate alterations. In addition, the response of the dopamine system to an amphetamine challenge and to a stress challenge has also been examined, and did not show alterations. We review these studies here and conclude that cannabis dependence is an exception among commonly abused drugs in that it is not associated with blunting of the dopamine system. PMID:24513022

  5. Dopamine receptors – IUPHAR Review 13

    PubMed Central

    Beaulieu, Jean-Martin; Espinoza, Stefano; Gainetdinov, Raul R

    2015-01-01

    The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors. PMID:25671228

  6. Metabolism of /sup 3/H-dopamine by human chorioamnion in vitro

    SciTech Connect

    Phillippe, M.; Niloff, J.M.

    1982-08-01

    Previous investigation has demonstrated biologically significant concentrations of catecholamines in amniotic fluid, which increase with gestation. The half life, metabolic clearance rate, and metabolic fate of these hormones in the amniotic compartment are yet to be established. This study was undertaken to demonstrate the ability of human chorioamnion to metabolize dopamine in vitro. Incubation experiments demonstrated that /sup 3/H-dopamine is rapidly metabolized to dihydroxyphenylacetic acid, 3-methoxy, 4-hydroxyphenylacetic acid, and 3-methoxy, 4-hydroxyphenylethanol-all products of monoamine oxidase. No significant 3-methoxytyramine, a catechol-o-methyltransferase product, was observed. Incubation experiments with pargyline, a monoamine oxidase inhibitor, resulted in significant reduction in /sup 3/H-dopamine metabolism. Catecholamines and their interaction with prostaglandin synthesis have been theorized to be a fetal signal for the initiation of parturition. The ability of chorioamnion to metabolize catecholamine could, therefore, provide another control mechanism by which fetal catecholamines are modulated.

  7. Efficient N-Acyldopamine Synthesis.

    PubMed

    Matsumoto, Yotaro; Ito, Akihiro; Uesugi, Motonari; Kittaka, Atsushi

    2016-01-01

    N-Acyldopamines are endogenous analogs of capsaicin that exhibit cannabinoid-like activities and were identified from brain extracts. Among them, N-arachidonoyldopamine (AADA) and N-oleoyldopamine (ODA) were characterized as transient receptor potential vanilloid type V1 channel (TRPV1) ligands. Recently, it was shown that N-acyldopamines may possess diverse physiological roles in addition to their ligand activities. To study the multiple functions and action mechanisms of endogenous N-acyldopamines, a simple and efficient method of N-acyldopamine synthesis was investigated. The eighteen potentially endogenous N-acyldopamines and two deuterated ones, N-palmitoyl dopamine-d5 and N-stearoyl dopamine-d5, were efficiently synthesized without protective groups in CH2Cl2 under optimized conditions using propylphosphoric acid cyclic anhydride (PPACA) as a condensation agent. PMID:27373649

  8. Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

    PubMed Central

    Menezes, Jefferson; Alves, Niége; Borges, Sidnei; Roehrs, Rafael; de Carvalho Myskiw, Jociane; Furini, Cristiane Regina Guerino; Izquierdo, Ivan; Mello-Carpes, Pâmela B.

    2015-01-01

    Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors. PMID:25775606

  9. Synthesis and characterization of dopamine substitue tripodal trinuclear [(salen/salophen/salpropen)M] (Mdbnd Cr(III), Mn(III), Fe(III) ions) capped s-triazine complexes: Investigation of their thermal and magnetic properties

    NASA Astrophysics Data System (ADS)

    Uysal, Şaban; Koç, Ziya Erdem

    2016-04-01

    In this work, we aimed to synthesize and characterize a novel tridirectional ligand including three catechol groups and its novel tridirectional-trinuclear triazine core complexes. For this purpose, we used melamine (2,4,6-triamino-1,3,5-triazine) (MA) as starting material. 2,4,6-tris(4-carboxybenzimino)-1,3,5-triazine (II) was synthesized by the reaction of an equivalent melamine (I) and three equivalent 4-carboxybenzaldehyde. 4,4‧,4″-((1E,1‧E,1″E)-((1,3,5-triazine-2,4,6-triyl)tris(azanylylidene))tris(methanylylidene))tris(N-(3,4-dihydroxyphenethyl)benzamide) L (IV) was synthesized by the reaction of one equivalent (II) and three equivalent dopamine (3,4-dihydroxyphenethylamine) (DA) by using two different methods. (II, III, IV) and nine novel trinuclear Cr(III), Mn(III) and Fe(III) complexes of (IV) were characterized by means of elemental analyses, 1H NMR, FT-IR spectrometry, LC-MS (ESI+) and thermal analyses. The metal ratios of the prepared complexes were performed using Atomic Absorption Spectrophotometry (AAS). We also synthesized novel tridirectional-trinuclear systems and investigated their effects on magnetic behaviors of [salen, salophen, salpropen Cr(III)/Mn(III)/Fe(III)] capped complexes. The complexes were determined to be low-spin distorted octahedral Mn(III) and Fe(III), and distorted octahedral Cr(III) all bridged by catechol group.

  10. Oxytocin, Motivation and the Role of Dopamine

    PubMed Central

    Love, Tiffany M.

    2013-01-01

    The hypothalamic neuropeptide oxytocin has drawn the attention of scientists for more than a century. The understanding of the function of oxytocin has expanded dramatically over the years from a simple peptide adept at inducing uterine contractions and milk ejection to a complex neuromodulator with a capacity to shape human social behavior. Decades of research have outlined oxytocin’s ability to enhance intricate social activities ranging from pair bonding, sexual activity, affiliative preferences, and parental behaviors. The precise neural mechanisms underlying oxytocin’s influence on such behaviors have just begun to be understood. Research suggests that oxytocin interacts closely with the neural pathways responsible for processing motivationally relevant stimuli. In particular, oxytocin appears to impact dopaminergic activity within the mesocorticolimbic dopamine system, which is crucial not only for reward and motivated behavior but also for the expression of affiliative behaviors. Though most of the work performed in this area has been done using animal models, several neuroimaging studies suggest similar relationships may be observed in humans. In order to introduce this topic further, this paper will review the recent evidence that oxytocin may exert some of its social-behavioral effects through its impact on motivational networks. PMID:23850525

  11. Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric PET studies combined with microdialysis analysis.

    PubMed

    Tsukada, H; Harada, N; Nishiyama, S; Ohba, H; Sato, K; Fukumoto, D; Kakiuchi, T

    2000-08-01

    The effects of ketamine, a noncompetitive antagonist of NMDA receptors, on the striatal dopaminergic system were evaluated multiparametrically in the monkey brain using high-resolution positron emission tomography (PET) in combination with microdialysis. L-[beta-(11)C]DOPA, [(11)C]raclopride, and [(11)C]beta-CFT were used to evaluate dopamine synthesis rate, D(2) receptor binding, and transporter availability, respectively, in conscious and ketamine-anesthetized animals. Dopamine concentrations in the striatal extracellular fluid (ECF) were simultaneously measured by PET. Thirty minutes prior to PET scan, intravenous administration of ketamine was started by continuous infusion at a rate of 3 or 10 mg/kg/h. Ketamine infusion dose-dependently decreased [(11)C]raclopride binding, but induced no significant changes in dopamine concentration in the striatal ECF as measured by microdialysis at any dose used. In contrast, ketamine increased both dopamine synthesis and DAT availability as measured by L-[beta-(11)C]DOPA and [(11)C]beta-CFT, respectively, in a dose-dependent manner. These results suggest that the inhibition of glutamatergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability to the same extent, resulting in no apparent changes in ECF dopamine concentration as measured by microdialysis. It also suggests that the alteration of [(11)C]raclopride binding in vivo as measured by PET might not simply be modulated by the static synaptic concentration of dopamine. PMID:10881030

  12. Dopamine: burning the candle at both ends.

    PubMed

    Pearson, John M; Platt, Michael L

    2013-09-01

    Dopamine neurons are well known for signaling reward-prediction errors. In this issue, Matsumoto and Takada (2013) show that some dopamine neurons also signal salient events during progression through a visual search task requiring working memory and sustained attention. PMID:24011998

  13. Dopamine as a Novel Electrolyte Additive for High-Voltage Lithium-Ion Batteries.

    PubMed

    Lee, Hoogil; Han, Taeyeong; Cho, Kuk Young; Ryou, Myung-Hyun; Lee, Yong Min

    2016-08-24

    Dopamine, which can be electrochemically oxidized to polydopamine on cathode surface, was introduced as an electrolyte additive for high-voltage lithium-ion batteries (LIBs). The addition of 0.1 wt % dopamine to the electrolyte led to the formation of a polydopamine-containing layer on the cathode, thereby resulting in suppression of the oxidative decomposition of the electrolyte during high-voltage operation (up to 4.5 V) of a LiNi1/3Co1/3Mn1/3O2/artificial graphite cell. The addition of dopamine to the electrolyte improved the capacity retention of the cell from 136 to 147 mAh g(-1) after 100 cycles at a rate of 1 C and a cutoff voltage of 4.5 V, while the cycle performance and rate capability with a cutoff voltage of 4.3 V were comparable to those of the cell without dopamine. Further evidence of the positive impact of dopamine on high-voltage LIBs was the lower DC-IRs and AC impedances, as well as the retention of the cathode morphology even after operation at 4.5 V. PMID:27509406

  14. Inhibition of potassium-stimulated dopamine release by the nitric oxide generator isosorbide dinitrate.

    PubMed

    Sun, P; Kanthasamy, A; Yim, G K; Isom, G E

    1995-02-01

    In PC12 cells, isosorbide dinitrate (ISDN) and S-nitrosol-acetyl-penicillamine (SNAP), both nitric oxide (NO) generators, attenuated K+ (56 mM)-stimulated release of dopamine. The attenuation was not observed with isosorbide, an ISDN analog lacking NO generating capacity. In this model, A23187 (Ca2+ ionophore), Bay K8644 (Ca2+ slow channel agonist) and veratridine (Na+ channel agonist) stimulated dopamine release. Treatment with ISDN enhanced Bay K8644 and veratridine-evoked dopamine release, while ISDN had no significant effect on the A23187 response. Incubation with 8-bromo-cGMP (membrane permeable cGMP analog) had no effect on basal or stimulated dopamine release in these cells, suggesting NO's response was not mediated by cGMP. In additional studies, K+ (56 mM), Bay K8644 and veratridine elevated cytosolic free calcium levels ([Ca2+]i). ISDN reduced K(+)-stimulated increase in [Ca2+]i, but enhanced the increases of [Ca2+]i induced by Bay K8644 or veratridine. These results suggest NO interacts with K(+)-induced membrane depolarization (possibly by inhibiting membrane conductance to K+) to attenuate Ca2+ influx and Ca(2+)-mediated dopamine secretion stimulated by K+. PMID:7542370

  15. Novel Poly-Dopamine Adhesive for a Halloysite Nanotube-Ru(bpy)32+ Electrochemiluminescent Sensor

    PubMed Central

    Xing, Bo; Yin, Xue-Bo

    2009-01-01

    Herein, for the first time, the electrochemiluminescent sensor based on Ru(bpy)32+-modified electrode using dopamine as an adhesive was successfully developed. After halloysite nanotube slurry was cast on a glassy carbon electrode and dried, an alkaline dopamine solution was added on the electrode surface. Initially, polydopamine belts with dimensions of tens to hundreds of nanometers formed via oxidization of the dopamine by ambient oxygen. As the incubation time increased, the nanobelts became broader and then united with each other to form a polydopamine film. The halloysite nanotubes were embedded within the polydopamine film. The above electrode was soaked in Ru(bpy)32+ aqueous solution to adsorb Ru(bpy)32+ into the active sites of the halloysite nanotubes via cation-exchange procedure. Through this simple procedure, a Ru(bpy)32+-modified electrode was obtained using only 6.25 µg Ru(bpy)32+, 15.0 µg dopamine, and 9.0 µg halloysite nanotubes. The electrochemistry and electrochemiluminescence (ECL) of the modified electrode was investigated using tripropylamine (TPA) and nitrilotriacetic acid (NTA) as co-reactants. The different ECL behaviors of the modified electrode using NTA and TPA as well as the contact angle measurements reflected the hydrophilic character of the electrode. The results indicate that halloysite nanotubes have a high loading capacity for Ru(bpy)32+ and that dopamine is suitable for the preparation of modified electrodes. PMID:19649294

  16. Urinary dopamine in man and rat: effects of inorganic salts on dopamine excretion.

    PubMed

    Ball, S G; Oats, N S; Lee, M R

    1978-08-01

    1. Plasma and urine free dopamine (3,4-dihydroxyphenethylamine) were measured in six normal male volunteer subjects and the urinary clearance of dopamine was calculated for each subject. 2. The excretion rates for free dopamine in man were greater than could be explained by simple renal clearance. It was concluded that free dopamine must, therefore, be formed in the kidney. 3. Changes in urinary dopamine excretion were studied in four groups of rats initially maintained on low sodium diet and then given equimolar dietary supplements of NaCl, NaHCO3, KCl or NH4Cl, to study the specificity of the previously observed increase in dopamine excretion after increased dietary NaCl. 4. The mean dopamine excretion increased significantly in rats given NaCl, KCl and NH4Cl, whereas dopamine excretion decreased in those given NaHCO3. 5. The failure of dopamine excretion to rise in response to loading with NaHCO3 was unexpected, and argues against a simple effect of volume expansion by the sodium ion. The increase in dopamine excretion with KCl and NH4Cl showed that this response was not specific to the sodium ion. PMID:28196

  17. Pramipexole, a dopamine D2 autoreceptor agonist, decreases the extracellular concentration of dopamine in vivo.

    PubMed

    Carter, A J; Müller, R E

    1991-07-23

    Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 micrograms/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 micrograms/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 micrograms/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor. PMID:1685123

  18. Polypharmacology of dopamine receptor ligands.

    PubMed

    Butini, S; Nikolic, K; Kassel, S; Brückmann, H; Filipic, S; Agbaba, D; Gemma, S; Brogi, S; Brindisi, M; Campiani, G; Stark, H

    2016-07-01

    Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular. PMID:27234980

  19. Dopamine beta-hydroxylase deficiency

    PubMed Central

    Senard, Jean-Michel; Rouet, Philippe

    2006-01-01

    Dopamine beta-hydroxylase (DβH) deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS). Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance. PMID:16722595

  20. An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics.

    PubMed

    Tallarico, J A; Depew, K M; Pelish, H E; Westwood, N J; Lindsley, C W; Shair, M D; Schreiber, S L; Foley, M A

    2001-01-01

    The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics. PMID:11350255

  1. Dopamine receptor heteromeric complexes and their emerging functions.

    PubMed

    George, Susan R; Kern, Andras; Smith, Roy G; Franco, Rafael

    2014-01-01

    Dopamine neurotransmission is traditionally accepted as occurring through the five dopamine receptors that transduce its signal. Recent evidence has demonstrated that the range of physiologically relevant dopamine signaling complexes is greatly expanded by the ability of dopamine receptors to interact with other dopamine receptors and with receptors of other endogenous signaling ligands. These novel heteromeric complexes have functional properties distinct from the component receptors or are able to modulate the canonical signaling and function of the cognate receptors. These dopamine receptor heteromers provide new insight into physiological mechanisms and pathophysiological processes involving dopamine. PMID:24968781

  2. Cardiac mitochondrial proteome dynamics with heavy water reveals stable rate of mitochondrial protein synthesis in heart failure despite decline in mitochondrial oxidative capacity.

    PubMed

    Shekar, Kadambari Chandra; Li, Ling; Dabkowski, Erinne R; Xu, Wenhong; Ribeiro, Rogerio Faustino; Hecker, Peter A; Recchia, Fabio A; Sadygov, Rovshan G; Willard, Belinda; Kasumov, Takhar; Stanley, William C

    2014-10-01

    We recently developed a method to measure mitochondrial proteome dynamics with heavy water ((2)H2O)-based metabolic labeling and high resolution mass spectrometry. We reported the half-lives and synthesis rates of several proteins in the two cardiac mitochondrial subpopulations, subsarcolemmal and interfibrillar (SSM and IFM), in Sprague Dawley rats. In the present study, we tested the hypothesis that the mitochondrial protein synthesis rate is reduced in heart failure, with possible differential changes in SSM versus IFM. Six to seven week old male Sprague Dawley rats underwent transverse aortic constriction (TAC) and developed moderate heart failure after 22weeks. Heart failure and sham rats of the same age received heavy water (5% in drinking water) for up to 80days. Cardiac SSM and IFM were isolated from both groups and the proteins were separated by 1D gel electrophoresis. Heart failure reduced protein content and increased the turnover rate of several proteins involved in fatty acid oxidation, electron transport chain and ATP synthesis, while it decreased the turnover of other proteins, including pyruvate dehydrogenase subunit in IFM, but not in SSM. Because of these bidirectional changes, the average overall half-life of proteins was not altered by heart failure in both SSM and IFM. The kinetic measurements of individual mitochondrial proteins presented in this study may contribute to a better understanding of the mechanisms responsible for mitochondrial alterations in the failing heart. PMID:24995939

  3. Dopamine receptors in human gastrointestinal mucosa

    SciTech Connect

    Hernandez, D.E.; Mason, G.A.; Walker, C.H.; Valenzuela, J.E.

    1987-12-21

    Dopamine is a putative enteric neurotransmitter that has been implicated in exocrine secretory and motility functions of the gastrointestinal tract of several mammalian species including man. This study was designed to determine the presence of dopamine binding sites in human gastric and duodenal mucosa and to describe certain biochemical characteristics of these enteric receptor sites. The binding assay was performed in triplicate with tissue homogenates obtained from healthy volunteers of both sexes using /sup 3/H-dopamine as a ligand. The extent of nonspecific binding was determined in the presence of a 100-fold excess of unlabeled dopamine. Scatchard analysis performed with increasing concentrations of /sup 3/H-dopamine (20-500 nM) revealed a single class of saturable dopamine binding sites in gastric and duodenal mucosa. The results of this report demonstrate the presence of specific dopamine receptors in human gastric and duodenal mucosa. These biochemical data suggest that molecular abnormalities of these receptor sites may be operative in the pathogenesis of important gastrointestinal disorders. 33 references, 2 figures.

  4. Hermetically Coated and Well-Separated Co3 O4 Nanophase within Porous Graphitic Carbon Nanosheets: Synthesis, Confinement Effect, and Improved Lithium-Storage Capacity and Durability.

    PubMed

    Zhang, Jingfei; Ren, Wangyu; Zhou, Yunyun; Li, Pei; Xu, Lin; Sun, Dongmei; Wu, Ping; Zhou, Yiming; Tang, Yawen

    2016-07-01

    Considerable lithium-driven volume changes and loss of crystallinity on cycling have impeded the sustainable use of transition metal oxides (MOs) as attractive anode materials for advanced lithium-ion batteries that have almost six times the capacity of carbon per unit volume. Herein, Co3 O4 was used as a model MO in a facile process involving two pyrolysis steps for in situ encapsulation of nanosized MO in porous two-dimensional graphitic carbon nanosheets (2D-GCNs) with high surface areas and abundant active sites to overcome the above-mentioned problems. The proposed method is inexpensive, industrially scalable, and easy to operate with a high yield. TEM revealed that the encaged Co3 O4 is well separated and uniformly dispersed with surrounding onionlike graphitic layers. By taking advantage of the high electronic conductivity and confinement effect of the surrounding 2D-GCNs, a hierarchical GCNs-coated Co3 O4 (Co3 O4 @GCNs) anode with 43.5 wt % entrapped active nanoparticles delivered a remarkable initial specific capacity of 1816 mAh g(-1) at a current density of 100 mA g(-1) . After 50 cycles, the retained capacity is as high as 987 mAh g(-1) . When the current density was increased to 1000 mA g(-1) , the anode showed a capacity retention of 416 mAh g(-1) . Enhanced reversible rate capability and prolonged cycling stability were found for Co3 O4 @GCN compared to pure GCNs and Co3 O4 . The Co3 O4 @GCNs hybrid holds promise as an efficient candidate material for anodes due to its low cost, environmentally friendly nature, high capacity, and stability. PMID:27245378

  5. Human dopamine receptor and its uses

    DOEpatents

    Civelli, Olivier; Van Tol, Hubert Henri-Marie

    1999-01-01

    The present invention is directed toward the isolation, characterization and pharmacological use of the human D4 dopamine receptor. The nucleotide sequence of the gene corresponding to this receptor and alleleic variant thereof are provided by the invention. The invention also includes recombinant eukaryotic expression constructs capable of expressing the human D4 dopamine receptor in cultures of transformed eukaryotic cells. The invention provides cultures of transformed eukaryotic cells which synthesize the human D4 dopamine receptor, and methods for characterizing novel psychotropic compounds using such cultures.

  6. Phasic dopamine release in appetitive behaviors and drug abuse

    PubMed Central

    Wanat, Matthew J.; Willuhn, Ingo; Clark, Jeremy J.; Phillips, Paul E. M.

    2010-01-01

    Short phasic bursts of neuronal activity in dopamine neurons produce rapid and transient increases in extracellular dopamine concentrations throughout the mesocorticolimbic system, which are associated with the initiation of goal-directed behaviors. It is well established that acute exposure to many addictive drugs produce increases in tonic dopamine levels that occur on the order of minutes. However, recent studies suggest that abused drugs similarly enhance phasic dopamine release events that occur on a subsecond time scale. Furthermore, drug experience modulates the synaptic and intrinsic properties of dopamine neurons, which could affect dopamine burst firing and phasic dopamine release. This review will provide a general introduction to the mesolimbic dopamine system, as well as the primary methods used to detect dopamine neurons and dopamine release. We present the role of phasic dopamine release in appetitive behaviors in the context of contemporary theories regarding the function of dopamine. Next we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience attenuates tonic/basal dopamine levels but promotes phasic dopamine release, which may result in aberrant goal-directed behaviors contributing to the development of addiction. PMID:19630749

  7. MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behavior in males.

    PubMed

    Schlüter, Thorben; Winz, Oliver; Henkel, Karsten; Eggermann, Thomas; Mohammadkhani-Shali, Siamak; Dietrich, Claudia; Heinzel, Alexander; Decker, Michel; Cumming, Paul; Zerres, Klaus; Piel, Markus; Mottaghy, Felix M; Vernaleken, Ingo

    2016-01-15

    A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening sample, strictly case-matched groups of 2×12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening sample MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie; MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism. PMID:26481676

  8. Diagnosing dopamine-responsive dystonias.

    PubMed

    Malek, N; Fletcher, N; Newman, E

    2015-10-01

    The clinical spectrum of dopamine-responsive dystonias (DRDs) has expanded over the last decade to comprise several distinct disorders. At the milder end of the clinical spectrum is the autosomal-dominant guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), and at the more severe end is the much less common autosomal recessive tyrosine hydroxylase deficiency syndrome (TH-DRD), with intermediate forms in between. Understanding the pathophysiology of DRDs can help in their optimal diagnosis and management. These are conditions with the potential to be either underdiagnosed when not considered or overdiagnosed if there is an equivocal L-dopa (levo-3,4-dihydroxyphenylalanine) response. In this article, we discuss the clinical phenotypes of these disorders, and we outline how investigations can help in confirming the diagnosis. PMID:26045581

  9. Facile formation of a Li3PO4 coating layer during the synthesis of a lithium-rich layered oxide for high-capacity lithium-ion batteries

    NASA Astrophysics Data System (ADS)

    Lee, Yongho; Lee, Jieun; Lee, Kwan Young; Mun, Junyoung; Lee, Joong Kee; Choi, Wonchang

    2016-05-01

    The facile surface modification of transition-metal hydroxide precursors with ammonium dihydrogen phosphate was performed by ball-milling before the calcination process. The prepared precursors were mixed with the required amount of lithium hydroxide and then simply calcined to obtain lithium-phosphate-coated lithium transition metal oxide cathodes during the one-pot calcination process. A thin, homogeneous Li3PO4 coating is firstly formed on the surface of the precursor owing to the abundance of lithium at a lower-temperature range, and subsequent formation of lithium transition metal oxide is achieved at a higher-temperature range during the calcination process. The Li3PO4-coated cathode electrode with the high loading level over 12 mg cm-1 exhibits a discharge capacity of 106 mAh g-1 at 5C at ambient temperature. Furthermore, it delivers 90% capacity retention after 50 cycles at 60 °C.

  10. Synthesis, characterisation and methyl orange adsorption capacity of ferric oxide-biochar nano-composites derived from pulp and paper sludge

    NASA Astrophysics Data System (ADS)

    Chaukura, Nhamo; Murimba, Edna C.; Gwenzi, Willis

    2016-02-01

    A Fe2O3-biochar nano-composite (Fe2O3-BC) was prepared from FeCl3-impregnated pulp and paper sludge (PPS) by pyrolysis at 750 °C. The characteristics and methyl orange (MO) adsorption capacity of Fe2O3-BC were compared to that of unactivated biochar (BC). X-ray diffraction (XRD) and scanning electron microscopy (SEM) confirmed the composite material was nano-sized. Fourier transform infrared (FTIR) spectroscopy revealed the presence of hydroxyl and aromatic groups on BC and on Fe2O3-BC, but Brunauer-Emmett-Teller (BET) surface area and Barrett-Joyner-Halenda (BJH) porosity were lower for Fe2O3-BC than BC. Despite the lower BET surface area and porosity of Fe2O3-BC, its MO adsorption capacity was 52.79 % higher than that of BC. The equilibrium adsorption data were best represented by the Freundlich model with a maximum adsorption capacity of 20.53 mg g-1 at pH 8 and 30 min contact time. MO adsorption obeyed pseudo-second-order kinetics for both BC and Fe2O3-BC with R 2 values of 0.996 and 0.999, respectively. Higher MO adsorption capacity for Fe2O3-BC was attributed to the hybrid nature of the nano-composites; adsorption occurred on both biochar matrix and Fe2O3 nanocrystals. Gibbs free energy calculations confirmed the adsorption is energetically favourable and spontaneous with a high preference for adsorption on both adsorbents. The nano-composite can be used for the efficient removal of MO (>97 %) from contaminated wastewater.

  11. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous parkinsonism-inducing toxin, strongly potentiates MAO-dependent dopamine oxidation and impairs dopamine release: ex vivo and in vivo neurochemical studies.

    PubMed

    Wasik, Agnieszka; Romańska, Irena; Antkiewicz-Michaluk, Lucyna

    2009-01-01

    1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause a parkinsonism-like syndrome in rodents and primates. In this study we evaluated the effects of single and multiple 1BnTIQ (50 mg/kg i.p.) administration on the concentrations of dopamine, serotonin, and respective metabolites (homovanillic acid, HVA; 3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and 5-hydroxyindolacetic acid, 5-HIAA), in substantia nigra, striatum (STR), and nucleus accumbens of Wistar rats. In addition, the effect of 1BnTIQ on locomotor activity and dopamine release in vivo was also estimated in rat STR. In a behavioral study, acute administration of 1BnTIQ (50 mg/kg i.p.) produced a significant decrease in exploratory locomotor activity. A high-performance liquid chromatography with electrochemical detection ex vivo study showed that a single injection of 1BnTIQ produced a dramatic fall in the dopamine concentration in the noted brain regions (approximately 65%; P < 0.01), but not in striatal serotonin. Moreover, 1BnTIQ reduced the content of the extraneuronal dopamine metabolite 3-MT by 70% (P < 0.01). Conversely, levels of DOPAC, HVA, and 5-HIAA were elevated by 220, 320, and 185%, respectively (P < 0.01). Interestingly, multiple 1BnTIQ treatments (50 mg/kg/day i.p. x 10 days) resulted in development of tolerance to its dopamine depressing effect, while the impairment of dopamine synthesis was persisted. An in vivo microdialysis study demonstrated that 1BnTIQ (50 mg/kg i.p.) produced a profound and long-lasting decrease in extraneuronal striatal dopamine. Concurrently, however, DOPAC and HVA were elevated. This comparison between ex vivo and in vivo effects of 1BnTIQ provides greater insight into the neurotoxic actions of 1BnTIQ specific to dopamine neurons. 1BnTIQ neurotoxicity may be related to an impairment of dopamine storage, leading to a fall in intraneuronal dopamine and enhanced dopamine catabolism through a monoamine oxidize

  12. Catalyst-free synthesis of Si-SiOx core-shell nanowire anodes for high-rate and high-capacity lithium-ion batteries.

    PubMed

    Lim, Kwan Woo; Lee, Jung-In; Yang, Jieun; Kim, Young-Ki; Jeong, Hu Young; Park, Soojin; Shin, Hyeon Suk

    2014-05-14

    Si-SiOx core-shell nanowires (NWs) ranging from 10 to 30 nm in diameter are prepared by a simple evaporation of silicon monoxide and control of substrate temperatures without any catalyst. The Si-SiOx NWs grown at 735 and 955 °C are strongly anchored to the Cu current collector by forming copper silicide at the interface between Si and Cu, and subsequently used as anodes in lithium-ion batteries, in which no binder or conducting materials are used. The Si-SiOx NWs anodes show excellent electrochemical performances in terms of capacity retention and rate capability. In particular, the Si-SiOx NW anode grown at 955 °C shows a reversible capacity of ∼1000 mAh g(-1) even at a high-rate of 50 C. This catalyst-free synthetic route of Si-SiOx NWs that are strongly anchored to the Cu current collector opens up an effective process for fabricating other high-capacity anodes in lithium-ion batteries (LIBs). PMID:24754908

  13. Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder--lack of effect of methylphenidate.

    PubMed

    Warton, Fleur L; Howells, Fleur M; Russell, Vivienne A

    2009-12-01

    Attention-deficit/hyperactivity disorder (ADHD) is a behavioural disorder that has been associated with dysfunction of the dopaminergic system. Abnormal dopamine function could be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transporter, synthesis, receptor function) or an indirect result of impaired glutamate and/or noradrenergic regulation of dopamine neurons. There is considerable evidence to suggest that dopamine release is impaired at mesolimbic and nigrostriatal dopaminergic terminals. However, it is not known whether dysregulation occurs at the level of the cell bodies in the ventral tegmental area of the midbrain (VTA) and substantia nigra (SN). An in vitro superfusion technique was used to measure dopamine release in a widely used model of ADHD, the spontaneously hypertensive rat (SHR), and its normotensive Wistar-Kyoto (WKY) control. At approximately 30 days of age, rats were analysed for behavioural differences in the open field in response to acute treatment with methylphenidate (0.5 to 2 mg/kg in condensed milk, oral self-administration). In addition, rats were treated chronically with methylphenidate (2 mg/kg, oral self-administration, twice daily for 14 days from postnatal day 21 to 34) before the VTA and the SN were analysed for glutamate-stimulated and depolarization-evoked release of dopamine in these areas. In support of its use as an animal model for ADHD, SHR were more active in the open field and displayed less anxiety-like behaviour than WKY. Neither strain showed any effect of treatment with methylphenidate. A significant difference was observed in glutamate-stimulated release of dopamine in the SN of SHR and WKY, with SHR releasing more dopamine, consistent with the hypothesis of altered glutamate regulation of dopamine neurons in SHR. PMID:19821016

  14. Detection of Dopamine Dynamics in the Brain.

    ERIC Educational Resources Information Center

    Wightman, R. Mark; And Others

    1988-01-01

    Explores neurochemical events in the extra cellular space of the brain by use of in vivo voltammetric microelectrodes. Reports dopamine concentrations and pathways, and discusses techniques used for analysis. Recognizes current problems and future directions for research. (ML)

  15. Dopamine neurons encode errors in predicting movement trigger occurrence.

    PubMed

    Pasquereau, Benjamin; Turner, Robert S

    2015-02-15

    The capacity to anticipate the timing of events in a dynamic environment allows us to optimize the processes necessary for perceiving, attending to, and responding to them. Such anticipation requires neuronal mechanisms that track the passage of time and use this representation, combined with prior experience, to estimate the likelihood that an event will occur (i.e., the event's "hazard rate"). Although hazard-like ramps in activity have been observed in several cortical areas in preparation for movement, it remains unclear how such time-dependent probabilities are estimated to optimize response performance. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys during an arm-reaching task for which the foreperiod preceding the "go" signal varied randomly along a uniform distribution. After extended training, the monkeys' reaction times correlated inversely with foreperiod duration, reflecting a progressive anticipation of the go signal according to its hazard rate. Many dopamine neurons modulated their firing rates as predicted by a succession of hazard-related prediction errors. First, as time passed during the foreperiod, slowly decreasing anticipatory activity tracked the elapsed time as if encoding negative prediction errors. Then, when the go signal appeared, a phasic response encoded the temporal unpredictability of the event, consistent with a positive prediction error. Neither the anticipatory nor the phasic signals were affected by the anticipated magnitudes of future reward or effort, or by parameters of the subsequent movement. These results are consistent with the notion that dopamine neurons encode hazard-related prediction errors independently of other information. PMID:25411459

  16. Dopamine-oxytocin interactions in penile erection.

    PubMed

    Baskerville, T A; Allard, J; Wayman, C; Douglas, A J

    2009-12-01

    Dopamine and oxytocin have established roles in the central regulation of penile erection in rats; however, the neural circuitries involved in a specific erectile context and the interaction between dopamine and oxytocin mechanisms remain to be elucidated. The medial preoptic area (MPOA), supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus may serve as candidate sites because they contain oxytocin cells, receive dopaminergic inputs and have been implicated in mediating masculine sexual behavior. Double immunofluorescence revealed that substantial numbers of oxytocin cells in the MPOA, SON and PVN possess dopamine D(2), D(3) and D(4) receptors. In anaesthetized rats, using intracavernous pressure as a physiological indicator of erection, blockade of lumbosacral oxytocin receptors (UK, 427843) reduced erectile responses to a nonselective dopamine agonist (apomorphine), suggesting that dopamine recruits a paraventriculospinal oxytocin pathway. In conscious males in the absence of a female, penile erection elicited by a D(2)/D(3) (Quinelorane) but not D(4) (PD168077) agonist was associated with activation of medial parvocellular PVN oxytocin cells. In another experiment where males were given full access to a receptive female, a D(4) (L-745870) but not D(2) or D(3) antagonist (L-741626; nafadotride) inhibited penile erection (intromission), and this was correlated with SON magnocellular oxytocin neuron activation. Together, the data suggest dopamine's effects on hypothalamic oxytocin cells during penile erection are context-specific. Dopamine may act via different parvocellular and magnocellular oxytocin subpopulations to elicit erectile responses, depending upon whether intromission is performed. This study demonstrates the potential existence of interaction between central dopamine and oxytocin pathways during penile erection, with the SON and PVN serving as integrative sites. PMID:20128851

  17. Activation of group III metabotropic glutamate receptors inhibits basal and amphetamine-stimulated dopamine release in rat dorsal striatum: an in vivo microdialysis study.

    PubMed

    Mao, L; Lau, Y S; Wang, J Q

    2000-09-22

    Group III metabotropic glutamate (mGlu) receptors are negatively coupled to adenylate cyclase and are distributed pre-synaptically in the striatum. A behavioral study previously conducted in this laboratory shows that activation of this group of mGlu receptors attenuates acute amphetamine-stimulated motor activity. By administering a group III selective agonist or antagonist via the dialysis probe, the present study employed in vivo microdialysis to evaluate the capacity of the group III selective agents to alter extracellular levels of dopamine in the dorsal striatum of normal and amphetamine-treated rats. It was found that the group III agonist L-2-amino-4-phosphonobutyrate (L-AP4) dose-dependently (1, 10 and 100 microM) reduced basal levels of extracellular dopamine. In contrast, the group III antagonist alpha-methyl-4-phosphonophenylglycine (MPPG) dose-dependently (10, 50 and 250 microM) elevated the basal release of extracellular dopamine. This elevation was antagonized by co-perfusion of L-AP4. Perfusion of 5-microM amphetamine through the dialysis probe increased extracellular dopamine in the dorsal striatum. Co-perfusion of L-AP4 (100 microM) significantly reduced amphetamine-stimulated dopamine levels, whereas co-perfusion of L-AP4 (100 microM) and MPPG (100 microM) did not alter the capacity of amphetamine to elicit dopamine release. The data obtained from this study demonstrate the presence of a tonically active glutamatergic tone on group III mGlu receptors in the dorsal striatum to pre-synaptically regulate basal dopamine release in an inhibitory fashion. Moreover, activation of L-AP4-sensitive group III mGlu receptors can suppress the phasic release of dopamine induced by a dopamine stimulant amphetamine. PMID:10996594

  18. Multiple human D sub 5 dopamine receptor genes: A functional receptor and two pseudogenes

    SciTech Connect

    Grandy, D.K.; Yuan Zhang; Bouvier, C.; Qunyong Zhou; Johnson, R.A.; Allen, L.; Buck, K.; Bunzow, J.R.; Salon, J.; Civelli, O. )

    1991-10-15

    Three genes closely related to the D{sub 1} dopamine receptor were identified in the human genome. One of the genes lacks introns and encodes a functional human dopamine receptor, D{sub 5}, whose deduced amino acid sequence is 49% identical to that of the human D{sub 1} receptor. Compared with the human D{sub 1} dopamine receptor, the D{sub 5} receptor displayed a higher affinity for dopamine and was able to stimulate a biphasic rather than a monophasic intracellular accumulation of cAMP. Neither of the other two genes was able to direct the synthesis of a receptor. nucleotide sequence analysis revealed that these two genes are 98% identical to each other and 95% identical to the D{sub 5} sequence. Relative to the D{sub 5} sequence, both contain insertions and deletions that result in several in-frame termination codons. Premature termination of translation is the most likely explanation for the failure of these genes to produce receptors in COS-7 and 293 cells even though their messages are transcribed. The authors conclude that the two are pseudogenes. Blot hybridization experiments performed on rat genomic DNA suggest that there is one D{sub 5} gene in this species and that the pseudogenes may be the result of a relatively recent evolutionary event.

  19. Dopamine-first’ mechanism enables the rational engineering of the norcoclaurine synthase aldehyde activity profile

    PubMed Central

    Lichman, Benjamin R; Gershater, Markus C; Lamming, Eleanor D; Pesnot, Thomas; Sula, Altin; Keep, Nicholas H; Hailes, Helen C; Ward, John M

    2015-01-01

    Norcoclaurine synthase (NCS) (EC 4.2.1.78) catalyzes the Pictet–Spengler condensation of dopamine and an aldehyde, forming a substituted (S)-tetrahydroisoquinoline, a pharmaceutically important moiety. This unique activity has led to NCS being used for both in vitro biocatalysis and in vivo recombinant metabolism. Future engineering of NCS activity to enable the synthesis of diverse tetrahydroisoquinolines is dependent on an understanding of the NCS mechanism and kinetics. We assess two proposed mechanisms for NCS activity: (a) one based on the holo X-ray crystal structure and (b) the ‘dopamine-first’ mechanism based on computational docking. Thalictrum flavum NCS variant activities support the dopamine-first mechanism. Suppression of the non-enzymatic background reaction reveals novel kinetic parameters for NCS, showing it to act with low catalytic efficiency. This kinetic behaviour can account for the ineffectiveness of recombinant NCS in in vivo systems, and also suggests NCS may have an in planta role as a metabolic gatekeeper. The amino acid substitution L76A, situated in the proposed aldehyde binding site, results in the alteration of the enzyme's aldehyde activity profile. This both verifies the dopamine-first mechanism and demonstrates the potential for the rational engineering of NCS activity. PMID:25620686

  20. Neurotrophic effects of L-DOPA in postnatal midbrain dopamine neuron/cortical astrocyte cocultures.

    PubMed

    Mena, M A; Davila, V; Sulzer, D

    1997-10-01

    L-DOPA is toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of L-DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum-free, glia-conditioned medium. L-DOPA (50 microM) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia-free cultures, where L-DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 microM L-DOPA. The stereoisomer D-DOPA (50-400 microM) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25 microM) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of L-DOPA is stereospecific but independent of the production of dopamine. However, L-DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by L-buthionine sulfoximine (3 microM for 24 h) blocked the neurotrophic action of L-DOPA. N-Acetyl-L-cysteine (250 microM for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of L-DOPA. These data suggest that the neurotrophic effect of L-DOPA may be mediated, at least in part, by elevation of glutathione content. PMID:9326268

  1. The Effects of Acute Dopamine Precursor Depletion on the Reinforcing Value of Exercise in Anorexia Nervosa

    PubMed Central

    O’Hara, Caitlin B.; Keyes, Alexandra; Renwick, Bethany; Leyton, Marco; Campbell, Iain C.; Schmidt, Ulrike

    2016-01-01

    This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN), specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15) were recruited. The acute phenylalanine/tyrosine depletion (APTD) method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR) exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN. PMID:26808920

  2. The Effects of Acute Dopamine Precursor Depletion on the Reinforcing Value of Exercise in Anorexia Nervosa.

    PubMed

    O'Hara, Caitlin B; Keyes, Alexandra; Renwick, Bethany; Leyton, Marco; Campbell, Iain C; Schmidt, Ulrike

    2016-01-01

    This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN), specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15) were recruited. The acute phenylalanine/tyrosine depletion (APTD) method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR) exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN. PMID:26808920

  3. Hodgkin-Reed-Sternberg Cells in Classical Hodgkin Lymphoma Show Alterations of Genes Encoding the NADPH Oxidase Complex and Impaired Reactive Oxygen Species Synthesis Capacity

    PubMed Central

    Sosna, Justyna; Döring, Claudia; Klapper, Wolfram; Küppers, Ralf; Böttcher, Sebastian; Adam, Dieter; Siebert, Reiner; Schütze, Stefan

    2013-01-01

    The membrane bound NADPH oxidase involved in the synthesis of reactive oxygen species (ROS) is a multi-protein enzyme encoded by CYBA, CYBB, NCF1, NCF2 and NCF4 genes. Growing evidence suggests a role of ROS in the modulation of signaling pathways of non-phagocytic cells, including differentiation and proliferation of B-cell progenitors. Transcriptional downregulation of the CYBB gene has been previously reported in cell lines of the B-cell derived classical Hodgkin lymphoma (cHL). Thus, we explored functional consequences of CYBB downregulation on the NADPH complex. Using flow cytometry to detect and quantify superoxide anion synthesis in cHL cell lines we identified recurrent loss of superoxide anion production in all stimulated cHL cell lines in contrast to stimulated non-Hodgkin lymphoma cell lines. As CYBB loss proved to exert a deleterious effect on the NADPH oxidase complex in cHL cell lines, we analyzed the CYBB locus in Hodgkin and Reed-Sternberg (HRS) cells of primary cHL biopsies by in situ hybridisation and identified recurrent deletions of the gene in 8/18 cases. Immunohistochemical analysis to 14 of these cases revealed a complete lack of detectable CYBB protein expression in all HRS cells in all cases studied. Moreover, by microarray profiling of cHL cell lines we identified additional alterations of NADPH oxidase genes including CYBA copy number loss in 3/7 cell lines and a significant downregulation of the NCF1 transcription (p=0.006) compared to normal B-cell subsets. Besides, NCF1 protein was significantly downregulated (p<0.005) in cHL compared to other lymphoma cell lines. Together this findings show recurrent alterations of the NADPH oxidase encoding genes that result in functional inactivation of the enzyme and reduced production of superoxide anion in cHL. PMID:24376854

  4. One-pot synthesis of a metal–organic framework as an anode for Li-ion batteries with improved capacity and cycling stability

    SciTech Connect

    Gou, Lei Hao, Li-Min; Shi, Yong-Xin; Ma, Shou-Long; Fan, Xiao-Yong; Xu, Lei; Li, Dong-Lin Wang, Kang

    2014-02-15

    Metal–organic framework is a kind of novel electrode materials for lithium ion batteries. Here, a 3D metal–organic framework Co{sub 2}(OH){sub 2}BDC (BDC=1,4-benzenedicarboxylate) was synthesized for the first time by the reaction of Co{sup 2+} with a bio-inspired renewable organic ligand 1,4-benzenedicarboxylic acid through a solvothermal method. As an anode material for lithium ion batteries, this material exhibited an excellent cyclic stability as well as a large reversible capacity of ca. 650 mA h g{sup −1} at a current density of 50 mA g{sup −1} after 100 cycles within the voltage range of 0.02–3.0 V, higher than that of other BDC based anode. - Graphical abstract: The PXRD pattern and the cycleability curves (inset) of Co{sub 2}(OH){sub 2}BDC. Display Omitted - Highlights: • Co{sub 2}(OH){sub 2}BDC was synthesized through a one pot solvothermal process. • The solvent had a great effect on the purity of this material. • This material was used as anode material for lithium ion batteries for the first time. • Co{sub 2}(OH){sub 2}BDC showed improved capacity and cycling stability.

  5. Facile synthesis of LiMn2O4 octahedral nanoparticles as cathode materials for high capacity lithium ion batteries with long cycle life

    NASA Astrophysics Data System (ADS)

    Cai, Yanjun; Huang, Yudai; Wang, Xingchao; Jia, Dianzeng; Pang, Weikong; Guo, Zaiping; Du, Yaping; Tang, Xincun

    2015-03-01

    Spinel lithium manganate octahedral nanoparticles have been prepared by high temperature solid-state combustion reaction using cellulose as fuel. The crystal structure, morphology, and electrochemical performance of the as-prepared materials are analyzed by X-ray diffraction (XRD), electron microscopy, and electrochemical testing. The XRD results show that the materials are single-phase and perfectly crystalline with a spinel structure. Microscopic observations reveal that the nanoparticles possess octahedral morphology, with an average particle size of about 165.4 nm and a uniform particle size distribution. The lithium manganate octahedral nanoparticles exhibit excellent initial discharge capacity of 118.5 and 78.3 mAh g-1, and about 72.49% and 94.6% of its initial discharge capacity can be retained even after 1600 cycles at 10 C and 3000 cycles at 20 C, respectively. The excellent electrochemical performance of the lithium manganate can be mainly attributed to the strong MnO6 framework mitigates the occurrence of Mn dissolution, maintains structural stability, and allows higher Li+ diffusion during electrochemical cycling. Furthermore, the nano-sized octahedral structure not only facilitates fast ion diffusion, but also mitigates the manganese dissolution due to the exposed (111) crystal planes, where the solid electrolyte interphase (SEI) forms.

  6. One-step synthesis of Si@C nanoparticles by laser pyrolysis: high-capacity anode material for lithium-ion batteries.

    PubMed

    Sourice, Julien; Quinsac, Axelle; Leconte, Yann; Sublemontier, Olivier; Porcher, Willy; Haon, Cedric; Bordes, Arnaud; De Vito, Eric; Boulineau, Adrien; Jouanneau Si Larbi, Séverine; Herlin-Boime, Nathalie; Reynaud, Cécile

    2015-04-01

    Carbon-covered silicon nanoparticles (Si@C) were synthesized for the first time by a one-step continuous process in a novel two stages laser pyrolysis reactor. Crystallized silicon cores formed in a first stage were covered in the second stage by a continuous shell mainly consisting in low organized sp(2) carbon. At the Si/C interface silicon carbide is absent. Moreover, the presence of silicon oxide is reduced compared to materials synthesized in several steps, allowing the use of such material as promising anode material in lithium-ion batteries (LIB). Auger Electron Spectroscopy (AES) analysis of the samples at both SiKLL and SiLVV edges proved the uniformity of the carbon coating. Cyclic voltammetry was used to compare the stability of Si and Si@C active materials. In half-cell configuration, Si@C exhibits a high and stable capacity of 2400 mAh g(-1) at C/10 and up to 500 mAh g(-1) over 500 cycles at 2C. The retention of the capacity is attributed to the protective effect of the carbon shell, which avoids direct contact between the silicon surface and the electrolyte. PMID:25761636

  7. Synthesis, Structure, and Electrochemical Performance of High Capacity Li2Cu0.5Ni0.5O2 Cathodes

    DOE PAGESBeta

    Ruther, Rose E; Zhou, Hui; Dhital, Chetan; Saravanan, Kuppan; Kercher, Andrew K.; Chen, Guoying; Huq, Ashfia; Delnick, Frank M.; Nanda, Jagjit

    2015-09-08

    Orthorhombic Li2NiO2, Li2CuO2, and solid solutions thereof have been studied as potential cathode materials for lithium-ion batteries due to their high theoretical capacity and relatively low cost. While neither endmember shows good cycling stability, the intermediate composition, Li2Cu0.5Ni0.5O2, yields reasonably high reversible capacities. A new synthetic approach and detailed characterization of this phase and the parent Li2CuO2 are presented. The cycle life of Li2Cu0.5Ni0.5O2 is shown to depend critically on the voltage window. The formation of Cu1+ at low voltage and oxygen evolution at high voltage limit the electrochemical reversibility. In situ X-ray absorption spectroscopy (XAS), in situ Raman spectroscopy,more » and gas evolution measurements are used to follow the chemical and structural changes that occur as a function of cell voltage.« less

  8. CTAB-assisted synthesis of mesoporous F-N-codoped TiO{sub 2} powders with high visible-light-driven catalytic activity and adsorption capacity

    SciTech Connect

    Xie Yi Zhao Xiujian Li Yuanzhi; Zhao Qingnan; Zhou Xuedong; Yuan Qihua

    2008-08-15

    This article describes the preparation of mesoporous rod-like F-N-codoped TiO{sub 2} powder photocatalysts with anatase phase via a sol-gel route at the temperature of 373 K, using cetyltrimethyl ammonium bromide (CTAB) as surfactant. The as-prepared photocatalysts were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and UV-visible diffuse reflectance spectra (UV-vis DRS). The results showed that the photocatalysts possessed a homogeneous pore diameter and a high surface area of 106.3-160.7 m{sup 3} g{sup -1}. The increasing CTAB reactive concentration extended the visible-light absorption up to 600 nm. The F-N-codoped TiO{sub 2} powders exhibited significant higher adsorption capacity for methyl orange (MO) than that of Degussa P25 and showed more than 6 times higher visible-light-induced catalytic degradation for MO than that of P25. - Graphical abstract: The introduction of surfactant CTAB not only extended the visible light absorption of mesoporous F-N-codoped TiO{sub 2} up to 600 nm but also significantly enhanced the adsorption capacity and visible-light-induced degradation for methyl orange. Mesoporous rod-like F-N-codoped TiO{sub 2} powder photocatalysts were synthesized via a sol-gel route at low temperature of 373 K.

  9. Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

    PubMed Central

    Sidharthan, Neelima P.; Minchin, Rodney F.; Butcher, Neville J.

    2013-01-01

    Dopamine neurotoxicity is associated with several neurodegenerative diseases, and neurons utilize several mechanisms, including uptake and metabolism, to protect them from injury. Metabolism of dopamine involves three enzymes: monoamine oxidase, catechol O-methyltransferase, and sulfotransferase. In primates but not lower order animals, a sulfotransferase (SULT1A3) is present that can rapidly metabolize dopamine to dopamine sulfate. Here, we show that SULT1A3 and a closely related protein SULT1A1 are highly inducible by dopamine. This involves activation of the D1 and NMDA receptors. Both ERK1/2 phosphorylation and calcineurin activation are required for induction. Pharmacological agents that inhibited induction or siRNA targeting SULT1A3 significantly increased the susceptibility of cells to dopamine toxicity. Taken together, these results show that dopamine can induce its own metabolism and protect neuron-like cells from damage, suggesting that SULT1A3 activity may be a risk factor for dopamine-dependent neurodegenerative diseases. PMID:24136195

  10. Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

    PubMed Central

    Cardinal, R. N.; Rygula, R.; Hong, Y. T.; Fryer, T. D.; Sawiak, S. J.; Ferrari, V.; Cockcroft, G.; Aigbirhio, F. I.; Robbins, T. W.; Roberts, A. C.

    2014-01-01

    Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. PMID:24872570

  11. Surfactant-free synthesis of octahedral ZnO/ZnFe2O4 heterostructure with ultrahigh and selective adsorption capacity of malachite green

    PubMed Central

    Liu, Jue; Zeng, Min; Yu, Ronghai

    2016-01-01

    A new octahedral ZnO/ZnFe2O4 heterostructure has been fabricated through a facile surfactant-free solvothermal method followed by thermal treatment. It exhibits a record-high adsorption capacity (up to 4983.0 mg·g−1) of malachite green (MG), which is a potentially harmful dye in prevalence and should be removed from wastewater and other aqueous solutions before discharging into the environment. The octahedral ZnO/ZnFe2O4 heterostructure also demonstrates strong selective adsorption towards MG from two kinds of mixed solutions: MG/methyl orange (MO) and MG/rhodamine B (RhB) mixtures, indicating its promise in water treatment. PMID:27142194

  12. Surfactant-free synthesis of octahedral ZnO/ZnFe2O4 heterostructure with ultrahigh and selective adsorption capacity of malachite green

    NASA Astrophysics Data System (ADS)

    Liu, Jue; Zeng, Min; Yu, Ronghai

    2016-05-01

    A new octahedral ZnO/ZnFe2O4 heterostructure has been fabricated through a facile surfactant-free solvothermal method followed by thermal treatment. It exhibits a record-high adsorption capacity (up to 4983.0 mg·g‑1) of malachite green (MG), which is a potentially harmful dye in prevalence and should be removed from wastewater and other aqueous solutions before discharging into the environment. The octahedral ZnO/ZnFe2O4 heterostructure also demonstrates strong selective adsorption towards MG from two kinds of mixed solutions: MG/methyl orange (MO) and MG/rhodamine B (RhB) mixtures, indicating its promise in water treatment.

  13. Surfactant-free synthesis of octahedral ZnO/ZnFe2O4 heterostructure with ultrahigh and selective adsorption capacity of malachite green.

    PubMed

    Liu, Jue; Zeng, Min; Yu, Ronghai

    2016-01-01

    A new octahedral ZnO/ZnFe2O4 heterostructure has been fabricated through a facile surfactant-free solvothermal method followed by thermal treatment. It exhibits a record-high adsorption capacity (up to 4983.0 mg·g(-1)) of malachite green (MG), which is a potentially harmful dye in prevalence and should be removed from wastewater and other aqueous solutions before discharging into the environment. The octahedral ZnO/ZnFe2O4 heterostructure also demonstrates strong selective adsorption towards MG from two kinds of mixed solutions: MG/methyl orange (MO) and MG/rhodamine B (RhB) mixtures, indicating its promise in water treatment. PMID:27142194

  14. Ternary Cu2SnS3 cabbage-like nanostructures: large-scale synthesis and their application in Li-ion batteries with superior reversible capacity

    NASA Astrophysics Data System (ADS)

    Qu, Baihua; Li, Hongxing; Zhang, Ming; Mei, Lin; Chen, Libao; Wang, Yanguo; Li, Qiuhong; Wang, Taihong

    2011-10-01

    In this paper, novel ternary Cu2SnS3 cabbage-like nanostructures are synthesized on a large scale via a facile solvothermal route. The individual Cu2SnS3 cabbage-like hierarchitecture is constructed from 2D nanosheets with thickness of about 15.6 nm. The Cu2SnS3 electrodes exhibit an initial reversible capacity of 842 mAh g-1 and still reach 621 mAh g-1 after 50 cycles. Such an admirable performance could be related to their 3D porous structural features as well as the high electrical conductivity induced by Cu. The electrochemical properties of the 3D hierarchical nanostructures imply its potential application in high energy density Li-ion batteries.

  15. Ultrasmall SnO2 Nanocrystals: Hot-bubbling Synthesis, Encapsulation in Carbon Layers and Applications in High Capacity Li-Ion Storage

    PubMed Central

    Ding, Liping; He, Shulian; Miao, Shiding; Jorgensen, Matthew R.; Leubner, Susanne; Yan, Chenglin; Hickey, Stephen G.; Eychmüller, Alexander; Xu, Jinzhang; Schmidt, Oliver G.

    2014-01-01

    Ultrasmall SnO2 nanocrystals as anode materials for lithium-ion batteries (LIBs) have been synthesized by bubbling an oxidizing gas into hot surfactant solutions containing Sn-oleate complexes. Annealing of the particles in N2 carbonifies the densely packed surface capping ligands resulting in carbon encapsulated SnO2 nanoparticles (SnO2/C). Carbon encapsulation can effectively buffer the volume changes during the lithiation/delithiation process. The assembled SnO2/C thus deliver extraordinarily high reversible capacity of 908 mA·h·g−1 at 0.5 C as well as excellent cycling performance in the LIBs. This method demonstrates the great potential of SnO2/C nanoparticles for the design of high power LIBs. PMID:24732294

  16. Endogenous Dopamine Suppresses Initiation of Swimming in Prefeeding Zebrafish Larvae

    PubMed Central

    Thirumalai, Vatsala; Cline, Hollis T.

    2008-01-01

    Dopamine is a key neuromodulator of locomotory circuits, yet the role that dopamine plays during development of these circuits is less well understood. Here, we describe a suppressive effect of dopamine on swim circuits in larval zebrafish. Zebrafish larvae exhibit marked changes in swimming behavior between 3 days postfertilization (dpf) and 5dpf. We found that swim episodes were fewer and of longer durations at 3 than at 5dpf. At 3dpf, application of dopamine as well as bupropion, a dopamine reuptake blocker, abolished spontaneous fictive swim episodes. Blocking D2 receptors increased frequency of occurrence of episodes and activation of adenylyl cyclase, a downstream target inhibited by D2-receptor signaling, blocked the inhibitory effect of dopamine. Dopamine had no effect on motor neuron firing properties, input impedance, resting membrane potential, or the amplitude of spike afterhyperpolarization. Application of dopamine either to the isolated spinal cord or locally within the cord does not decrease episode frequency, whereas dopamine application to the brain silences episodes, suggesting a supraspinal locus of dopaminergic action. Treating larvae with 10 μM MPTP reduced catecholaminergic innervation in the brain and increased episode frequency. These data indicate that dopamine inhibits the initiation of fictive swimming episodes at 3dpf. We found that at 5dpf, exogenously applied dopamine inhibits swim episodes, yet the dopamine reuptake blocker or the D2-receptor antagonist have no effect on episode frequency. These results led us to propose that endogenous dopamine release transiently suppresses swim circuits in developing zebrafish. PMID:18562547

  17. Genetic disruption of dopamine production results in pituitary adenomas and severe prolactinemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dopamine release from tuberoinfundibular dopamine neurons into the median eminence activates dopamine-D2 receptors in the pituitary gland where it inhibits lactotroph function. We have previously described genetic dopamine-deficient mouse models which lack the ability to synthesize dopamine. Because...

  18. Dopamine systems in the forebrain

    PubMed Central

    Cave, John W.; Baker, Harriet

    2009-01-01

    The brain contains a number of distinct regions that share expression of dopamine (DA) and its requisite biosynthetic machinery, but otherwise encompass a diverse array of features and functions. Across the vertebrate family, the olfactory bulb (OB) contains the major DA system in the forebrain. OB DA cells are primarily periglomerular interneurons that define the glomerular structures in which they receive innervation from olfactory receptor neurons as well as mitral and tufted cells, the primary OB output neurons. The OB DA cells are necessary for both discrimination and the dynamic range over which odorant sensory information can be detected. In the embryo, OB DA neurons are derived from the ventricular area of the evaginating telencephalon, the dorsal lateral ganglionic eminence, and the septum. However, most OB DA interneurons are generated post-natally and continue to be produced throughout adult life from neural stem cells in the subventricular zone of the lateral ventricle and rostral migratory stream. Adult born OB DA neurons are capable of integrating into existing circuits and do not appear to degenerate in Parkinson’s disease. Several genes have been identified that regulate the differentiation of OB DA interneurons from neural stem cells. These include transcription factors that modify the expression of tyrosine hydroxylase, the first enzyme in the DA biosynthetic pathway and a reliable marker of the DA phenotype. Elucidation of the molecular genetic pathways of OB DA differentiation may advance the development of strategies to treat neurological disease. PMID:19731547

  19. Addiction: Beyond dopamine reward circuitry

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Fowler, J.S.; Tomasi, D.; Telang, F.

    2011-09-13

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

  20. Dopamine, behavioral economics, and effort.

    PubMed

    Salamone, John D; Correa, Merce; Farrar, Andrew M; Nunes, Eric J; Pardo, Marta

    2009-01-01

    There are numerous problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and lines of inquiry. The present review is focused upon the involvement of nucleus accumbens DA in behavioral activation and effort-related processes. Viewed from the framework of behavioral economics, the effects of accumbens DA depletions and antagonism on food-reinforced behavior are highly dependent upon the work requirements of the instrumental task, and DA depleted rats are more sensitive to increases in response costs (i.e., ratio requirements). Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related choice behavior. Rats with accumbens DA depletions or antagonism reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead these rats select a less-effortful type of food-seeking behavior. Nucleus accumbens DA and adenosine interact in the regulation of effort-related functions, and other brain structures (anterior cingulate cortex, amygdala, ventral pallidum) also are involved. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue or anergia in depression and other neurological disorders. PMID:19826615

  1. Dopamine and Psychosis: Theory, Pathomechanisms and Intermediate Phenotypes

    PubMed Central

    Tost, Heike; Alam, Tajvar; Meyer-Lindenberg, Andreas

    2009-01-01

    Schizophrenia is a chronic, severe, and disabling brain disorder arising from the adverse interaction of predisposing risk genes and environmental factors. The psychopathology is characterized by a wide array of disturbing cognitive, emotional, and behavioral symptoms that interfere with the individual's capacity to function in society. Contemporary pathophysiological models assume that psychotic symptoms are triggered by a dysregulation of dopaminergic activity in the brain, a theory that is tightly linked to the serendipitous discovery of the first effective antipsychotic agents in the early 1950s. In recent years, the availability of modern neuroimaging techniques has significantly expanded our understanding of the key mediator circuits that bridge the gap between genetic susceptibility and clinical phenotype. This paper discusses the pathophysiological concepts, molecular mechanisms and neuroimaging evidence that link psychosis to disturbances in dopamine neurotransmission. PMID:19559045

  2. A unique conformation of the anticodon stem-loop is associated with the capacity of tRNAfMet to initiate protein synthesis.

    PubMed

    Barraud, Pierre; Schmitt, Emmanuelle; Mechulam, Yves; Dardel, Frédéric; Tisné, Carine

    2008-09-01

    In all organisms, translational initiation takes place on the small ribosomal subunit and two classes of methionine tRNA are present. The initiator is used exclusively for initiation of protein synthesis while the elongator is used for inserting methionine internally in the nascent polypeptide chain. The crystal structure of Escherichia coli initiator tRNA(f)(Met) has been solved at 3.1 A resolution. The anticodon region is well-defined and reveals a unique structure, which has not been described in any other tRNA. It encompasses a Cm32*A38 base pair with a peculiar geometry extending the anticodon helix, a base triple between A37 and the G29-C41 pair in the major groove of the anticodon stem and a modified stacking organization of the anticodon loop. This conformation is associated with the three GC basepairs in the anticodon stem, characteristic of initiator tRNAs and suggests a mechanism by which the translation initiation machinery could discriminate the initiator tRNA from all other tRNAs. PMID:18653533

  3. Characterization of dopamine D2 receptors in the pituitary of the African catfish, Clarias gariepinus

    SciTech Connect

    Van Asselt, L.A.; Goos, H.J.; De Leeuw, R.; Peter, R.E.; Hol, E.M.; Wassenberg, F.P.; Van Oordt, P.G. )

    1990-10-01

    Dopamine receptors in the pituitary of the African catfish, Clarias gariepinus, were characterized using ({sup 3}H)spiperone as radioligand. Specific binding of ({sup 3}H)spiperone to pituitary membranes reached equilibrium within 60 min of incubation. The binding of the radioligand was tissue specific since the amount of binding was linear with pituitary membrane content in the incubations. In addition, pituitary membranes were observed to bind considerably more ({sup 3}H)spiperone, compared to membrane preparation of various other tissues. Saturation experiments revealed the presence of a single class of high affinity/low capacity binding sites. The binding characteristics, estimated by Scatchard analysis, were: Kd = 3.2 +/- 0.5 x 10(-9) M and Bmax = 105 +/- 5 fmol/mg protein. Specific binding was displaceable with dopamine and with various specific D2 agonists and antagonists. The nature of displacement curves resembles those observed in studies on mammalian dopamine receptors. Binding experiments with cell fractions, obtained after centrifugation of dispersed pituitary cells over a Percoll density gradient, showed that most ({sup 3}H)spiperone binding was obtained in an enriched gonadotropic cell fraction. This observation indicates that the receptor characteristics, estimated with the ({sup 3}H)spiperone assay, are representative for dopamine receptors on the gonadotropic cells.

  4. Synthesis of the Danish Experience with Combating Nutrient Pollution of Surface Waters: The Old Regulatory Approach and a New Targeted Approach Utilising the Natural Attenuation Capacity in Landscapes

    NASA Astrophysics Data System (ADS)

    Kronvang, Brian; Windolf, Jørgen; Blicher-Mathiesen, Gitte; Tornbjerg, Henrik; Højberg, Anker; Rieman, Bo

    2016-04-01

    Excess nitrogen (N) and phosphorus (P) emissions to surface waters are a high priority environmental problem worldwide for protection of water resources in times of population growth and climate change. As clean water is a scarce resource the struggle for reducing nutrient emissions are an ongoing issue for many countries and regions. Since the mid1980s a wide range of national regulatory general measures have been implemented to reduce land based nitrogen (N) and phosphorus (P) loadings of the Danish aquatic environment. These measures have addressed both point source emissions and emissions from diffuse sources especially from agricultural production. Following nearly 4 decades of combating nutrient pollution our surface waters such as lakes and estuaries are only slowly responding on the 50% reduction in N and 56% reduction in P. Therefore, the implementation of the EU Water Framework Directive in Danish surface waters still call for further reductions of N and P loadings. Introduction of a new paradigm of targeted implemented measures was the proposed outcome of a Commission on Nature and Agriculture established by the Danish Government in 2013. Their White Book points to the need of increased growth and better environment through more targeted and efficient regulation using advanced technological mitigation methods that are implemented intelligently according to the local natural attenuation capacity for nutrients in the landscape. As a follow up a national consensus model for N was established chaining existing leaching, 3D groundwater and surface water models. The new model concept enables a calculation of the N dynamics and attenuation capacity within a scale of 15 km2. Moreover, several research projects have been conducted to investigate the effect of a suite of targeted mitigation measures such as restored natural wetlands, constructed wetlands, controlled drainage and intelligent buffer zones. The outcome of six Danish management plans for nutrient load

  5. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1

    PubMed Central

    Dong, Zhizhong; Ferger, Boris; Paterna, Jean-Charles; Vogel, Denise; Furler, Sven; Osinde, Maribel; Feldon, Joram; Büeler, Hansruedi

    2003-01-01

    Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1. AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantia nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP. PMID:14530399

  6. Genetics Home Reference: dopamine beta-hydroxylase deficiency

    MedlinePlus

    ... CONGENITAL Sources for This Page Cubells JF, Zabetian CP. Human genetics of plasma dopamine beta-hydroxylase activity: ... GeneReview: Dopamine Beta-Hydroxylase Deficiency Kim CH, Zabetian CP, Cubells JF, Cho S, Biaggioni I, Cohen BM, Robertson ...

  7. Brain May Compensate for Dopamine Neuron Loss Early in Parkinson's

    MedlinePlus

    ... More Science News Brain May Compensate for Dopamine Neuron Loss Early in Parkinson’s - May 09 2014 Scientists ... at least 25 percent of the brain’s dopamine neurons already have been lost. So why do symptoms ...

  8. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease

    SciTech Connect

    Lindvall, O.; Brundin, P.; Widner, H.; Rehncrona, S.; Gustavii, B.; Frackowiak, R.; Leenders, K.L.; Sawle, G.; Rothwell, J.C.; Marsden, C.D. )

    1990-02-02

    Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-({sup 18}F)fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the on-off phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.

  9. Fabrication of gold nanorods with tunable longitudinal surface plasmon resonance peaks by reductive dopamine.

    PubMed

    Su, Gaoxing; Yang, Chi; Zhu, Jun-Jie

    2015-01-20

    Hydroxyphenol compounds are often used as reductants in controlling the growth of nanoparticles. Herein, dopamine was used as an effective reductant in seed-mediated synthesis of gold nanorods (GNRs). The as-prepared GNRs (83 × 16 nm) were monodisperse and had a high degree of purity. The conversion ratio from gold ions to GNRs was around 80%. In addition, dopamine worked as an additive. At a very low concentration of hexadecyltrimethylammonium bromide (CTAB; 0.025 M), thinner and shorter GNRs (60 × 9 nm) were successfully prepared. By regulating the concentration of silver ions, CTAB, seeds, and reductant, GNRs with longitudinal surface plasmon resonance (LSPR) peaks ranging from 680 to 1030 nm were synthesized. The growth process was tracked using UV-vis-NIR spectroscopy, and it was found that a slow growth rate was beneficial to the formation of GNRs. PMID:25521416

  10. Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

    PubMed

    MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

    2016-07-01

    Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists. PMID:26942320