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Sample records for human dopamine d2long

  1. Increased consumption of ethanol and sugar water in mice lacking the dopamine D2 long receptor.

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    Bulwa, Zachary B; Sharlin, Jordan A; Clark, Peter J; Bhattacharya, Tushar K; Kilby, Chessa N; Wang, Yanyan; Rhodes, Justin S

    2011-11-01

    Individual differences in dopamine D2 receptor (D2R) expression in the brain are thought to influence motivation and reinforcement for ethanol and other rewards. D2R exists in two isoforms, D2 long (D2LR) and D2 short (D2SR), produced by alternative splicing of the same gene. The relative contributions of D2LR versus D2SR to ethanol and sugar water drinking are not known. Genetic engineering was used to produce a line of knockout (KO) mice that lack D2LR and consequently have increased expression of D2SR. KO and wild-type (WT) mice of both sexes were tested for intake of 20% ethanol, 10% sugar water and plain tap water using established drinking-in-the-dark procedures. Mice were also tested for effects of the D2 antagonist eticlopride on intake of ethanol to determine whether KO responses were caused by lack of D2LR or overrepresentation of D2SR. Locomotor activity on running wheels and in cages without wheels was also measured for comparison. D2L KO mice drank significantly more ethanol than WT in both sexes. KO mice drank more sugar water than WT in females but not in males. Eticlopride dose dependently decreased ethanol intake in all groups except male KO. KO mice were less physically active than WT in cages with or without running wheels. Results suggest that overrepresentation of D2SR contributes to increased intake of ethanol in the KO mice. Decreasing wheel running and general levels of physical activity in the KO mice rules out the possibility that higher intake results from higher motor activity. Results extend the literature implicating altered expression of D2R in risk for addiction by delineating the contribution of individual D2R isoforms. These findings suggest that D2LR and D2SR play differential roles in consumption of alcohol and sugar rewards.

  2. Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

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    Rothmond Debora A

    2012-02-01

    Full Text Available Abstract Background Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5, catechol-O-methyltransferase, and monoamine oxidase (A and B in the developing human DLPFC (6 weeks -50 years. Results Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p O-methyltransferase (p = 0.024 were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027. In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002 and dopamine D1 receptor protein expression increased throughout development (p Conclusions We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

  3. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

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    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  4. Dopamine receptor activation increases HIV entry into primary human macrophages.

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    Peter J Gaskill

    Full Text Available Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

  5. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

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    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R. [Department of Molecular Genetics, Weizmann Institute of Science Rehovot 76100 (Israel)

    1996-09-01

    Human neuroblastoma NMB cells take up [{sup 3}H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [{sup 3}H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [{sup 3}H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996

  6. Dopamine in the medial amygdala network mediates human bonding

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    Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

    2017-01-01

    Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

  7. Dopamine function and the efficiency of human movement.

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    Gepshtein, Sergei; Li, Xiaoyan; Snider, Joseph; Plank, Markus; Lee, Dongpyo; Poizner, Howard

    2014-03-01

    To sustain successful behavior in dynamic environments, active organisms must be able to learn from the consequences of their actions and predict action outcomes. One of the most important discoveries in systems neuroscience over the last 15 years has been about the key role of the neurotransmitter dopamine in mediating such active behavior. Dopamine cell firing was found to encode differences between the expected and obtained outcomes of actions. Although activity of dopamine cells does not specify movements themselves, a recent study in humans has suggested that tonic levels of dopamine in the dorsal striatum may in part enable normal movement by encoding sensitivity to the energy cost of a movement, providing an implicit "motor motivational" signal for movement. We investigated the motivational hypothesis of dopamine by studying motor performance of patients with Parkinson disease who have marked dopamine depletion in the dorsal striatum and compared their performance with that of elderly healthy adults. All participants performed rapid sequential movements to visual targets associated with different risk and different energy costs, countered or assisted by gravity. In conditions of low energy cost, patients performed surprisingly well, similar to prescriptions of an ideal planner and healthy participants. As energy costs increased, however, performance of patients with Parkinson disease dropped markedly below the prescriptions for action by an ideal planner and below performance of healthy elderly participants. The results indicate that the ability for efficient planning depends on the energy cost of action and that the effect of energy cost on action is mediated by dopamine.

  8. Dopamine receptor repertoire of human granulosa cells

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    Kunz Lars

    2007-10-01

    Full Text Available Abstract Background High levels of dopamine (DA were described in human ovary and recently evidence for DA receptors in granulosa and luteal cells has been provided, as well. However, neither the full repertoire of ovarian receptors for DA, nor their specific role, is established. Human granulosa cells (GCs derived from women undergoing in vitro fertilization (IVF are an adequate model for endocrine cells of the follicle and the corpus luteum and were therefore employed in an attempt to decipher their DA receptor repertoire and functionality. Methods Cells were obtained from patients undergoing IVF and examined using cDNA-array, RT-PCR, Western blotting and immunocytochemistry. In addition, calcium measurements (with FLUO-4 were employed. Expression of two DA receptors was also examined by in-situ hybridization in rat ovary. Effects of DA on cell viability and cell volume were studied by using an ATP assay and an electronic cell counter system. Results We found members of the two DA receptor families (D1- and D2 -like associated with different signaling pathways in human GCs, namely D1 (as expected and D5 (both are Gs coupled and linked to cAMP increase and D2, D4 (Gi/Gq coupled and linked to IP3/DAG. D3 was not found. The presence of the trophic hormone hCG (10 IU/ml in the culture medium for several days did not alter mRNA (semiquantitative RT-PCR or protein levels (immunocytochemistry/Western blotting of D1,2,4,5 DA receptors. Expression of prototype receptors for the two families, D1 and D2, was furthermore shown in rat granulosa and luteal cells by in situ hybridization. Among the DA receptors found in human GCs, D2 expression was marked both at mRNA and protein levels and it was therefore further studied. Results of additional RT-PCR and Western blots showed two splice variants (D2L, D2S. Irrespective of these variants, D2 proved to be functional, as DA raised intracellular calcium levels. This calcium mobilizing effect of DA was observed

  9. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

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    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  10. Dorsal striatal dopamine, food preference and health perception in humans

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    Wallace, D.L.; Aarts, E.; Dang, L.C.; Greer, S.M.; Jagust, W.J.; D'Esposito, M.

    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 [(18)F]fluorometatyrosine (FMT), correlates with food-related

  11. Dorsal striatal dopamine, food preference and health perception in humans.

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    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 [(18)F]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.

  12. Seasonal effects on human striatal presynaptic dopamine synthesis.

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    Eisenberg, Daniel P; Kohn, Philip D; Baller, Erica B; Bronstein, Joel A; Masdeu, Joseph C; Berman, Karen F

    2010-11-01

    Past studies in rodents have demonstrated circannual variation in central dopaminergic activity as well as a host of compelling interactions between melatonin--a scotoperiod-responsive neurohormone closely tied to seasonal adaptation--and dopamine in the striatum and in midbrain neuronal populations with striatal projections. In humans, seasonal effects have been described for dopaminergic markers in CSF and postmortem brain, and there exists a range of affective, psychotic, and substance abuse disorders that have been associated with both seasonal symptomatic fluctuations and dopamine neurotransmission abnormalities. Together, these data indirectly suggest a potentially crucial link between circannual biorhythms and central dopamine systems. However, seasonal effects on dopamine function in the living, healthy human brain have never been tested. For this study, 86 healthy adults underwent (18)F-DOPA positron emission tomography scanning, each at a different time throughout the year. Striatal regions of interest (ROIs) were evaluated for differences in presynaptic dopamine synthesis, measured by the kinetic rate constant, K(i), between fall-winter and spring-summer scans. Analyses comparing ROI average K(i) values showed significantly greater putamen (18)F-DOPA K(i) in the fall-winter relative to the spring-summer group (p = 0.038). Analyses comparing voxelwise K(i) values confirmed this finding and evidenced intrastriatal localization of seasonal effects to the caudal putamen (p rate corrected), a region that receives dopaminergic input predominantly from the substantia nigra. These data are the first to directly demonstrate a seasonal effect on striatal presynaptic dopamine synthesis and merit future research aimed at elucidating underlying mechanisms and implications for neuropsychiatric disease and new treatment approaches.

  13. The crystal structure of human dopamine  β-hydroxylase at 2.9 Å resolution

    DEFF Research Database (Denmark)

    Vendelboe, Trine Vammen; Harris, Pernille; Zhao, Y.

    2016-01-01

    , Alzheimer’s disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600...

  14. Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake.

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    Yuan, Yaxia; Quizon, Pamela M; Sun, Wei-Lun; Yao, Jianzhuang; Zhu, Jun; Zhan, Chang-Guo

    2016-06-02

    HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the Vmax of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the Vmax of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND.

  15. Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein.

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    Lam, Hoa A; Wu, Nanping; Cely, Ingrid; Kelly, Rachel L; Hean, Sindalana; Richter, Franziska; Magen, Iddo; Cepeda, Carlos; Ackerson, Larry C; Walwyn, Wendy; Masliah, Eliezer; Chesselet, Marie-Françoise; Levine, Michael S; Maidment, Nigel T

    2011-07-01

    Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine. Copyright © 2011 Wiley-Liss, Inc.

  16. Measuring dopamine release in the human brain with PET

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    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York at Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry; Fowler, J.S.; Logan, J.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)

    1995-12-01

    The dopamine system is involved in the regulation of brain regions that subserve motor, cognitive and motivational behaviors. Disruptions of dopamine (DA) function have ben implicated in neurological and psychiatric illnesses including substance abuse as well as on some of the deficits associated with aging of the human brain. This has made the DA system an important topic in research in the neurosciences and neuroimaging as well as an important molecular target for drug development. Positron Emission Tomography (PET), was the first technology that enabled direct measurement of components of the DA system in the living human brain. Imaging studies of DA in the living brain have been indirect, relying on the development of radiotracers to label DA receptors, DA transporters, compounds which have specificity for the enzymes which degrade synaptic DA. Additionally, through the use of tracers that provide information on regional brain activity (ie brain glucose metabolism and cerebral blood flow) and of appropriate pharmacological interventions, it has been possible to assess the functional consequences of changes in brain DA activity. DA specific ligands have been useful in the evaluation of patients with neuropsychiatric illnesses as well as to investigate receptor blockade by antipsychotic drugs. A limitation of strategies that rely on the use of DA specific ligands is that the measures do not necessarily reflect the functional state of the dopaminergic system and that there use to study the effects of drugs is limited to the investigation of receptor or transporter occupancy. Newer strategies have been developed in an attempt to provide with information on dopamine release and on the functional responsivity of the DA system in the human brain. This in turn allows to investigate the effects of pharmacological agent in an analogous way to what is done with microdialysis techniques.

  17. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN

    2007-01-01

    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  18. Human cognitive flexibility depends on dopamine D2 receptor signaling

    NARCIS (Netherlands)

    Holstein, M.G.A. van; Aarts, E.; Schaaf, M.E. van der; Geurts, D.E.M.; Verkes, R.J.; Franke, B.; Schouwenburg, M.R. van; Cools, R.

    2011-01-01

    RATIONALE: Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling.

  19. Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans

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    Niewinski, Piotr; Tubek, Stanislaw; Banasiak, Waldemar; Paton, Julian F R; Ponikowski, Piotr

    2014-01-01

    Low-dose dopamine inhibits peripheral chemoreceptors and attenuates the hypoxic ventilatory response (HVR) in humans. However, it is unknown: (1) whether it also modulates the haemodynamic reactions to acute hypoxia, (2) whether it also modulates cardiac baroreflex sensitivity (BRS) and (3) if there is any effect of dopamine withdrawal. We performed a double-blind, placebo-controlled study on 11 healthy male volunteers. At sea level over 2 days every subject was administered low-dose dopamine (2 μg kg–1 min–1) or saline infusion, during which we assessed both ventilatory and haemodynamic responses to acute hypoxia. Separately, we evaluated effects of initiation and withdrawal of each infusion and BRS. The initiation of dopamine infusion did not affect minute ventilation (MV) or mean blood pressure (MAP), but increased both heart rate (HR) and cardiac output. Concomitantly, it decreased systemic vascular resistance. Dopamine blunted the ventilatory, MAP and HR reactions (hypertension, tachycardia) to acute hypoxia. Dopamine attenuated cardiac BRS to falling blood pressure. Dopamine withdrawal evoked an increase in MV. The magnitude of the increment in MV due to dopamine withdrawal correlated with the size of the HVR and depended on the duration of dopamine administration. The ventilatory reaction to dopamine withdrawal constitutes a novel index of peripheral chemoreceptor function. PMID:24396060

  20. Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans.

    Science.gov (United States)

    Niewinski, Piotr; Tubek, Stanislaw; Banasiak, Waldemar; Paton, Julian F R; Ponikowski, Piotr

    2014-03-15

    Low-dose dopamine inhibits peripheral chemoreceptors and attenuates the hypoxic ventilatory response (HVR) in humans. However, it is unknown: (1) whether it also modulates the haemodynamic reactions to acute hypoxia, (2) whether it also modulates cardiac baroreflex sensitivity (BRS) and (3) if there is any effect of dopamine withdrawal. We performed a double-blind, placebo-controlled study on 11 healthy male volunteers. At sea level over 2 days every subject was administered low-dose dopamine (2 μg kg(-1) min(-1)) or saline infusion, during which we assessed both ventilatory and haemodynamic responses to acute hypoxia. Separately, we evaluated effects of initiation and withdrawal of each infusion and BRS. The initiation of dopamine infusion did not affect minute ventilation (MV) or mean blood pressure (MAP), but increased both heart rate (HR) and cardiac output. Concomitantly, it decreased systemic vascular resistance. Dopamine blunted the ventilatory, MAP and HR reactions (hypertension, tachycardia) to acute hypoxia. Dopamine attenuated cardiac BRS to falling blood pressure. Dopamine withdrawal evoked an increase in MV. The magnitude of the increment in MV due to dopamine withdrawal correlated with the size of the HVR and depended on the duration of dopamine administration. The ventilatory reaction to dopamine withdrawal constitutes a novel index of peripheral chemoreceptor function.

  1. Study of human dopamine sulfotransferases based on gene expression programming.

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    Si, Hongzong; Zhao, Jiangang; Cui, Lianhua; Lian, Ning; Feng, Hanlin; Duan, Yun-Bo; Hu, Zhide

    2011-09-01

    A quantitative model is developed to predict the Km of 47 human dopamine sulfotransferases by gene expression programming. Each kind of compound is represented by several calculated structural descriptors of moment of inertia A, average electrophilic reactivity index for a C atom, relative number of triple bonds, RNCG relative negative charge, HA-dependent HDSA-1, and HBCA H-bonding charged surface area. Eight fitness functions of the gene expression programming method are used to find the best nonlinear model. The best quantitative model with squared standard error and square of correlation coefficient are 0.096 and 0.91 for training data set, and 0.102 and 0.88 for test set, respectively. It is shown that the gene expression programming-predicted results with fitness function are in good agreement with experimental ones.

  2. Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

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    Soden, Marta E; Jones, Graham L; Sanford, Christina A; Chung, Amanda S; Güler, Ali D; Chavkin, Charles; Luján, Rafael; Zweifel, Larry S

    2013-11-20

    The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.

  3. Role of dopamine D2 receptors in human reinforcement learning.

    Science.gov (United States)

    Eisenegger, Christoph; Naef, Michael; Linssen, Anke; Clark, Luke; Gandamaneni, Praveen K; Müller, Ulrich; Robbins, Trevor W

    2014-09-01

    Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.

  4. New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

    Science.gov (United States)

    Shumay, Elena; Wiers, Corinde E; Shokri-Kojori, Ehsan; Kim, Sung Won; Hodgkinson, Colin A; Sun, Hui; Tomasi, Dardo; Wong, Christopher T; Weinberger, Daniel R; Wang, Gene-Jack; Fowler, Joanna S; Volkow, Nora D

    2017-05-10

    The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [(11)C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [(11)C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase

  5. Does human presynaptic striatal dopamine function predict social conformity?

    Science.gov (United States)

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  6. Expression, purification and characterization of human Dopamine ß-monooxygenase

    DEFF Research Database (Denmark)

    Vendelboe, Trine Vammen

    This thesis deals with expression, purification and characterization of the copper containing enzyme dopamine ß-monooxygenase (DBM). DBM is an ascorbate dependent protein that requires Cu in the active site in order to be functional. DBM is made of four domains; An Nterminal DOMON domain, the two...... others, one of the reasons why these proteins are considered to follow the same mechanism. DBM converts dopamine (DA) into Norepinphrine (NE). Both substrate and product functions as neurotransmitters and the levels of these are involved in many different disorders such as depression and hypertension...

  7. Dopamine natriuresis in salt-repleted, water-loaded humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Olsen, M H; Bonde, J

    1997-01-01

    The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers.......The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers....

  8. Dopamine natriuresis in salt-repleted, water-loaded humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Olsen, M H; Bonde, J

    1997-01-01

    The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers.......The purpose of the present study was to define the dose-response relationship between exogenous dopamine and systemic haemodynamics, renal haemodynamics, and renal excretory function at infusion rates in the range 0 to 12.5 microg kg(-1) min(-1) in normal volunteers....

  9. Expression, purification and characterization of human Dopamine ß-monooxygenase

    DEFF Research Database (Denmark)

    Vendelboe, Trine Vammen

    This thesis deals with expression, purification and characterization of the copper containing enzyme dopamine ß-monooxygenase (DBM). DBM is an ascorbate dependent protein that requires Cu in the active site in order to be functional. DBM is made of four domains; An Nterminal DOMON domain, the two...... others, one of the reasons why these proteins are considered to follow the same mechanism. DBM converts dopamine (DA) into Norepinphrine (NE). Both substrate and product functions as neurotransmitters and the levels of these are involved in many different disorders such as depression and hypertension...

  10. Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Volkow N. D.; Fowler J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi F.

    2012-03-23

    Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [{sup 11}C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([{sup 11}C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [{sup 11}C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

  11. Autoradiographic localisation of D-3-dopamine receptors in the human brain using the selective D-3-dopamine receptor agonist (+)-[H-3]PD 128907

    NARCIS (Netherlands)

    Hall, H; Halldin, C; Dijkstra, D; Wikstrom, H; Wise, LD; Pugsley, TA; Sokoloff, P; Pauli, S; Farde, L; Sedvall, G

    1996-01-01

    The selective D-3-dopamine receptor agonist 4aR,10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-[N-propyl-2,3- H-3]-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol ([H-3]PD 128907) was used to visualise D-3-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [H-3]PD 128907 has an 18

  12. Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro

    NARCIS (Netherlands)

    Nugroho, AK; Li, L; Dijkstra, D; Wikstrom, H; Danhof, M; Bouwstra, JA

    2005-01-01

    The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and

  13. BOLD and its connection to dopamine release in human striatum: a cross-cohort comparison

    Science.gov (United States)

    Lohrenz, Terry; Kishida, Kenneth T.

    2016-01-01

    Activity in midbrain dopamine neurons modulates the release of dopamine in terminal structures including the striatum, and controls reward-dependent valuation and choice. This fluctuating release of dopamine is thought to encode reward prediction error (RPE) signals and other value-related information crucial to decision-making, and such models have been used to track prediction error signals in the striatum as encoded by BOLD signals. However, until recently there have been no comparisons of BOLD responses and dopamine responses except for one clear correlation of these two signals in rodents. No such comparisons have been made in humans. Here, we report on the connection between the RPE-related BOLD signal recorded in one group of subjects carrying out an investment task, and the corresponding dopamine signal recorded directly using fast-scan cyclic voltammetry in a separate group of Parkinson's disease patients undergoing DBS surgery while performing the same task. The data display some correspondence between the signal types; however, there is not a one-to-one relationship. Further work is necessary to quantify the relationship between dopamine release, the BOLD signal and the computational models that have guided our understanding of both at the level of the striatum. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’. PMID:27574306

  14. Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter.

    Science.gov (United States)

    Shekar, Aparna; Aguilar, Jenny I; Galli, Greta; Cozzi, Nicholas V; Brandt, Simon D; Ruoho, Arnold E; Baumann, Michael H; Matthies, Heinrich J G; Galli, Aurelio

    2017-10-01

    Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act at the dopamine (DA) transporter (DAT). Several groups have described the ability of MDPV to block the DAT with high-affinity. In this study, we demonstrate for the first time a new mode of action of MDPV, namely its ability to promote DAT-mediated DA efflux. Using single cell amperometric assays, we determined that low concentrations of MDPV (1nM) can cause reverse transport of DA via DAT. Notably, administration of MDPV leads to hyperlocomotion in Drosophila melanogaster. These data describe further how MDPV acts at the DAT, possibly paving the way for novel treatment strategies for individuals who abuse bath salts. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Constitutive oligomerization of human D2 dopamine receptors expressed in Spodoptera frugiperda 9 (Sf9) and in HEK293 cells. Analysis using co-immunoprecipitation and time-resolved fluorescence resonance energy transfer.

    Science.gov (United States)

    Gazi, Lucien; López-Giménez, Juan F; Rüdiger, Martin P; Strange, Philip G

    2003-10-01

    Human D2Long (D2L) and D2Short (D2S) dopamine receptor isoforms were modified at their N-terminus by the addition of a human immunodeficiency virus (HIV) or a FLAG epitope tag. The receptors were then expressed in Spodoptera frugiperda 9 (Sf9) cells using the baculovirus system, and their oligomerization was investigated by means of co-immunoprecipitation and time-resolved fluorescence resonance energy transfer (FRET). [3H]Spiperone labelled D2 receptors in membranes prepared from Sf9 cells expressing epitope-tagged D2L or D2S receptors, with a pKd value of approximately 10. Co-immunoprecipitation using antibodies specific for the tags showed constitutive homo-oligomerization of D2L and D2S receptors in Sf9 cells. When the FLAG-tagged D2S and HIV-tagged D2L receptors were co-expressed, co-immunoprecipitation showed that the two isoforms can also form hetero-oligomers in Sf9 cells. Time-resolved FRET with europium and XL665-labelled antibodies was applied to whole Sf9 cells and to membranes from Sf9 cells expressing epitope-tagged D2 receptors. In both cases, constitutive homo-oligomers were revealed for D2L and D2S isoforms. Time-resolved FRET also revealed constitutive homo-oligomers in HEK293 cells expressing FLAG-tagged D2S receptors. The D2 receptor ligands dopamine, R-(-)propylnorapomorphine, and raclopride did not affect oligomerization of D2L and D2S in Sf9 and HEK293 cells. Human D2 dopamine receptors can therefore form constitutive oligomers in Sf9 cells and in HEK293 cells that can be detected by different approaches, and D2 oligomerization in these cells is not regulated by ligands.

  16. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    Science.gov (United States)

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  17. Human Dopamine Receptors Interaction Network (DRIN): a systems biology perspective on topology, stability and functionality of the network.

    Science.gov (United States)

    Podder, Avijit; Jatana, Nidhi; Latha, N

    2014-09-21

    Dopamine receptors (DR) are one of the major neurotransmitter receptors present in human brain. Malfunctioning of these receptors is well established to trigger many neurological and psychiatric disorders. Taking into consideration that proteins function collectively in a network for most of the biological processes, the present study is aimed to depict the interactions between all dopamine receptors following a systems biology approach. To capture comprehensive interactions of candidate proteins associated with human dopamine receptors, we performed a protein-protein interaction network (PPIN) analysis of all five receptors and their protein partners by mapping them into human interactome and constructed a human Dopamine Receptors Interaction Network (DRIN). We explored the topology of dopamine receptors as molecular network, revealing their characteristics and the role of central network elements. More to the point, a sub-network analysis was done to determine major functional clusters in human DRIN that govern key neurological pathways. Besides, interacting proteins in a pathway were characterized and prioritized based on their affinity for utmost drug molecules. The vulnerability of different networks to the dysfunction of diverse combination of components was estimated under random and direct attack scenarios. To the best of our knowledge, the current study is unique to put all five dopamine receptors together in a common interaction network and to understand the functionality of interacting proteins collectively. Our study pinpointed distinctive topological and functional properties of human dopamine receptors that have helped in identifying potential therapeutic drug targets in the dopamine interaction network.

  18. Predicting dopamine D2 receptor occupancy in humans using a physiology-based approach

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A.; Grimwood, Sarah; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2011-01-01

    Objectives: A hybrid physiology-based pharmacokinetic and pharmacodynamic model (PBPKPD) was used to predict the time course of dopamine receptor occupancy (D2RO) in human striatum following the administration of antipsychotic (AP) drugs, using in vitro and in silico information. Methods: A hybrid P

  19. Translational Modeling in Schizophrenia : Predicting Human Dopamine D2 Receptor Occupancy

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M M; Danhof, Meindert; Proost, Johannes H

    2015-01-01

    OBJECTIVES: To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs. METHODS: A hybrid PBPKPD model, previousl

  20. Dopamine Regulation of Human Speech and Bird Song: A Critical Review

    Science.gov (United States)

    Simonyan, Kristina; Horwitz, Barry; Jarvis, Erich D.

    2012-01-01

    To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and…

  1. Dopamine Regulation of Human Speech and Bird Song: A Critical Review

    Science.gov (United States)

    Simonyan, Kristina; Horwitz, Barry; Jarvis, Erich D.

    2012-01-01

    To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and…

  2. Dopamine D2 receptor expression in the corticotroph cells of the human normal pituitary gland.

    Science.gov (United States)

    Pivonello, Rosario; Waaijers, Marlijn; Kros, Johan M; Pivonello, Claudia; de Angelis, Cristina; Cozzolino, Alessia; Colao, Annamaria; Lamberts, Steven W J; Hofland, Leo J

    2017-08-01

    The dopamine D2 receptor is the main dopamine receptor expressed in the human normal pituitary gland. The aim of the current study was to evaluate dopamine D2 receptor expression in the corticotroph cell populations of the anterior lobe and pars intermedia, as well as posterior lobe of the human normal pituitary gland by immunohistochemistry. Human normal pituitary gland samples obtained from routine autopsies were used for the study. In all cases, histology together with immunostaining for adrenocorticotropic hormone, melanocyte-stimulating hormone, prolactin, and neurofilaments were performed and compared to the immunostaining for D2 receptor. D2 receptor was heterogeneously expressed in the majority of the cell populations of the anterior and posterior lobe as well as in the area localized between the anterior and posterior lobe, and arbitrary defined as "intermediate zone". This zone, characterized by the presence of nerve fibers included the residual pars intermedia represented by the colloid-filled cysts lined by the remnant melanotroph cells strongly expressing D2 receptors, and clusters of corticotroph cells, belonging to the anterior lobe but localized within the cysts and adjacent to the posterior lobe, variably expressing D2 receptors. D2 dopamine receptor is expressed in the majority of the cell populations of the human normal pituitary gland, and particularly, in the different corticotroph cell populations localized in the anterior lobe and the intermediate zone of the pituitary gland.

  3. Data on overlapping brain disorders and emerging drug targets in human Dopamine Receptors Interaction Network

    Directory of Open Access Journals (Sweden)

    Avijit Podder

    2017-06-01

    Full Text Available Intercommunication of Dopamine Receptors (DRs with their associate protein partners is crucial to maintain regular brain function in human. Majority of the brain disorders arise due to malfunctioning of such communication process. Hence, contributions of genetic factors, as well as phenotypic indications for various neurological and psychiatric disorders are often attributed as sharing in nature. In our earlier research article entitled “Human Dopamine Receptors Interaction Network (DRIN: a systems biology perspective on topology, stability and functionality of the network” (Podder et al., 2014 [1], we had depicted a holistic interaction map of human Dopamine Receptors. Given emphasis on the topological parameters, we had characterized the functionality along with the vulnerable properties of the network. In support of this, we hereby provide an additional data highlighting the genetic overlapping of various brain disorders in the network. The data indicates the sharing nature of disease genes for various neurological and psychiatric disorders in dopamine receptors connecting protein-protein interactions network. The data also indicates toward an alternative approach to prioritize proteins for overlapping brain disorders as valuable drug targets in the network.

  4. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans.

    Science.gov (United States)

    Rogers, Robert D

    2011-01-01

    Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive

  5. Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport.

    Science.gov (United States)

    Quizon, Pamela M; Sun, Wei-Lun; Yuan, Yaxia; Midde, Narasimha M; Zhan, Chang-Guo; Zhu, Jun

    2016-12-14

    Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake. Other substitutions of histidine547 showed that DA uptake was not altered in H547R but decreased by 99% in H547P and 60% in H547D, respectively. These mutants did not alter DAT surface expression or surface DAT binding sites. H547 mutants attenuated Tat-induced inhibition of DA transport observed in WT hDAT. H547A displays a differential sensitivity to PMA- or BIM-induced activation or inhibition of DAT function relative to WT hDAT, indicating a change in basal PKC activity in H547A. These findings demonstrate that histidine547 on hDAT plays a crucial role in stabilizing basal DA transport and Tat-DAT interaction. This study provides mechanistic insights into identifying targets on DAT for Tat binding and improving DAT-mediated dysfunction of DA transmission.

  6. The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution.

    Science.gov (United States)

    Vendelboe, Trine V; Harris, Pernille; Zhao, Yuguang; Walter, Thomas S; Harlos, Karl; El Omari, Kamel; Christensen, Hans E M

    2016-04-01

    The norepinephrine pathway is believed to modulate behavioral and physiological processes, such as mood, overall arousal, and attention. Furthermore, abnormalities in the pathway have been linked to numerous diseases, for example hypertension, depression, anxiety, Parkinson's disease, schizophrenia, Alzheimer's disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600 other proteins, reveals a possible metal-binding site and a ligand-binding pocket. The catalytic core structure shows two different conformations: an open active site, as also seen in another member of this enzyme family [the peptidylglycine α-hydroxylating (and α-amidating) monooxygenase], and a closed active site structure, in which the two copper-binding sites are only 4 to 5 Å apart, in what might be a coupled binuclear copper site. The dimerization domain adopts a conformation that bears no resemblance to any other known protein structure. The structure provides new molecular insights into the numerous devastating disorders of both physiological and neurological origins associated with the dopamine system.

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

    Science.gov (United States)

    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.

  8. Striatal dopamine mediates the interface between motivational and cognitive control in humans: evidence from genetic imaging.

    Science.gov (United States)

    Aarts, Esther; Roelofs, Ardi; Franke, Barbara; Rijpkema, Mark; Fernández, Guillén; Helmich, Rick C; Cools, Roshan

    2010-08-01

    Dopamine has been hypothesized to provide the basis for the interaction between motivational and cognitive control. However, there is no evidence for this hypothesis in humans. We fill this gap by using fMRI, a novel behavioral paradigm and a common polymorphism in the DAT1 gene (SLC6A3). Carriers of the 9-repeat (9R) allele of a 40 base pair repeat polymorphism in the 3' untranslated region of DAT1, associated with high striatal dopamine, showed greater activity in the ventromedial striatum during reward anticipation than homozygotes for the 10-repeat allele, replicating previous genetic imaging studies. The crucial novel finding is that 9R carriers also exhibited a greater influence of anticipated reward on switch costs, as well as greater activity in the dorsomedial striatum during task switching in anticipation of high reward relative to low reward. These data establish a crucial role for human striatal dopamine in the modulation of cognitive flexibility by reward anticipation, thus, elucidating the neurochemical mechanism of the interaction between motivation and cognitive control.

  9. An Investigation of the Stoichiometry of Na+ Cotransport with Dopamine in Rat and Human Dopamine Transporters Expressed in Human Embryonic Kidney Cells

    Science.gov (United States)

    2001-05-01

    fine-tuning of movement and the coloring of mood (Blakely and Bauman, 2000). Dopamine and the neuronal dopamine transporter (DAT) have been studied... Halobacterium halobium. Translocation stoichiometries and apparent cooperativity. Biochemistry 17, 3011-3018. McElvain J. S. and Schenk J. O. (1992) A

  10. Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor

    DEFF Research Database (Denmark)

    Pedersen, U B; Norby, B; Jensen, Anders A.

    1994-01-01

    Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines...... for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl...... cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments...

  11. Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor

    DEFF Research Database (Denmark)

    Pedersen, U B; Norby, B; Jensen, Anders A.

    1994-01-01

    Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines...... for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl...... cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments...

  12. Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

    Science.gov (United States)

    Caravaggio, Fernando; Nakajima, Shinichiro; Borlido, Carol; Remington, Gary; Gerretsen, Philip; Wilson, Alan; Houle, Sylvain; Menon, Mahesh; Mamo, David; Graff-Guerrero, Ariel

    2014-01-01

    Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [11C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [11C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [11C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [11C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [11C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations. PMID:24874713

  13. Estimating endogenous dopamine levels at D2 and D3 receptors in humans using the agonist radiotracer [(11)C]-(+)-PHNO.

    Science.gov (United States)

    Caravaggio, Fernando; Nakajima, Shinichiro; Borlido, Carol; Remington, Gary; Gerretsen, Philip; Wilson, Alan; Houle, Sylvain; Menon, Mahesh; Mamo, David; Graff-Guerrero, Ariel

    2014-11-01

    Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [(11)C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [(11)C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [(11)C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [(11)C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [(11)C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations.

  14. Working memory capacity predicts dopamine synthesis capacity in the human striatum.

    NARCIS (Netherlands)

    Cools, R.; Gibbs, S.E.; Miyakawa, A.; Jagust, W.; D'Esposito, M.

    2008-01-01

    Evidence from psychopharmacological research has revealed that dopamine receptor agents have opposite effects on cognitive function depending on baseline levels of working memory capacity. These contrasting effects have been interpreted to reflect differential baseline levels of dopamine. Here we de

  15. Working memory capacity predicts dopamine synthesis capacity in the human striatum.

    NARCIS (Netherlands)

    Cools, R.; Gibbs, S.E.; Miyakawa, A.; Jagust, W.; D'Esposito, M.

    2008-01-01

    Evidence from psychopharmacological research has revealed that dopamine receptor agents have opposite effects on cognitive function depending on baseline levels of working memory capacity. These contrasting effects have been interpreted to reflect differential baseline levels of dopamine. Here we

  16. Dosage-dependent effect of dopamine D2 receptor activation on motor cortex plasticity in humans.

    Science.gov (United States)

    Fresnoza, Shane; Stiksrud, Elisabeth; Klinker, Florian; Liebetanz, David; Paulus, Walter; Kuo, Min-Fang; Nitsche, Michael A

    2014-08-06

    The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose-response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.

  17. Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism.

    Science.gov (United States)

    Sacchetti, P; Mitchell, T R; Granneman, J G; Bannon, M J

    2001-03-01

    The importance of the nuclear receptor nurr1 for the appropriate development of mesencephalic dopamine-synthesizing neurons has been clearly demonstrated through the targeted disruption of the nurr1 gene. The persistence of nurr1 expression in adult tissue suggests a possible role for this transcription factor in the maintenance, as well as development, of the dopaminergic phenotype. To address this issue, we analyzed the effects of nurr1 on the transcriptional expression of the human dopamine transporter gene (hDAT), one of the most specific phenotypic markers for dopaminergic neurons. Nurr1 enhanced the transcriptional activity of hDAT gene constructs transiently transfected into a newly described cell line (SN4741) that expresses a dopaminergic phenotype, whereas other members of the NGFI-B subfamily of nuclear receptors had lesser or no effects. Nurr1 activation of hDAT was not dependent upon heterodimerization with the retinoid X receptor. Unexpectedly, functional analysis of a series of gene constructs revealed that a region of the hDAT 5'-flanking sequence devoid of NGFI-B response element (NBRE)-like sites mediated nurr1 activation. Additional experiments using a nurr1 mutant construct suggest that nurr1 activates hDAT transcription via a novel NBRE-independent mechanism.

  18. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency

    Science.gov (United States)

    Kim, Chun-Hyung; Zabetian, Cyrus P.; Cubells, Joseph F.; Cho, Sonhae; Biaggioni, Italo; Cohen, Bruce M.; Robertson, David; Kim, Kwang-Soo

    2002-01-01

    Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.

  19. Expression of human dopamine receptor in potato (Solanum tuberosum results in altered tuber carbon metabolism

    Directory of Open Access Journals (Sweden)

    Świędrych Anna

    2005-02-01

    Full Text Available Abstract Background Even though the catecholamines (dopamine, norepinephrine and epinephrine have been detected in plants their role is poorly documented. Correlations between norepinephrine, soluble sugars and starch concentration have been recently reported for potato plants over-expressing tyrosine decarboxylase, the enzyme mediating the first step of catecholamine synthesis. More recently norepinephrine level was shown to significantly increase after osmotic stress, abscisic acid treatment and wounding. Therefore, it is possible that catecholamines might play a role in plant stress responses by modulating primary carbon metabolism, possibly by a mechanism similar to that in animal cells. Since to date no catecholamine receptor has been identified in plants we transformed potato plants with a cDNA encoding human dopamine receptor (HD1. Results Tuber analysis of transgenic plants revealed changes in the activities of key enzymes mediating sucrose to starch conversion (ADP-glucose phosphorylase and sucrose synthase and sucrose synthesis (sucrose phosphate synthase leading to altered content of both soluble sugars and starch. Surprisingly the catecholamine level measured in transgenic plants was significantly increased; the reason for this is as yet unknown. However the presence of the receptor affected a broader range of enzyme activities than those affected by the massive accumulation of norepinephrine reported for plants over-expressing tyrosine decarboxylase. Therefore, it is suggested that the presence of the exogenous receptor activates catecholamine cAMP signalling in plants. Conclusions Our data support the possible involvement of catecholamines in regulating plant carbon metabolism via cAMP signalling pathway.

  20. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    NARCIS (Netherlands)

    Bossong, MG; Mehta, Mitul; van Berckel, Bart; Howes, Oliver; Kahn, RS; Stokes, Paul

    2015-01-01

    RATIONALE: Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human

  1. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R

    2016-01-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...... and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A...

  2. Dopamine receptors and hypertension.

    Science.gov (United States)

    Banday, Anees Ahmad; Lokhandwala, Mustafa F

    2008-08-01

    Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D1-like and D2-like. Two D1-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D2-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D1-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D1-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.

  3. Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter.

    Science.gov (United States)

    Cameron, Krasnodara; Kolanos, Renata; Vekariya, Rakesh; Verkariya, Rakesh; De Felice, Louis; Glennon, Richard A

    2013-06-01

    Psychoactive "bath salts" represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated. Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes. Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine. Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine.

  4. Mephedrone and Methylenedioxypyrovalerone (MDPV), Major Constituents of Bath Salts, Produce Opposite Effects at the Human Dopamine Transporter*

    Science.gov (United States)

    Cameron, Krasnodara; Kolanos, Renata; Verkariya, Rakesh; De Felice, Louis; Glennon, Richard A.

    2013-01-01

    Rationale Psychoactive ‘bath salts’ represents a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of ‘bath salts’ include the cathinone analogs: mephedrone and methylenedioxy-pyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated. Materials and methods Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes. Results Whereas mephedrone was found to have the signature of a dopamine releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine. Conclusions Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in ‘bath salts’) might produce effects similar to a combination of methamphetamine and cocaine. PMID:23371489

  5. Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Chien, Ellen Y.T.; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A.; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A.; Cherezov, Vadim; Stevens, Raymond C. (Cornell); (Scripps); (NIDA); (Columbia); (UCSD); (Receptos)

    2010-11-30

    Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

  6. Presence of dopamine D-2 receptors in human tumoral cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Sokoloff, P.; Riou, J.F.; Martres, M.P.; Schwartz, J.C. (Centre Paul Broca, Paris (France))

    1989-07-31

    ({sup 125}I) Iodosulpride binding was examined on eight human cell lines derived from lung, breast and digestive tract carcinomas, neuroblastomas and leukemia. Specific binding was detected in five of these cell lines. In the richest cell line N417, derived from small cell lung carcinoma, ({sup 125}I) iodosulpride bound with a high affinity (Kd = 1.3 nM) to an apparently homogeneous population of binding site (Bmax = 1,606 sites per cell). These sites displayed a typical D-2 specificity, established with several dopaminergic agonists and antagonists selective of either D-1 or D-2 receptor subtypes. In addition, dopamine, apomorphine and RU 24926 distinguished high- and low-affinity sites, suggesting that the binding sites are associated with a G-protein. The biological significance and the possible diagnostic implication of the presence of D-2 receptors on these cell lines are discussed.

  7. Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells.

    Science.gov (United States)

    Aguila, Julio Cesar; Blak, Alexandra; van Arensbergen, Joris; Sousa, Amaia; Vázquez, Nerea; Aduriz, Ariane; Gayosso, Mayela; Lopez Mato, Maria Paz; Lopez de Maturana, Rakel; Hedlund, Eva; Sonntag, Kai-Christian; Sanchez-Pernaute, Rosario

    2014-09-01

    Human embryonic and induced pluripotent stem cells are potential cell sources for regenerative approaches in Parkinson disease. Inductive differentiation protocols can generate midbrain dopamine neurons but result in heterogeneous cell mixtures. Therefore, selection strategies are necessary to obtain uniform dopamine cell populations. Here, we developed a selection approach using lentivirus vectors to express green fluorescent protein under the promoter region of FOXA2, a transcription factor that is expressed in the floor plate domain that gives rise to dopamine neurons during embryogenesis. We first validated the specificity of the vectors in human cell lines against a promoterless construct. We then selected FOXA2-positive neural progenitors from several human pluripotent stem cell lines, which demonstrated a gene expression profile typical for the ventral domain of the midbrain and floor plate, but failed to enrich for dopamine neurons. To investigate whether this was due to the selection approach, we overexpressed FOXA2 in neural progenitors derived from human pluripotent stem cell lines. FOXA2 forced expression resulted in an increased expression of floor plate but not mature neuronal markers. Furthermore, selection of the FOXA2 overexpressing fraction also failed to enrich for dopamine neurons. Collectively, our results suggest that FOXA2 is not sufficient to induce a dopaminergic fate in this system. On the other hand, our study demonstrates that a combined approach of promoter activation and lentivirus vector technology can be used as a versatile tool for the selection of a defined cell population from a variety of human pluripotent stem cell lines. ©AlphaMed Press.

  8. An optical spot test for the detection of dopamine in human urine using stabilized in air lipid films.

    Science.gov (United States)

    Nikolelis, Dimitrios P; Drivelos, Dimitrios A; Simantiraki, Maria G; Koinis, Spyros

    2004-04-15

    The present technique describes a simple, sensitive spot test for the rapid one-shot detection of dopamine in human urine using lipid films with incorporated resorcin[4]arene receptor that are synthesized by a chemical reaction with a methacrylate polymer on a glass fiber filter. The lipid films without the receptor provided fluorescence under a UV lamp. The use of the receptor in these films quenched this fluorescence, and the color became similar to that of the filters without the lipid films. A drop of dopamine or urine containing this stimulant provided a "switching on" of the fluorescence, which allows the rapid detection of this stimulant in human urine at 10(-8) M concentrations. The novelty of the present work is that it opens new routes in the field of biosensing, i.e., development of sensitive, rapid, and simple methods for detecting species based on the fluorescence of the lipid membranes on a polymer film, and provides a spot test technique for the rapid detection of dopamine. The effect of potent interferences including a wide range of compounds usually found in human urine (i.e., ascorbic aid, glucose, leucine, glycine, tartrate, citrate, bicarbonate, and caffeine) was examined using an aqueous buffered solution that contained the potent interference and dopamine at two lower concentration levels (i.e., 3 x 10(-8)-10(-8) M). The effect of proteins and lipids was also investigated at these two lower dopamine concentration levels in aqueous buffered solution. The results showed no interferences from all these constituents at concentrations usually found in human urine samples; for example, albumin up to 3.22 g/L concentration levels did not provide any interference (i.e., no fluorescence). A drop of urine containing this stimulant provided similar results, i.e., a "switching on" of the fluorescence that allows a technique for the rapid detection of this stimulant in human urine at 10(-8) M concentrations. The technique is not based on a calibration

  9. Effects of dopamine D2 receptor partial agonist antipsychotic aripiprazole on dopamine synthesis in human brain measured by PET with L-[β-11C]DOPA.

    Directory of Open Access Journals (Sweden)

    Hiroshi Ito

    Full Text Available Dopamine D(2 receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D(2 receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [(11C]raclopride and L-[β-(11C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D(2 receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D(2 receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

  10. Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning

    NARCIS (Netherlands)

    Schaaf, M.E. van der; Schouwenburg, M.R. van; Geurts, D.E.M.; Schellekens, A.F.A.; Buitelaar, J.; Verkes, R.J.; Cools, R.

    2014-01-01

    Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment lea

  11. [sup 123]I-SCH 23982 is not suitable for dopamine D1 receptor imaging in vivo in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Verhoeff, N.P.L.G.; Fennema, P.; Royen, E.A. van (Academic Medical Centre, Amsterdam (Netherlands). Dept. of Nuclear Medicine); Bekier, A. (Kantonsspital, St Gallen (Switzerland). Inst. for Nuclear Medicine); Beer, H.-F.; Schubiger, P.A. (Paul Scherrer Inst. (PSI), Villigen (Switzerland))

    1993-02-01

    The tracer [sup 123]I-SCH 23982 was tested with regard to its ability to image dopamine D1 receptor in the human brain in vivo with single photon emission computed tomography (SPECT). The tracer did not reach equilibrium with regard to its bindign to dopamine D1 receptors, presumably owing to fast metabolism to hydrophilic products and deiodination. It is concluded that [sup 123]I-SCH 23982 is not suitable for dopamine D1 receptor imaging with SPECT in the human brain. (author).

  12. Identification of human dopamine D1-like receptor agonist using a cell-based functional assay

    Institute of Scientific and Technical Information of China (English)

    Nan JIANG; Ke-qing OU-YANG; Shao-xi CAI; Ying-he HU; Zhi-liang XU

    2005-01-01

    Aim: To establish a cell-based assay to screen human dopamine D1 and D5 receptor agonists against compounds from a natural product compound library.Methods: Synthetic responsive elements 6×cAMP response elements (CRE) and a mini promoter containing a TATA box were inserted into the pGL3 basic vector to generate the reporter gene construct pCRE/TA/Luci. CHO cells were co-transfected with the reporter gene construct and human D1 or D5 receptor cDNA in mammalian expression vectors. Stable cell lines were established for agonist screening. A natural product compound library from over 300 herbs has been established. The extracts from these herbs were used for human D1 and D5 receptor agonist screenings. Results: A number of extracts were identified that activated both D1 and D5 receptors. One of the herb extracts, SBG492, demonstrated distinct pharmacological characteristics with human D1 and D5 receptors.The EC50 values of SBG492 were 342.7 μg/mL for the D1 receptor and 31.7 μg/mL for the D5 receptor. Conclusion: We have established a cell-based assay for high-throughput drug screening to identify D 1-like receptor agonists from natural products. Several extracts that can active D1-like receptors were discovered.These compounds could be useful tools for studies on the functions of these receptors in the brain and could potentially be developed into therapeutic drugs for the treatment of central nervous system diseases.

  13. Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson's disease aetiology

    OpenAIRE

    Caneda-Ferrón, B; Girolamo, De, A.; Costa, T; Beck, KE; Layfield, R; Billett, EE

    2008-01-01

    Mitochondrial impairment, glutathione depletion and oxidative stress have been implicated in the pathogenesis of Parkinson’s disease (PD), linked recently to proteasomal dysfunction. Our study analysed how these factors influence the various activities of the proteasome in human SH-SY5Y neuroblastoma cells treated with the PD mimetics MPP+ (a complex 1 inhibitor) or dopamine. Treatment with these toxins led to dose- and time-dependent reductions in ATP and glutathione and also chymotrypsin-li...

  14. Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1998-01-01

    remained unchanged by pretreatment with metoprolol, and a comparison of dopamine and dobutamine in doses producing similar increases in cardiac output demonstrated that only dopamine increased ERPF. These findings indicate that indirect haemodynamic effects secondary to increases in cardiac contractility...... at these high doses. Although not affecting the percentage increase in CNa, metoprolol suppressed the absolute, maximal response to non-pressor doses of dopamine, suggesting that a reduced adrenergic beta(1) receptor activity may indirectly affect the natriuretic response, probably by decreasing renal perfusion...

  15. The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists

    Science.gov (United States)

    Kalani, M. Yashar S.; Vaidehi, Nagarajan; Hall, Spencer E.; Trabanino, Rene J.; Freddolino, Peter L.; Kalani, Maziyar A.; Floriano, Wely B.; Tak Kam, Victor Wai; Goddard, William A., III

    2004-03-01

    Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.e., we did not use bioinformatic or experimental 3D structural information in predicting structures). The predicted 3D structure is validated by comparison of the predicted binding site and the relative binding affinities of dopamine, three known dopamine agonists (antiparkinsonian), and seven known antagonists (antipsychotic) in the D2 receptor to experimentally determined values. These structures correctly predict the critical residues for binding dopamine and several antagonists, identified by mutation studies, and give relative binding affinities that correlate well with experiments. The predicted binding site for dopamine and agonists is located between transmembrane (TM) helices 3, 4, 5, and 6, whereas the best antagonists bind to a site involving TM helices 2, 3, 4, 6, and 7 with minimal contacts to TM helix 5. We identify characteristic differences between the binding sites of agonists and antagonists.

  16. Dopamine and angiotensin type 2 receptors cooperatively inhibit sodium transport in human renal proximal tubule cells.

    Science.gov (United States)

    Gildea, John J; Wang, Xiaoli; Shah, Neema; Tran, Hanh; Spinosa, Michael; Van Sciver, Robert; Sasaki, Midori; Yatabe, Junichi; Carey, Robert M; Jose, Pedro A; Felder, Robin A

    2012-08-01

    Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D(1)-like receptors (D(1)R/D(5)R) and the angiotensin type 2 receptor (AT(2)R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D(1)R/D(5)R stimulation increased plasma membrane AT(2)R 4-fold via a D(1)R-mediated, cAMP-coupled, and protein phosphatase 2A-dependent specific signaling pathway. D(1)R/D(5)R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal-regulated kinase, an effect that was partially reversed by an AT(2)R antagonist. Fenoldopam did not increase AT(2)R recruitment in renal proximal tubule cells with D(1)Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D(1)Rs and AT(2)Rs heterodimerized and cooperatively increased cAMP and cGMP production, protein phosphatase 2A activation, sodium-potassium-ATPase internalization, and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension.

  17. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims.

    Science.gov (United States)

    Mash, D C; Staley, J K

    1999-06-29

    Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one-to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.

  18. Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

    Science.gov (United States)

    Newton, Thomas F; Haile, Colin N; Mahoney, James J; Shah, Ravi; Verrico, Christopher D; De La Garza, Richard; Kosten, Thomas R

    2015-11-30

    Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

  19. Renal hemodynamics, tubular function, and response to low-dose dopamine during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Hansen, J M; Kanstrup, I L

    1993-01-01

    , heart rate, and plasma norepinephrine. Effective renal plasma flow (ERPF) decreased at HA by 10% (P sodium clearance (CNa), and urine flow remained unchanged compared with SL. Dopamine at SL and HA increased ERPF by 47% (P

  20. Effects of acute beta-adrenoceptor blockade with metoprolol on the renal response to dopamine in normal humans

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Lang-Jensen, T; Hansen, J M

    1994-01-01

    The present study investigated the contribution of adrenergic beta 1-receptor stimulation to the cardiovascular and renal effects of low-dose dopamine in eight normal, water-loaded humans. Metoprolol (100 mg) or placebo was administered orally at 08.00 h in a randomized, double-blind fashion on two...... different days. Renal clearance studies were performed during a 1 h baseline period, two 1 h periods with dopamine infusion (3 micrograms kg-1 min-1), and a 1 h recovery period. Cardiac output was measured by an ultrasonic Doppler method, and lithium clearance (CLLi) was used to estimate proximal tubular...... outflow. Baseline values of heart rate, systolic pressure and mean arterial pressure decreased with metoprolol compared with placebo, but cardiac output, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were not significantly changed. Metoprolol significantly decreased baseline CLLi...

  1. Binding of levomepromazine and cyamemazine to human recombinant dopamine receptor subtypes

    Directory of Open Access Journals (Sweden)

    Lalit K. Srivastava

    Full Text Available Background and Objectives: Clozapine (CLOZ and levomepromazine (LMP improve treatment-resistant schizophrenia. The superior efficacy of CLOZ compared with other antipsychotic agents has been attributed to an effect on D1-like and D4 receptors. We examined the binding of LMP, CLOZ and cyamemazine (CMZ, a neuroleptic analog of LMP, to human recombinant dopamine (rDA receptor subtypes. Methods: Binding studies were performed on frozen membrane suspensions of human rDA receptor subtypes expressed in Sf9 cells. Results: (i LMP has a high affinity (Ki, nM for rD2 receptor subtypes (rD2L 8.6; rD2S 4.3; rD3 8.3; rD4.2 7.9; (ii LMP and CLOZ have comparable affinities for the rD1 receptor (54.3 vs 34.6; (iii CMZ has high affinities for rD2-like and rD1-like receptors (rD2L 4.6; rD2S 3.3; rD3 6.2; rD4.2 8.5; rD1 3.9; rD5 10.7; (iv CMZ is 9 times more potent than CLOZ at the rD1 receptor and 5 times more potent than CLOZ at the rD4.2 receptor; (v CMZ has high affinities for rD1 and rD5 receptor subtypes compared with LMP and CLOZ. Conclusions: If D1 and D4 receptors are important sites for the unique action of CLOZ, the present study points to a need for clinical trials comparing CMZ with CLOZ in schizophrenia and in particular, treatment-resistant schizophrenia, especially given the risk for agranulocytosis with CLOZ.

  2. Binding of levomepromazine and cyamemazine to human recombinant dopamine receptor subtypes

    Directory of Open Access Journals (Sweden)

    Lalit K. Srivastava

    2009-09-01

    Full Text Available Background and Objectives: Clozapine (CLOZ and levomepromazine (LMP improve treatment-resistant schizophrenia. The superior efficacy of CLOZ compared with other antipsychotic agents has been attributed to an effect on D1-like and D4 receptors. We examined the binding of LMP, CLOZ and cyamemazine (CMZ, a neuroleptic analog of LMP, to human recombinant dopamine (rDA receptor subtypes. Methods: Binding studies were performed on frozen membrane suspensions of human rDA receptor subtypes expressed in Sf9 cells. Results: (i LMP has a high affinity (Ki, nM for rD2 receptor subtypes (rD2L 8.6; rD2S 4.3; rD3 8.3; rD4.2 7.9; (ii LMP and CLOZ have comparable affinities for the rD1 receptor (54.3 vs 34.6; (iii CMZ has high affinities for rD2-like and rD1-like receptors (rD2L 4.6; rD2S 3.3; rD3 6.2; rD4.2 8.5; rD1 3.9; rD5 10.7; (iv CMZ is 9 times more potent than CLOZ at the rD1 receptor and 5 times more potent than CLOZ at the rD4.2 receptor; (v CMZ has high affinities for rD1 and rD5 receptor subtypes compared with LMP and CLOZ. Conclusions: If D1 and D4 receptors are important sites for the unique action of CLOZ, the present study points to a need for clinical trials comparing CMZ with CLOZ in schizophrenia and in particular, treatment-resistant schizophrenia, especially given the risk for agranulocytosis with CLOZ.

  3. Dopamine Activation Preserves Visual Motion Perception Despite Noise Interference of Human V5/MT

    Science.gov (United States)

    Yousif, Nada; Fu, Richard Z.; Abou-El-Ela Bourquin, Bilal; Bhrugubanda, Vamsee; Schultz, Simon R.

    2016-01-01

    When processing sensory signals, the brain must account for noise, both noise in the stimulus and that arising from within its own neuronal circuitry. Dopamine receptor activation is known to enhance both visual cortical signal-to-noise-ratio (SNR) and visual perceptual performance; however, it is unknown whether these two dopamine-mediated phenomena are linked. To assess this, we used single-pulse transcranial magnetic stimulation (TMS) applied to visual cortical area V5/MT to reduce the SNR focally and thus disrupt visual motion discrimination performance to visual targets located in the same retinotopic space. The hypothesis that dopamine receptor activation enhances perceptual performance by improving cortical SNR predicts that dopamine activation should antagonize TMS disruption of visual perception. We assessed this hypothesis via a double-blinded, placebo-controlled study with the dopamine receptor agonists cabergoline (a D2 agonist) and pergolide (a D1/D2 agonist) administered in separate sessions (separated by 2 weeks) in 12 healthy volunteers in a William's balance-order design. TMS degraded visual motion perception when the evoked phosphene and the visual stimulus overlapped in time and space in the placebo and cabergoline conditions, but not in the pergolide condition. This suggests that dopamine D1 or combined D1 and D2 receptor activation enhances cortical SNR to boost perceptual performance. That local visual cortical excitability was unchanged across drug conditions suggests the involvement of long-range intracortical interactions in this D1 effect. Because increased internal noise (and thus lower SNR) can impair visual perceptual learning, improving visual cortical SNR via D1/D2 agonist therapy may be useful in boosting rehabilitation programs involving visual perceptual training. SIGNIFICANCE STATEMENT In this study, we address the issue of whether dopamine activation improves visual perception despite increasing sensory noise in the visual cortex

  4. Cloning, expression, and functional analysis of human dopamine D1 receptors

    Institute of Scientific and Technical Information of China (English)

    Wan-chun SUN; Lei JIN; Yan CAO; Li-zhen WANG; Fan MENG; Xing-zu ZHU

    2005-01-01

    Aim: To construct an HEK293 cell line stably expressing human dopamine D1 receptor (D1R). Methods: cDNA was amplified by RT-PCR using total RNA from human embryo brain tissue as the template. The PCR products were subcloned into the plasmid pcDNA3 and cloned into the plasmid pcDNA3.1. The cloned D1R cDNA was sequenced and stably expressed in HEK293 cells. Expression of D1R in HEK293 cells was monitored by the [3H]SCH23390 binding assay. The function of D1R was studied by the cAMP accumulation assay, CRE-SEAP reporter gene activity assay, and intracellular calcium assay. Results: An HEK293 cell line stably expressing human D1R was obtained. A saturation radioligand binding experiment with [3H]SCH23390 demonstrated that the Kd and Bmax values were 1.5±0.2 nmol/L and 2.94±0.15 nmol/g of protein, respectively. In the[3H]SCH23390 competition assay, D1R agonist SKF38393 displaced[3H]SCH23390 with an IC50 value of 2.0 (1.5-2.8) μmol/L. SKF38393 increased the intracellular cAMP level and CRE-SEAP activity through D1R expressed in HEK293 cells in a concentration-dependent manner with an EC50 value of 0.25(0.12-0.53) μmol/L and 0.39 (0.27-0.57) μmol/L at 6 h/0.59 (0.22-1.58) μmol/L at 12 h, respectively. SKF38393 also increased the intracellular calcium level in a concentration-dependent manner with EC50 value of 27 (8.6-70) nmol/L.Conclusion: An HEK293 cell line stably expressing human D1R was obtained successfuly. The study also demonstrated that the CRE-SEAP activity assay could be substituted for the cAMP accumulation assay for measuring increase in cAMP levels. Thus, both intracellular calcium measurements and the CRE-SEAP activity assay are suitable for high-throughput screening in drug research.

  5. Further development and validation of the model for in vivo quantification of human dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Wong, D.F.; Gjedde, A.; Wagner, H.N. Jr.; Douglass, K.H.; Dannels, R.F.; Snyder, S.H.; Kuhar, M.J.

    1985-05-01

    A goal in neuroreceptor PET imaging is to estimate receptor density (Bmax) and affinity (KD). Previously the authors reported the linearity of the Caudate/Cerebellar activity (CA/CB) with time in 100 subjects injected with C-11 n-methylspiperone (NMSP). In the proposed 3 compartment model the binding rate to the receptor, K3 was the slope of CA/CB vs. 'exposure time', i.e. the plasma conc. integral/plasma conc. of NMSP (PI/P). The authors have now expanded the model to estimate B/sub max/ and K/sub D/. They have observed in 10 normal subjects: The CB distribution vol. (CB/plasma activity) decreased with PI/P indicating some plasma metabolites did not cross into brain. The CA dist. volume increased with PI/P becoming linear because of specific binding of the ligand to the receptor with negligible dissociation. The CB vs. PI/P curve was used to calculate a metabolite corrected plasma curve which correlated well with HPLC measurements. The corrected plasma curve was then used to estimate a new PI/P (NPI/P). The K3 estimated from the slope of CA/CB vs. NPI/P (ranged .015-.024/min.) After blocking the receptors with unlabelled haloperidol (H) (N=2), an estimate of the inhibitory constant Ki for H (1.7, 2.0 nM) and (Bmax)*(koff) was obtained. The koff dissociation rate for H) was assumed to be the -.13/min., yielding a Bmax (30, 35 pM) which is comparable to in vitro human data. Thus, using 2 different mass injection of labelled C-11 NMSP or 1 with and without a cold competing ligand, in vivo dopamine receptor affinity and Bmax can be estimated. The model can be extended to serotonin receptors where the authors found a significant dissociation (k4).

  6. Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter.

    Science.gov (United States)

    Cameron, Krasnodara N; Kolanos, Renata; Solis, Ernesto; Glennon, Richard A; De Felice, Louis J

    2013-04-01

    Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT. We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor. DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (-60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non-substrate blocker. Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  7. Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25{+-}2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% {+-} 1.3% and 10.6% {+-} 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% {+-} 4.5% vs. 6.6% {+-} 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release.

  8. Pharmacokinetic-pharmacodynamic modeling of dopamine D2 receptor occupancy in humans using Bayesian modeling tools

    NARCIS (Netherlands)

    Johnson, Martin; Mafirakureva, Nyashadzaishe; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Liu, Jing; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2011-01-01

    Objectives: Blockade of dopamine-2 receptors is the key pharmacological component to the antipsychotic efficacy of both the typical and atypical antipsychotics (1). A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to describe the relationship between the plasma concentration of a

  9. Dopamine, dobutamine, and dopexamine. A comparison of renal effects in unanesthetized human volunteers

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal; Lund, J; Jensen, P F

    1993-01-01

    Recently, dopexamine (DX), which acts via adrenergic beta 2 and dopaminergic DA1 receptors, has been introduced in the treatment of low cardiac output states. However, the renal effects of DX have not been compared to those produced by equipotent inotropic doses of dopamine (DA), which predominan...

  10. Renal dopamine receptors and hypertension.

    Science.gov (United States)

    Hussain, Tahir; Lokhandwala, Mustafa F

    2003-02-01

    Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D(1) receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D(1) receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

  11. Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

    Science.gov (United States)

    Cubells, Joseph F; Schroeder, Jason P; Barrie, Elizabeth S; Manvich, Daniel F; Sadee, Wolfgang; Berg, Tiina; Mercer, Kristina; Stowe, Taylor A; Liles, L Cameron; Squires, Katherine E; Mezher, Andrew; Curtin, Patrick; Perdomo, Dannie L; Szot, Patricia; Weinshenker, David

    2016-01-01

    Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency

  12. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.

    Science.gov (United States)

    Grealish, Shane; Diguet, Elsa; Kirkeby, Agnete; Mattsson, Bengt; Heuer, Andreas; Bramoulle, Yann; Van Camp, Nadja; Perrier, Anselme L; Hantraye, Philippe; Björklund, Anders; Parmar, Malin

    2014-11-06

    Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson's disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease

    Science.gov (United States)

    Grealish, Shane; Diguet, Elsa; Kirkeby, Agnete; Mattsson, Bengt; Heuer, Andreas; Bramoulle, Yann; Van Camp, Nadja; Perrier, Anselme L.; Hantraye, Philippe; Björklund, Anders; Parmar, Malin

    2014-01-01

    Summary Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson’s disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson’s disease. PMID:25517469

  14. Changes in striatal dopamine release associated with human motor-skill acquisition.

    Directory of Open Access Journals (Sweden)

    Shoji Kawashima

    Full Text Available The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1 compared with acquired conditions (Day 2 using (11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The (11C-raclopride binding potential (BP in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that (11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition.

  15. 133 The Development of Human Embryonic Stem Cell-Derived Dopamine Neurons for Clinical Use in Parkinson Disease.

    Science.gov (United States)

    Tabar, Viviane S

    2016-08-01

    Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting a million people in the United States alone. The advent of deep brain stimulation (DBS) has made a significant impact on the quality of life of a subset of patients. However, reconstruction of basal ganglia circuitry remains an ultimate goal that stands a better chance of addressing various aspects of the disease in a permanent and sustained manner. Our team has developed robust protocols for the derivation of dopamine (DA) neurons from human embryonic stem cells (ES). We subsequently formed a consortium, supported by a 15 million dollar grant from New York State that aims at translating these findings into a clinical trial of cell therapy for PD. Key milestones will be described including the development of a large cell bank, validation assays, safety testing, and finally validation and efficacy in vivo in an animal model of Parkinson disease. Our data show that human ES-derived DA neurons survive grafting both in rodents and in primates; they extend complex neurites that innervate the striatum and result in the reversal of behavioral deficits in parkinsonian rats. There were no teratomas or overgrowth of neural progenitors. Key challenges in translating the work included the translation of our cell differentiation protocol to large-scale production, using only good manufacturing practice-compliant sources, the identification and validation of a cryopreservation medium that maintained high viability, and the development of release criteria for future cell lots. An overarching concern is the development of safety measures, such as suicide genes which, however, proved too onerous to survive a reasonable timeline. Ongoing work is focused on achieving Food and Drug Administration approval, anticipated in late 2017, and implementing a first in human clinical trial of ES-derived dopamine neurons for PD.

  16. Pyrolysed 3D-Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real-Time Dopamine Detection

    NARCIS (Netherlands)

    Amato, Letizia; Heiskanen, Arto; Caviglia, Claudia; Shah, Fozia; Zor, Kinga; Skolimowski, Maciej; Madou, Marc; Gammelgaard, Lauge; Hansen, Rasmus; Seiz, Emma G.; Ramos, Milagros; Ramos Moreno, Tania; Martinez-Serrano, Alberto; Keller, Stephan S.; Emneus, Jenny

    2014-01-01

    Structurally patterned pyrolysed three-dimensional carbon scaffolds (p3D-carbon) are fabricated and applied for differentiation of human neural stem cells (hNSCs) developed for cell replacement therapy and sensing of released dopamine. In the absence of differentiation factors (DF) the pyrolysed car

  17. Pyrolysed 3D-Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real-Time Dopamine Detection

    DEFF Research Database (Denmark)

    Amato, Letizia; Heiskanen, Arto; Caviglia, Claudia

    2014-01-01

    Structurally patterned pyrolysed three-dimensional carbon scaffolds (p3Dcarbon) are fabricated and applied for differentiation of human neural stem cells (hNSCs) developed for cell replacement therapy and sensing of released dopamine. In the absence of differentiation factors (DF) the pyrolysed...... carbon material induces spontaneous hNSC differentiation into mature dopamine-producing neurons and the 3D-topography promotes neurite elongation. In the presence and absence of DF, ≈73–82% of the hNSCs obtain dopaminergic properties on pyrolysed carbon, a to-date unseen efficiency in both two......-dimensional (2D) and 3D environment. Due to conductive properties and 3D environment, the p3D-carbon serves as a neurotransmitter trap, enabling electrochemical detection of a signifi cantly larger dopamine fraction released by the hNSC derived neurons than on conventional 2D electrodes. This is the first study...

  18. Estimating the effect of endogenous dopamine on baseline [(11) C]-(+)-PHNO binding in the human brain.

    Science.gov (United States)

    Caravaggio, Fernando; Kegeles, Lawrence S; Wilson, Alan A; Remington, Gary; Borlido, Carol; Mamo, David C; Graff-Guerrero, Ariel

    2016-11-01

    Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3 R) have been quantified in the living human brain using the agonist radiotracer [(11) C]-(+)-PHNO. As an agonist radiotracer, [(11) C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [(11) C]-(+)-PHNO binding to D2/3 Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND ) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [(11) C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [(11) C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3 R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [(11) C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3 R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers.

  19. Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion of serotonin and dopamine in a large human population

    Directory of Open Access Journals (Sweden)

    George J Trachte

    2009-04-01

    Full Text Available George J Trachte1, Thomas Uncini2, Marty Hinz31Department of Physiology and Pharmacology, University of MN Medical School Duluth, Duluth, MN, USA; 2Chief Medical Examiner, St. Louis County, Hibbing, MN, USA; 3Clinical Research, NeuroResearch Clinics, Inc., Duluth, MN, USA Abstract: Amino acid precursors of dopamine and serotonin have been administered for decades to treat a variety of clinical conditions including depression, anxiety, insomnia, obesity, and a host of other illnesses. Dietary administration of these amino acids is designed to increase dopamine and serotonin levels within the body, particularly the brain. Convincing evidence exists that these precursors normally elevate dopamine and serotonin levels within critical brain tissues and other organs. However, their effects on urinary excretion of neurotransmitters are described in few studies and the results appear equivocal. The purpose of this study was to define, as precisely as possible, the influence of both 5-hydroxytryptophan (5-HTP and tyrosine on urinary excretion of serotonin and dopamine in a large human population consuming both 5-HTP and tyrosine. Curiously, only 5-HTP exhibited a marginal stimulatory influence on urinary serotonin excretion when 5-HTP doses were compared to urinary serotonin excretion; however, a robust relationship was observed when alterations in 5-HTP dose were compared to alterations in urinary serotonin excretion in individual patients. The data indicate three statistically discernible components to 5-HTP responses, including inverse, direct, and no relationships between urinary serotonin excretion and 5-HTP doses. The response to tyrosine was more consistent but primarily yielded an unexpected reduction in urinary dopamine excretion. These data indicate that the urinary excretion pattern of neurotransmitters after consumption of their precursors is far more complex than previously appreciated. These data on urinary neurotransmitter excretion might

  20. A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure.

    Science.gov (United States)

    Tataranni, P A; Baier, L; Jenkinson, C; Harper, I; Del Parigi, A; Bogardus, C

    2001-04-01

    Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.

  1. Polymorphisms in the dopamine transporter gene (SLC6A3/DAT1) and alcohol dependence in humans: a systematic review

    NARCIS (Netherlands)

    Zwaluw, C.S. van der; Engels, R.C.M.E.; Buitelaar, J.K.; Verkes, R.J.; Franke, B.; Scholte, R.H.J.

    2009-01-01

    Dopamine neurotransmission has been a key player in attempts to identify genetic factors involved in alcohol dependence. The dopamine transporter terminates dopaminergic neurotransmission, making the gene encoding the transporter (SLC6A3/DAT1) an attractive candidate in clinical studies on alcohol d

  2. Polymorphisms in the dopamine transporter gene (SLC6A3/DAT1) and alcohol dependence in humans: a systematic review.

    NARCIS (Netherlands)

    Zwaluw, C.S. van der; Engels, R.C.M.E.; Buitelaar, J.K.; Verkes, R.J.; Franke, B.; Scholte, R.H.J.

    2009-01-01

    Dopamine neurotransmission has been a key player in attempts to identify genetic factors involved in alcohol dependence. The dopamine transporter terminates dopaminergic neurotransmission, making the gene encoding the transporter (SLC6A3/DAT1) an attractive candidate in clinical studies on alcohol d

  3. Salsolinol modulation of dopamine neurons

    Directory of Open Access Journals (Sweden)

    Guiqin eXie

    2013-05-01

    Full Text Available Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. However, the underlying neuronal mechanisms are unclear. Here we present an overview of some of the recent research on this topic. Electrophysiological studies reveal that dopaminergic neurons in the posterior ventral tegmental area (pVTA are a target of salsolinol. In acute brain slices from rats, salsolinol increases the excitability and accelerates the ongoing firing of dopamine neurons in the pVTA. Intriguingly, this action of salsolinol involves multiple pre- and post-synaptic mechanisms, including: (a depolarizing the membrane potential of dopamine neurons; (b activating mu opioid receptors on the GABAergic inputs to dopamine neurons, which decreases GABAergic activity and dopamine neurons are disinhibited; and (c enhancing presynaptic glutamatergic transmission onto dopamine neurons via activation of dopamine type 1 receptors, probably situated on the glutamatergic terminals. These novel mechanisms may contribute to the rewarding/reinforcing properties of salsolinol observed in vivo.

  4. Epigenetic Regulation of Dopamine Transporter mRNA Expression in Human Neuroblastoma Cells

    Science.gov (United States)

    Green, Ashley L.; Hossain, Muhammad M.; Tee, Siew C.; Zarbl, Helmut; Guo, Grace L.; Richardson, Jason R.

    2016-01-01

    The dopamine transporter (DAT) is a key regulator of dopaminergic neurotransmission. As such, proper regulation of DAT expression is important to maintain homeostasis, and disruption of DAT expression can lead to neurobehavioral dysfunction. Based on genomic features within the promoter of the DAT gene, there is potential for DAT expression to be regulated through epigenetic mechanisms, including DNA methylation and histone acetylation. However, the relative contribution of these mechanisms to DAT expression has not been empirically determined. Using pharmacologic and genetic approaches, we demonstrate that inhibition of DNA methyltransferase (DNMT) activity increased DAT mRNA approximately 1.5–2 fold. This effect was confirmed by siRNA knockdown of DNMT1. Likewise, the histone deacetylase (HDAC) inhibitors valproate and butyrate also increased DAT mRNA expression, but the response was much more robust with expression increasing over tenfold. Genetic knockdown of HDAC1 by siRNA also increased DAT expression, but not to the extent seen with pharmacological inhibition, suggesting additional isoforms of HDAC or other targets may contribute to the observed effect. Together, these data identify the relative contribution of DNMTs and HDACs in regulating expression. These finding may aid in understanding the mechanistic basis for changes in DAT expression in normal and pathophysiological states. PMID:25963949

  5. Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans

    Science.gov (United States)

    Tan, Hao-Yang; Nicodemus, Kristin K.; Chen, Qiang; Li, Zhen; Brooke, Jennifer K.; Honea, Robyn; Kolachana, Bhaskar S.; Straub, Richard E.; Meyer-Lindenberg, Andreas; Sei, Yoshitasu; Mattay, Venkata S.; Callicott, Joseph H.; Weinberger, Daniel R.

    2008-01-01

    AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. PMID:18497887

  6. Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans.

    Science.gov (United States)

    Caravaggio, Fernando; Fervaha, Gagan; Chung, Jun Ku; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2016-04-01

    While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C]-raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions.

  7. Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo

    Directory of Open Access Journals (Sweden)

    Dustin R. Wakeman

    2017-07-01

    Full Text Available A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

  8. Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates.

    Directory of Open Access Journals (Sweden)

    Tina Suominen

    Full Text Available An UPLC-MS/MS method was developed for the determination of serotonin (5-HT, dopamine (DA, their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain.

  9. Human brain dopamine metabolism in levodopa-induced dyskinesia and wearing-off.

    Science.gov (United States)

    Rajput, Ali H; Fenton, Mark E; Di Paolo, Thérèse; Sitte, Harold; Pifl, Christian; Hornykiewicz, Oleh

    2004-06-01

    The objective of this study was to identify dopamine (DA) metabolism pattern in Lewy body Parkinson's disease (PD) patients with dyskinesia (Dysk) only, with wearing-off (WO) only, or no motor complications (NMC) induced by levodopa (LD). DA, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3-methoxytyramine (3-MT) were measured individual basal ganglia nuclei of nine PD patients who received LD for 6-18 years. Three patients had only Dysk, three only WO, and three had neither Dysk nor WO. Biochemical measurements in PD brains were compared with four non-neurological control brains from individuals matched for age and post-mortem retrieval time. DA levels in the PD were reduced in the caudate by 87% and putamen by 99%. In the caudates, the HVA/DA molar ratio as an index of DA metabolism was similar in the WO and the Dysk patients. However, in the putamen, the ratio of HVA/DA was significantly higher in the WO compared with the Dysk (p = 0.03)and the NMC (p = 0.04) groups of patients. In the putamen, the DOPAC levels were higher in the WO cases while in the Dysk cases, 3-MT levels were higher. The results suggest that in the WO only cases, the putaminal DA was in large measure metabolized intraneuronally while the DA metabolism in our Dysk only patients was mainly extraneuronal. We conclude that the magnitude and the site (intra vs. extraneuronal) of the synaptic DA metabolism in the putamen plays a significant role in LD-induced Dysk and WO.

  10. Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans

    Science.gov (United States)

    Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

    2016-01-01

    Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity. PMID:27378550

  11. Dopamine, the kidney, and hypertension.

    Science.gov (United States)

    Harris, Raymond C; Zhang, Ming-Zhi

    2012-04-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.

  12. Relationship between dopamine transporter occupancy and methylphenidate induced high in humans

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)]|[SUNY-Stony Brook, NY (United States)] [and others

    1996-05-01

    The inhibition of the dopamine transporter (DAT) by cocaine has been shown to be indispensable for its reinforcing properties. The development of drugs that inibit the DAT has become a major target to prevent cocaine`s effects. However prevention of the {open_quotes}high{close_quotes} by DAT inhibitors has never been demonstrated. This study evaluates the ability to block methylphenidate (MP), a DAT inhibitor drug with similar reinforcing properties to cocaine, induced {open_quotes}high{close_quotes} by prior DAT inhibition. It uses PET and [{sup 11}C]d-threo-methylphenidate to measure the relationship between DAT occupancy prior to administration of MP and the intensity of the subjective perception of the {open_quotes}high{close_quotes} in 8 controls. MP (0.375 mg/kg iv) which was administered as a single injection and also as two sequential doses given 60 minutes apart significantly reduced the ratio of the distribution volume for [{sup 11}C]d-threo-methylphenidate in striatum to that in cerebellum from a baseline of 2.83 {plus_minus} 0.2 to 1.29 {plus_minus} 0.1 at 7 minutes and to 1.37 {plus_minus} 0.2 at 60 minutes after a single injection of MP and to 1.14 {plus_minus} 0.1 at 7 minutes after the second of two sequential MP doses. This corresponds to a DAT occupancy by MP of 84% {plus_minus} 7 at 7 minutes and of 77% {plus_minus} 6 at 60 minutes after a single injection of MP and of 93% {plus_minus} 7 at 7 after the second of two sequential MP doses. The subjective perception of {open_quotes}high{close_quotes} experienced after the second injection of MP was of a similar magnitude to that experienced after the first injection of MP was of a similar magnitude to that experienced after the first injection, in spite of the very different starting DAT occupancies (0 and 77%, respectively). DAT occupancy was not correlated with the {open_quotes}high{close_quotes}; and one subject with 100% DAT occupancy did not perceive the {open_quotes}high{close_quotes}.

  13. In vito Effect of Dithiocarbamate Pesticides and of CaNa2 EDTA on Human Serum Dopamine-β-hydroxylase

    Institute of Scientific and Technical Information of China (English)

    1995-01-01

    Serum dopamine-β-hydroxylase(DBH)inhibition has been reported in lead workers treated with CaNa2EDTA and in alcoholic patients repatedly treated with the alcohol aversive drug Disulfiram.The mechanism of inhibition involves Cu++ chelation at the active site of DBH.The effect of CaNa2EDTA and Disulfiram on serum DBH has been compared to the effect of dithiocarbamate pesticides in vitro for the possible use of serum DBH determination for the biological monitoring or workers exposed to these pesticides. Most dithiocarbamates inhibit human serum DBH at miromolar concentrtion(range of I50,0.027-1.6μmol/L).The inhibitory potency increased from methyl-and dimethyl dithiocarbamates to diethyl dithiocarbamates up to the most potent ethylene bisdithiocarbamates.The I50 of CaNa2 EDTA was 3.8μmol/L,higher than those of dithiocarbamates,Copper additin to the test system reactivated at stoichiometric concentrations dithiocarbamate-inhibited DBH indicating that both base line values and percent of inhibition can be calculated in a single blood sample.Results suggest that serum DBH determination could be useful in case of acute poisoning involving high doses of dithiocarbamate pesticides.

  14. From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter.

    Science.gov (United States)

    Zdrazil, Barbara; Hellsberg, Eva; Viereck, Michael; Ecker, Gerhard F

    2016-09-14

    Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets. In addition, potential hERG blocking liabilities were included. The workflow allowed studying the selectivity trends of scaffold series, identifying potentially harmful compound series, and performing SAR, docking studies and molecular dynamics (MD) simulations for a consistent data set of 56 cathinones. This delivered useful insights into driving determinants for hDAT selectivity over hSERT. With respect to the scaffold-based analyses it should be noted that the cathinone data set could be retrieved only when Murcko scaffold analyses were combined with similarity searches such as a common substructure search.

  15. “Deconstruction” of the Abused Synthetic Cathinone Methylenedioxypyrovalerone (MDPV) and an Examination of Effects at the Human Dopamine Transporter

    Science.gov (United States)

    2013-01-01

    Synthetic cathinones, β-keto analogues of amphetamine (or, more correctly, of phenylalkylamines), represent a new and growing class of abused substances. Several such analogues have been demonstrated to act as dopamine (DA) releasing agents. Methylenedioxypyrovalerone (MDPV) was the first synthetic cathinone shown to act as a cocaine-like DA reuptake inhibitor. MDPV and seven deconstructed analogues were examined to determine which of MDPV’s structural features account(s) for uptake inhibition. In voltage-clamped (−60 mV) Xenopus oocytes transfected with the human DA transporter (hDAT), all analogues elicited inhibitor-like behavior shown as hDAT-mediated outward currents. Using hDAT-expressing mammalian cells we determined the affinities of MDPV and its analogues to inhibit uptake of [3H]DA by hDAT that varied over a broad range (IC50 values ca. 135 to >25 000 nM). The methylenedioxy group of MDPV made a minimal contribution to affinity, the carbonyl group and a tertiary amine are more important, and the extended α-alkyl group seems most important. Either a tertiary amine, or the extended α-alkyl group (but not both), are required for the potent nature of MDPV as an hDAT inhibitor. PMID:24116392

  16. "Deconstruction" of the abused synthetic cathinone methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter.

    Science.gov (United States)

    Kolanos, Renata; Solis, Ernesto; Sakloth, Farhana; De Felice, Louis J; Glennon, Richard A

    2013-12-18

    Synthetic cathinones, β-keto analogues of amphetamine (or, more correctly, of phenylalkylamines), represent a new and growing class of abused substances. Several such analogues have been demonstrated to act as dopamine (DA) releasing agents. Methylenedioxypyrovalerone (MDPV) was the first synthetic cathinone shown to act as a cocaine-like DA reuptake inhibitor. MDPV and seven deconstructed analogues were examined to determine which of MDPV's structural features account(s) for uptake inhibition. In voltage-clamped (-60 mV) Xenopus oocytes transfected with the human DA transporter (hDAT), all analogues elicited inhibitor-like behavior shown as hDAT-mediated outward currents. Using hDAT-expressing mammalian cells we determined the affinities of MDPV and its analogues to inhibit uptake of [3H]DA by hDAT that varied over a broad range (IC50 values ca. 135 to >25,000 nM). The methylenedioxy group of MDPV made a minimal contribution to affinity, the carbonyl group and a tertiary amine are more important, and the extended α-alkyl group seems most important. Either a tertiary amine, or the extended α-alkyl group (but not both), are required for the potent nature of MDPV as an hDAT inhibitor.

  17. Simultaneous Determination of Epinephrine, Noradrenaline and Dopamine in Human Serum Samples by High Performance Liquid Chromatography with Chemiluminescence Detection

    Institute of Scientific and Technical Information of China (English)

    CHEN, Fu-Nan; ZHANG, Ying-Xue; ZHANG, Zhu-Jun

    2007-01-01

    A simple, rapid and accurate high performance liquid chromatographic (HPLC) technique coupled with chemiluminescence (CL) detection was developed for the simultaneous determination of epinephrine (E),noradrenaline (NA) and dopamine (DA). It was based on the analyte enhancement effect on the CL reaction between luminol and potassium ferricyanide. The effects of various parameters, such as potassium ferricyanide concentration, luminol concentration, pH value and component of the mobile phase on chromatographic behaviors of the analytes (E, NA and DA) were investigated. The separation was carried out on C18 column using the mobile tions, E, NA and DA showed good linear relationships in the range of 1×10-8-5×10-6, 5.0×10-9-1.0× 10-6 and 5.0×10-9-1.0×10-6 g/mL respectively. The detection limits for E, NA and DA were 4.0×10-9, 1.0×10-9 and 8.0×10-10 g/mL. The proposed method has been applied successfully to the analysis of E, NA and DA in human serum samples.

  18. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States). Dept. of Psychiatry; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1999-05-28

    The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability the authors compared the levels of DAT occupancies that they had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [{sup 11}C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [{sup 11}C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd+1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockage of DAT with an estimated ED{sub 50} for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine.

  19. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Guiqin eXie; Kresimir eKrnjevic; Jiang Hong Ye

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. ...

  20. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Xie, Guiqin; Krnjević, Krešimir; Ye, Jiang-Hong

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic (DA) system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumb...

  1. Reductions in carotid chemoreceptor activity with low-dose dopamine improves baroreflex control of heart rate during hypoxia in humans.

    Science.gov (United States)

    Mozer, Michael T; Holbein, Walter W; Joyner, Michael J; Curry, Timothy B; Limberg, Jacqueline K

    2016-07-01

    The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of heart rate with exposure to hypoxia. We hypothesized spontaneous cardiac baroreflex sensitivity (scBRS) would be reduced with hypoxia and this effect would be blunted when carotid chemoreceptor activity was reduced with low-dose dopamine. Fifteen healthy adults (11 M/4 F) completed two visits randomized to intravenous dopamine or placebo (saline). On each visit, subjects were exposed to 5-min normoxia (~99% SpO2), followed by 5-min hypoxia (~84% SpO2). Blood pressure (intra-arterial catheter) and heart rate (ECG) were measured continuously and scBRS was assessed by spectrum and sequence methodologies. scBRS was reduced with hypoxia (P dopamine (P dopamine (P dopamine did not attenuate the decrease in baroreflex sensitivity to falling pressures (scBRS "down-down"; P > 0.05). Present findings are consistent with a reduction in scBRS with systemic hypoxia. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when activity of the chemoreceptors is reduced with low-dose dopamine. However, the improvement in scBRS with dopamine appears to be specific to rising blood pressures. These results may have important implications for impairments in baroreflex function common in disease states of acute and/or chronic hypoxemia, as well as the experimental use of dopamine to assess such changes.

  2. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    DEFF Research Database (Denmark)

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar

    2015-01-01

    Autologous transplantation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility, and safety of iPSC-derived dopamine neurons in non-human primate...... models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found...... neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD....

  3. Single-nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells.

    Science.gov (United States)

    Jiang, Xiaoliang; Konkalmatt, Prasad; Yang, Yu; Gildea, John; Jones, John E; Cuevas, Santiago; Felder, Robin A; Jose, Pedro A; Armando, Ines

    2014-03-01

    The dopamine D2 receptor (D2R) negatively regulates inflammation in mouse renal proximal tubule cells (RPTCs), and lack or downregulation of the receptor in mice increases the vulnerability to renal inflammation independent of blood pressure. Some common single-nucleotide polymorphisms (SNPs; rs6276, rs6277, and rs1800497) in the human DRD2 gene are associated with decreased D2R expression and function, as well as high blood pressure. We tested the hypothesis that human RPTCs (hRPTCs) expressing these SNPs have increased expression of inflammatory and injury markers. We studied immortalized hRPTCs carrying D2R SNPs and compared them with cells carrying no D2R SNPs. RPTCs with D2R SNPs had decreased D2R expression and function. The expressions of the proinflammatory tumor necrosis factor-α and the profibrotic transforming growth factor-β1 and its signaling targets Smad3 and Snail1 were increased in hRPTC with D2R SNPs. These cells also showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins, assessed by increased vimentin, fibronectin 1, and collagen I a1. To test the specificity of these D2R SNP effects, hRPTC with D2R SNPs were transfected with a plasmid encoding wild-type DRD2. The expression of D2R was increased and that of transforming growth factor-β1, Smad3, Snail1, vimentin, fibronectin 1, and collagen I a1 was decreased in hRPTC with D2R SNPs transfected with wild-type DRD2 compared with hRPTC-D2R SNP transfected with empty vector. These data support the hypothesis that D2R function has protective effects in hRPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure.

  4. An electrochemical quartz crystal impedance study on anti-human immunoglobulin G immobilization in the polymer grown during dopamine oxidation at an Au electrode.

    Science.gov (United States)

    He, Hua; Xie, Qingji; Yao, Shouzhuo

    2005-09-15

    The polymeric film grown during dopamine oxidation at an Au electrode was studied as a novel matrix for immobilizing anti-human immunoglobulin G (IgG) via the electrochemical quartz crystal impedance analysis (EQCIA) method. The growth of the polymeric films at Au electrodes during dopamine oxidation in neutral phosphate buffer (pH 7.4) and the immobilization of anti-human IgG into the polymeric films during their growth have been traced at real time. Lysozyme control experiments suggested that anti-human IgG was electrostatically incorporated into the polymeric film. Also, the porosity of the polymeric films has been discussed by measuring the "wet" and "dry" frequency shifts. Compared with a polypyrrole film immobilized with anti-human IgG, the proposed matrix possessed a larger amount of specific binding sites for human IgG by subsequent immunoreaction tests. The association constant of the anti-human IgG immunoreaction was obtained with satisfactory results.

  5. Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.

    Science.gov (United States)

    Liang, Si-Cheng; Ge, Guang-Bo; Xia, Yang-Liu; Pei-Pei, Dong; Ping, Wang; Qi, Xiao-Yi; Cai-Xia, Tu; Ling, Yang

    2016-07-20

    1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50 values for daphnetin (0.51∼0.53 μM) and 8-O-methyldaphnetin (22.5∼24.3 μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 μM) and 8-O-methyldaphnetin (noncompetitive, 25.7 μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.

  6. Effect of variable number of tandem repeats polymorphism in the human dopamine transporter gene on conflict information processing according to event-related potential

    Institute of Scientific and Technical Information of China (English)

    Chunyu Han; Yuping Wang; Xin Wang; Ying Liu

    2010-01-01

    The dopamine transporter(DAT)is responsible for dopamine reuptake from the synaptic cleft.A variable number of tandem repeats polymorphism in the DAT gene is related to DAT availability and has been associated with cognition.With the advantage of high-time resolution,event-related potential is an important method to study the time course of human information processing.Previous results have suggested that dopamine exhibits a close relationship with conflicting information processing.Therefore,the present study assumed that conflicting information processing could be influenced by DAT variable number of tandem repeats polymorphism.To confirm this,the present study analyzed the influence of DAT genotypes on N270,which is presumed to reflect neural activity of conflict information processing in young healthy adults.A S1-S2 matching task was performed in healthy adults with 10/10 genotype(n = 14)and 10/9genotypes(n = 14),respectively,when event-related potentials were recorded.Results demonstrated that subjects with the 10/10 genotype exhibited shorter N270 latency and quicker reaction times compared with subjects with the 10/9 genotype.There were no differences in N270amplitude between the two genotypes.These results suggested that 10/10 genotype subjects more efficiently processed conflict information.

  7. The Human Dopamine Transporter: Investigating the Role of the C Terminus in Surface Targeting

    DEFF Research Database (Denmark)

    Vægter, Christian Bjerggaard

    2005-01-01

    Dopaminergic neurotransmission is involved in the modulation of locomotor activity, emotional behavior, memory and cognition. Hence, imbalances in the dopaminergic system in humans have been hypothesized to contribute to the pathogenesis of a number of illnesses, including Parkinson's disease...... also found evidence for a direct interaction between DAT and the Ca2+/calmodulin dependent kinase II α (CaMKIIα) and this interaction seems to depend on the same epitopes that are essential for surface targeting of DAT. Finally, using a fluorescently labelled cocaine analogue we were able to detect...

  8. The Human Dopamine Transporter: Investigating the Role of the C Terminus in Surface Targeting

    DEFF Research Database (Denmark)

    Vægter, Christian Bjerggaard

    2005-01-01

    Dopaminergic neurotransmission is involved in the modulation of locomotor activity, emotional behavior, memory and cognition. Hence, imbalances in the dopaminergic system in humans have been hypothesized to contribute to the pathogenesis of a number of illnesses, including Parkinson's disease...... expression of the DAT-PICK1 complex. By progressive substitutions with β2-adrenergic receptor sequence, and by triple-alanine substitutions in the DAT C terminus, we examined the importance of epitopes preceding the LKV motif. Substitution of residues just proximal to the LKV sequence with alanines caused...

  9. [{sup 11}C]d-threo-Methylphenidate, a new radiotracer for the dopamine transporter. Characterization in baboon and human brain

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Volkow, N.D.; Fowler, J.S. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    dl-threo Methylphenidate (MP, Ritalin) is a psychostimulant drug which binds to the dopamine transporter (DAT). We evaluated [{sup 11}C]d-threo-methylphenidate ([{sup 11}C]d-MP), the more active enantiomer, as a radiotracer for the DAT in baboons and human brain. Stereoselectivity, saturability and pharmacological specificity and reproducibility were examined. Stereoselectivity was examined in baboons by comparing [{sup 11C}]d-MP,[{sup 11}C]l-MP and [{sup 11}C]dl-MP. Unlabeled MP was used to assess the reversibility and saturability of the binding. GBR 12909,{beta}-(4-iodophenyl)tropane-2-carboxylic acid methyl ester ({beta}-CIT), tomoxetine and citalopram were used to assess the specificity of the binding. The ratios between the radioactivity in the striatum to that in cerebellum (ST/CB) were 3.3,2.2 and 1.1 for [{sup 11}C]d-MP,[{sup 11}C]dl-MP and [{sup 11}C]l-MP respectively. Most of the striatal binding of [{sup 11}C]d-threo-MP was displaced by injection of nonradioactive MP demonstrating reversibility. Pretreatment with MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) or {beta}-CIT (0.3 mg/kg) reduced ST/CB by about 60% and the ratios of distribution volumes at the steady-state for the triatum to cerebellum (DV{sub st/}DV{sub cb}) by about 50%. Pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, had no effect. Studies of [{sup 11}C]d-MP in the human brain showed highest uptake in basal ganglia with a half clearance time of about 60 minutes. Repeated studies in 6 normal human subjects showed differences in DV{sub st/}DV{sub cb} between -7% and 8%. MP pretreatment decreased BG but no cortical or cerebellar binding and reduced Bmax/Kd by 91%.

  10. Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study.

    Science.gov (United States)

    Woodward, Neil D; Zald, David H; Ding, Zhaohua; Riccardi, Patrizia; Ansari, M Sib; Baldwin, Ronald M; Cowan, Ronald L; Li, Rui; Kessler, Robert M

    2009-05-15

    The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may have important methodological implications for clinical studies of dopamine receptor ligand binding differences between control and patient groups. The association between cerebral morphology and dopamine receptor distribution was examined in 45 healthy subjects who completed T1-weighted structural MRI and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with binding potential (BP(ND)) images on a voxel-by-voxel basis using the Biological Parametric Mapping toolbox. Associations between cerebral morphology and BP(ND) were also examined for selected regions-of-interest (ROIs) after spatial normalization. Voxel-wise analyses indicated that grey matter volume and density positively correlated with BP(ND) throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between BP(ND) and cerebral morphology in the caudate, thalamus, and amygdala. Few negative correlations between morphology and BP(ND) were observed. Overall, grey matter density appeared more strongly correlated with BP(ND) than grey matter volume. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Clinical studies comparing dopamine receptor availability between clinical and control groups may benefit by accounting for potential differences in cerebral morphology that exist even after spatial normalization.

  11. Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study.

    Science.gov (United States)

    Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

    2013-02-01

    Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.

  12. Single photon emission computer tomography of dopamine transporters in monkeys and humans with 99mTc-TRODAT-1

    Institute of Scientific and Technical Information of China (English)

    胡平; 陈玲; 张海琴; 黎锦如; 梁宏

    2004-01-01

    Background The diagnosis of Parkinson's disease is presently based on non-specific symptoms. However, radionuclide dopamine transporters imaging can provide specific diagnostic tool for Parkinson's disease. This study was designed to investigate the effects of imaging of dopamine transporters with 99mTc-TRODAT-1 in early diagnosis or differential diagnosis of Parkinson's disease.Methods Nine normal monkeys were used to establish N-methyl-4-phenyl-1, 2, 3, 6-tetra-hydropyridine (MPTP) hemi-Parkinsonian animal models, and they were subjected to imaging. Twenty-nine patients with Parkinson's disease, 12 age-matched healthy volunteers, and 18 age-matched patients with Parkinson's syndrome were investigated. Single photon emission computer tomography (SPECT) was performed 3 hours after intravenous injection of 740 MBq 99mTc-TRODAT-1. Striatum specific uptake of 99mTc-TRODAT-1 was calculated according to the ratio of striatum (ST) to cerebellum (CB)in dopamine transporters uptake.Results In normal monkeys, bilateral ratio of ST/CB was 2.34±0.41. After the injection of MPTP, uptake rate of 99mTc-TRODAT-1 at damaged region was much lower than that at the contralateral region, resulting in a significant difference in the ratio of ST/CB (right: ST/CB=1.73±0.35; left: ST/CB=1.90±0.30), especially in hemi-Parkinsonian model monkeys (right: ST/CB=1.29±0.17; left: ST/CB=1.80±0.33). The ratios of ST/CB were 1.57±0.17 and 1.61±0.14 for the right and left respectively in the healthy volunteers, 1.04±0.29 and 1.06±0.30 in the age-matched patients with Parkinson's disease, and 1.56±0.17 and 1.59±0.18 in the age-matched patients with Parkinson's disease syndrome. A significant difference was noted between group of Parkinson's disease, normal controls and Parkinson's disease syndrome. Conclusion The results suggest that 99mTc-TRODAT-1 dopamine transporters SPECT has clinical application value in early diagnosis or differential diagnosis of Parkinson's disease.

  13. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    role for dopamine in modulating, mainly suppressing immune functions (Qui et al., 1994. Animals treated with bromocriptine, a dopamine agonist, also showed suppression of antibody production to SRBC and LPS (Besedovsky and del Ray, 1996 and suppressed activities of lymphocytes in mixed lymphocyte culture (Hiestand et al., 1986. Moreover, the interest regarding the role of dopamine on immune system becomes more relevant when some of important neurological disease like Parkinson’s disease and schizophrenia with hypo- and hyperactivity (Birtwistle et al., 1988 of central dopamine system are well-correlated with severe abnormalities of immune functions (Muller et al., 1993. Therefore, in the present review, we have evaluated information from our laboratory as well as from others regarding the role of dopamine on immune function in both human and experimental animals in order to understand the current status of dopamine-mediated control of the immunological surveillance system.

  14. Presence of D4 dopamine receptors in human prefrontal cortex: a postmortem study Presença de receptores dopaminérgicos D4 em córtex cerebral humano: um estudo post-mortem

    Directory of Open Access Journals (Sweden)

    Donatella Marazziti

    2007-06-01

    Full Text Available OBJECTIVE: The aim of our study was to explore the presence and the distribution of D4 dopamine receptors in postmortem human prefrontal cortex, by means of the binding of [³H]YM-09151-2, an antagonist that has equal affinity for D2, D3 and D4 receptors. It was therefore necessary to devise a unique assay method in order to distinguish and detect the D4 component. METHOD: Frontal cortex samples were harvested postmortem, during autopsy sessions, from 5 subjects. In the first assay, tissue homogenates were incubated with increasing concentrations of [³H]YM-09151-2, whereas L-745870, which has a high affinity for D4 and a low affinity for D2/D3 receptors, was used as the displacer. In the second assay, raclopride, which has a high affinity for D2/D3 receptors and a low affinity for D4 receptors, was used to block D2/D3. The L-745870 (500 nM was added to both assays in order to determine the nonspecific binding. RESULTS: Our experiments revealed the presence of specific and saturable binding of [³H]YM-09151-2. The blockade of D2 and D3 receptors with raclopride ensured that the D4 receptors were labeled. The mean maximum binding capacity was 88 ± 25 fmol/mg protein, and the dissociation constant was 0.8 ± 0.4 nM. DISCUSSION AND CONCLUSIONS: Our findings, although not conclusive, suggest that the density of D4 receptors is low in the human prefrontal cortex.OBJETIVO: O objetivo deste estudo foi quantificar a presença e a distribuição de receptores dopaminérgicos do tipo 4 (D4 no córtex cerebral humano em amostras post-mortem através do bloqueio com ³H-YM-09151-2 - um antagonista com afinidade equivalente pelos receptores D2, D3 e D4 - e do desenvolvimento de um método para a detecção específica do componente D4. MÉTODO: Foram obtidas amostras de córtex cerebral de cinco cadáveres. Em um primeiro ensaio, os homogeneizados de tecido cerebral foram incubados em concentrações crescentes de ³H-YM-09151-2, enquanto que o L-745

  15. Dopamine receptor and hypertension.

    Science.gov (United States)

    Zeng, Chunyu; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2005-01-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and reactive oxygen and by interacting with vasopressin, renin-angiotensin, and the sympathetic nervous system. Decreased renal dopamine production and/or impaired dopamine receptor function have been reported in hypertension. Disruption of any of the dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) results in hypertension. In this paper, we review the mechanisms by which hypertension develops when dopamine receptor function is perturbed.

  16. Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function?

    Science.gov (United States)

    Gleich, Tobias; Deserno, Lorenz; Lorenz, Robert Christian; Boehme, Rebecca; Pankow, Anne; Buchert, Ralph; Kühn, Simone; Heinz, Andreas; Schlagenhauf, Florian; Gallinat, Jürgen

    2015-07-01

    Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role

  17. Synergy Between Choroid Plexus Epithelial Cell-Conditioned Medium and Knockout Serum Replacement Converts Human Adipose-Derived Stem Cells to Dopamine-Secreting Neurons.

    Science.gov (United States)

    Boroujeni, Mahdi Eskandarian; Gardaneh, Mossa; Shahriari, Mehrnoosh Hasan; Aliaghaei, Abbas; Hasani, Sanaz

    2017-08-01

    Human adipose-derived stem cells (hADSCs) have great capacity to differentiate into mesodermal origins as well as nonmesodermal lineages, including neural cells. This valuable feature paves the way for the therapeutic application of hADSCs for neurodegenerative maladies such as Parkinson's disease (PD). We tested the capacity of choroid plexus epithelial cell-conditioned medium (CPEC-CM) alone or cocktailed with knockout serum (KS) to induce dopaminergic (DAergic) differentiation of hADSCs. To this end, hADSCs from lipoaspirate were phenotypically characterized and shown to maintain mesodermal multipotency so that selected media easily differentiated them into osteoblasts, chondrocytes, and adipocytes. To begin inducing hADSC neuronal differentiation, we isolated CPECs from rat brain and expanded them in culture to obtain CPEC-CM. We then treated hADSCs with optimized quantities of collected CPEC-CM, KS, or both. The ADSCs treated with either CPEC-CM or CPEC-CM and KS displayed morphological changes typical of neuron-like phenotypes. As revealed by reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), and immunostaining analyses, hADSCs cotreated with CPEC-CM and KS expressed significantly higher levels of neuronal and DAergic markers in comparison with single-treated groups. Moreover, the hADSCs began expressing dopamine-biosynthesizing enzymes mainly after cotreatment with CPEC-CM and KS. Consequently, only cotreated hADSCs were capable of synthesizing and releasing dopamine detectable by high-performance liquid chromatography (HPLC). Finally, hADSCs growing in an ordinary medium were found positive for astrocytic marker glial fibrillary acidic protein (GFAP), but stopped GFAP expression on either single or cotreatments. These combined results suggest that CPEC-CM and KS can synergize to remarkably augment DAergic induction of hADSCs, an effect that has implications for cell replacement therapy for PD and related disorders.

  18. Human biodistribution and dosimetry of [{sup 123}I]FP-CIT: a potent radioligand for imaging of dopamine transporters

    Energy Technology Data Exchange (ETDEWEB)

    Booij, J.; Busemann Sokole, E.; De Bruin, K.; Van Royen, E.A. [Graduate School of Neurosciences, Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (Netherlands); Stabin, M.G. [Radiation Internal Dose Information Center, Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee (United States); Janssen, A.G.M. [Amersham Cygne and Eindhoven University of Technology, Eindhoven (Netherlands)

    1998-01-01

    This study reports on the biodistribution and radiation dosimetry of iodine-123-labelled N-{omega}-(flu- oropropyl)-2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ([{sup 123}I]FP-CIT), a promising radioligand for the imaging of dopamine transporters. In 12 healthy volunteers, conjugate whole-body scans were performed up to 48 h following intravenous injection of approximately 100 MBq [{sup 123}I]FP-CIT. Attenuation correction was performed using a transmission whole-body scan obtained prior to injection of the radioligand, employing a {sup 123}I flood source. Blood samples were taken and urine was freely collected up to 48 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, striatum, lungs and liver were fitted to a multicompartmental model to give time-activity curves. The cumulative urine activity curve was used to model the urinary excretion rate and, indirectly, to predict faecal excretion. Using the MIRD method, nine source organs were considered in estimating absorbed radiation doses for organs of the body. The images showed rapid lung uptake and hepatobiliary excretion. Diffuse uptake and retention of activity was seen in the brain, especially in the striatum. At 48 h following the injection of [{sup 123}I]FP-CIT, mean measured urine excretion was 60%{+-}9% (SD), and mean predicted excretion in faeces was 14%{+-}1%. In general, the striatum received the highest absorbed dose (average 0.23 mGy/MBq), followed by the urinary bladder wall (average 0.054 mGy/MBq) and lungs (average 0.043 mGy/MBq). The average effective dose equivalent of [{sup 123}I]FP-CIT was estimated to be 0.024 mSv/MBq. The amount of [{sup 123}I]FP-CIT required for adequate dopamine transporter imaging results in an acceptable effective dose equivalent to the patient. (orig.) With 3 figs., 4 tabs., 39 refs.

  19. Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis

    NARCIS (Netherlands)

    R. Pivonello (Rosario)

    2005-01-01

    markdownabstract__Abstract__ Dopamine is the predominant catecholamine neurotransmitter in the human central nervous system, where it controls a variety of functions including cognition, emotion, locomotor activity, food intake and endocrine regulation. Dopamine also plays multiple roles in

  20. Delusions, superstitious conditioning and chaotic dopamine neurodynamics.

    Science.gov (United States)

    Shaner, A

    1999-02-01

    Excessive mesolimbic dopaminergic neurotransmission is closely related to the psychotic symptoms of schizophrenia. A mathematical model of dopamine neuron firing rates, developed by King and others, suggests a mechanism by which excessive dopaminergic transmission could produce psychotic symptoms, especially delusions. In this model, firing rates varied chaotically when the efficacy of dopaminergic transmission was enhanced. Such non-contingent changes in firing rates in mesolimbic reward pathways could produce delusions by distorting thinking in the same way that non-contingent reinforcement produces superstitious conditioning. Though difficult to test in humans, the hypothesis is testable as an explanation for a common animal model of psychosis--amphetamine stereotypy in rats. The hypothesis predicts that: (1) amphetamine will cause chaotic firing rates in mesolimbic dopamine neurons; (2) non-contingent brain stimulation reward will produce stereotypy; (3) non-contingent microdialysis of dopamine into reward areas will produce stereotypy; and (4) dopamine antagonists will block all three effects.

  1. Transcriptional activation of the human brain-derived neurotrophic factor gene promoter III by dopamine signaling in NT2/N neurons.

    Science.gov (United States)

    Fang, Hung; Chartier, Joanne; Sodja, Caroline; Desbois, Angele; Ribecco-Lutkiewicz, Maria; Walker, P Roy; Sikorska, Marianna

    2003-07-18

    We have identified a functional cAMP-response element (CRE) in the human brain-derived neurotrophic factor (BDNF) gene promoter III and established that it participated in the modulation of BDNF expression in NT2/N neurons via downstream signaling from the D1 class of dopamine (DA) receptors. The up-regulation of BDNF expression, in turn, produced neuroprotective signals through receptor tyrosine kinase B (TrkB) and promoted cell survival under the conditions of oxygen and glucose deprivation. To our knowledge this is the first evidence showing the presence of a functional CRE in the human BDNF gene and the role of DA signaling in establishing transcriptional competence of CRE in post-mitotic NT2/N neurons. This ability of DA to regulate the expression of the BDNF survival factor has a profound significance for the nigrostriatal pathway, because it indicates the existence of a feedback loop between the neutrophin, which promotes both the maturation and survival of dopaminergic neurons, and the neurotransmitter, which the mature neurons ultimately produce and release.

  2. Sorting nexin 1 loss results in D5 dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice.

    Science.gov (United States)

    Villar, Van Anthony M; Jones, John Edward; Armando, Ines; Asico, Laureano D; Escano, Crisanto S; Lee, Hewang; Wang, Xiaoyan; Yang, Yu; Pascua-Crusan, Annabelle M; Palmes-Saloma, Cynthia P; Felder, Robin A; Jose, Pedro A

    2013-01-04

    The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D(5)R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D(5)R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D(5)R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D(5)R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D(5)R trafficking and that SNX1 depletion results in D(5)R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension.

  3. Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model.

    Directory of Open Access Journals (Sweden)

    Thomas Stockner

    Full Text Available The high-resolution crystal structure of the leucine transporter (LeuT is frequently used as a template for homology models of the dopamine transporter (DAT. Although similar in structure, DAT differs considerably from LeuT in a number of ways: (i when compared to LeuT, DAT has very long intracellular amino and carboxyl termini; (ii LeuT and DAT share a rather low overall sequence identity (22% and (iii the extracellular loop 2 (EL2 of DAT is substantially longer than that of LeuT. Extracellular zinc binds to DAT and restricts the transporter's movement through the conformational cycle, thereby resulting in a decrease in substrate uptake. Residue H293 in EL2 praticipates in zinc binding and must be modelled correctly to allow for a full understanding of its effects. We exploited the high-affinity zinc binding site endogenously present in DAT to create a model of the complete transmemberane domain of DAT. The zinc binding site provided a DAT-specific molecular ruler for calibration of the model. Our DAT model places EL2 at the transporter lipid interface in the vicinity of the zinc binding site. Based on the model, D206 was predicted to represent a fourth co-ordinating residue, in addition to the three previously described zinc binding residues H193, H375 and E396. This prediction was confirmed by mutagenesis: substitution of D206 by lysine and cysteine affected the inhibitory potency of zinc and the maximum inhibition exerted by zinc, respectively. Conversely, the structural changes observed in the model allowed for rationalizing the zinc-dependent regulation of DAT: upon binding, zinc stabilizes the outward-facing state, because its first coordination shell can only be completed in this conformation. Thus, the model provides a validated solution to the long extracellular loop and may be useful to address other aspects of the transport cycle.

  4. Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model.

    Science.gov (United States)

    Stockner, Thomas; Montgomery, Therese R; Kudlacek, Oliver; Weissensteiner, Rene; Ecker, Gerhard F; Freissmuth, Michael; Sitte, Harald H

    2013-01-01

    The high-resolution crystal structure of the leucine transporter (LeuT) is frequently used as a template for homology models of the dopamine transporter (DAT). Although similar in structure, DAT differs considerably from LeuT in a number of ways: (i) when compared to LeuT, DAT has very long intracellular amino and carboxyl termini; (ii) LeuT and DAT share a rather low overall sequence identity (22%) and (iii) the extracellular loop 2 (EL2) of DAT is substantially longer than that of LeuT. Extracellular zinc binds to DAT and restricts the transporter's movement through the conformational cycle, thereby resulting in a decrease in substrate uptake. Residue H293 in EL2 praticipates in zinc binding and must be modelled correctly to allow for a full understanding of its effects. We exploited the high-affinity zinc binding site endogenously present in DAT to create a model of the complete transmemberane domain of DAT. The zinc binding site provided a DAT-specific molecular ruler for calibration of the model. Our DAT model places EL2 at the transporter lipid interface in the vicinity of the zinc binding site. Based on the model, D206 was predicted to represent a fourth co-ordinating residue, in addition to the three previously described zinc binding residues H193, H375 and E396. This prediction was confirmed by mutagenesis: substitution of D206 by lysine and cysteine affected the inhibitory potency of zinc and the maximum inhibition exerted by zinc, respectively. Conversely, the structural changes observed in the model allowed for rationalizing the zinc-dependent regulation of DAT: upon binding, zinc stabilizes the outward-facing state, because its first coordination shell can only be completed in this conformation. Thus, the model provides a validated solution to the long extracellular loop and may be useful to address other aspects of the transport cycle.

  5. Genetic and Functional Analysis of Polymorphisms in the Human Dopamine Receptor and Transporter Genes in Small Cell Lung Cancer.

    Science.gov (United States)

    Cherubini, Emanuela; Di Napoli, Arianna; Noto, Alessia; Osman, Giorgia Amira; Esposito, Maria Cristina; Mariotta, Salvatore; Sellitri, Rossella; Ruco, Luigi; Cardillo, Giuseppe; Ciliberto, Gennaro; Mancini, Rita; Ricci, Alberto

    2016-02-01

    The regulatory role of dopamine (DA) in endocrine, cardiovascular and renal functions has been extensively studied and used for clinical purposes. More recently DA has been indicated as a regulatory molecule for immune cells and malignant cell proliferation. We assessed the expression and the functional role DA, DA receptors, and transporters in primary small cell lung cancer (SCLC). By HPLC DA plasma levels were more elevated in SCLC patients in comparison with NSCLC patients and healthy controls. SCLC cell expressed DA D1- and D2-like receptors and membrane and vesicular transporters at protein and mRNA levels. We also investigated the effects of independent D1- or D2-like receptor stimulation on SCLC cell cultures. DA D1 receptor agonist SKF38393 induced the increase of cAMP levels and DARPP-32 protein expression without affecting SCLC growth rate. Cell treatment with the DA D1 receptor antagonist SCH23390 inhibited SKF38393 effects. In contrast, the DA D2 receptor agonist quinpirole (10 μM) counteracted, in a dose and time dependent way, SCLC cell proliferation, it did not affect cAMP levels and decreased phosphorylated AKT that was induced by DA D2 receptor antagonist sulpiride. However, in only one SCLC line, stimulation of DA D2 receptor failed to inhibit cell proliferation in vitro. This effect was associated to the existence of rs6275 and rs6277 polymorphisms in the D2 gene. These results gave more insight into DA control of lung cancer cell behavior and suggested the existence of different SCLC phenotypes.

  6. Conditional transgenic mice expressing C-terminally truncated human α-synuclein (αSyn119 exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons

    Directory of Open Access Journals (Sweden)

    Flint Beal M

    2009-07-01

    Full Text Available Abstract Background Missense mutations and multiplications of the α-synuclein gene cause autosomal dominant familial Parkinson's disease (PD. α-Synuclein protein is also a major component of Lewy bodies, the hallmark pathological inclusions of PD. Therefore, α-synuclein plays an important role in the pathogenesis of familial and sporadic PD. To model α-synuclein-linked disease in vivo, transgenic mouse models have been developed that express wild-type or mutant human α-synuclein from a variety of neuronal-selective heterologous promoter elements. These models exhibit a variety of behavioral and neuropathological features resembling some aspects of PD. However, an important deficiency of these models is the observed lack of robust or progressive nigrostriatal dopaminergic neuronal degeneration that is characteristic of PD. Results We have developed conditional α-synuclein transgenic mice that can express A53T, E46K or C-terminally truncated (1–119 human α-synuclein pathological variants from the endogenous murine ROSA26 promoter in a Cre recombinase-dependent manner. Using these mice, we have evaluated the expression of these α-synuclein variants on the integrity and viability of nigral dopaminergic neurons with age. Expression of A53T α-synuclein or truncated αSyn119 selectively in nigrostriatal pathway dopaminergic neurons for up to 12 months fails to precipitate dopaminergic neuronal loss in these mice. However, αSyn119 expression in nigral dopaminergic neurons for up to 12 months causes a marked reduction in the levels of striatal dopamine and its metabolites together with other subtle neurochemical alterations. Conclusion We have developed and evaluated novel conditional α-synuclein transgenic mice with transgene expression directed selectively to nigrostriatal dopaminergic neurons as a potential new mouse model of PD. Our data support the pathophysiological relevance of C-terminally truncated α-synuclein species in vivo. The

  7. [{sup 125}I]{beta}-CIT-FE and [{sup 125}I]{beta}-CIT-FP are superior to [{sup 125}I]{beta}-CIT for dopamine transporter visualization: Autoradiographic evaluation in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Guenther, Ilonka; Hall, Haakan; Halldin, Christer; Swahn, Carl-Gunnar; Farde, Lars; Sedvall, Goeran

    1997-10-01

    The binding of the three dopamine transporter radioligands ([{sup 125}I]{beta}-CIT, [{sup 125}I]{beta}-CIT-FE, and [{sup 125}I]{beta}-CIT-FP) was studied using whole-hemisphere autoradiography on postmortem human brains. The autoradiograms revealed an intense and homogeneous labeling of the nucleus caudatus and putamen but also to varying extent to serotonergic and noradrenergic transporters of neocortex and thalamus. The order of specificity estimated (striatum over neocortex ratios) was {beta}-CIT-FP > {beta}-CIT-FE >> {beta}-CIT, suggesting that {beta}-CIT-FE and {beta}-CIT-FP should be preferred for in vivo studies of the dopamine transporter in the human brain.

  8. The effects of dopamine on cardiogenic and endotoxin experimental shock.

    Science.gov (United States)

    Marchetti, G; Longo, T; Merlo, L; Noseda, V

    1973-01-01

    Studies on dogs show that dopamine improves cardiac performance and increases renal and mesenteric flow. This paper investigates the cardiovascular effects of dopamine on narcotized dogs. 0.2 ml. of mercury was administered into the circumflex branch of the left coronary artery of 2 groups of anesthetized dogs to induce myocardial infarction. 1-3 mg/lg of Eschrichia coli endotoxin was injected in 2 other groups of dogs to induce endotoxin shock. Dopamine was administered intravenousely in one group with cardiogenic shock and in the other group with endotoxin shock; noradrenaline was administered in the other 2 groups. Coronary resistances increased after induction of shock and declined towards normal after dopamine was injected. The effect of dopamine on mesenteric and renal resistance was not signficant. Noradrenaline's effect on cardiac performance was similar to that of dopamine, although unlike dopamine, it contributed to a significant increase of total peripheral, coronary, mesenteric, renal and femoral resistances. The effects of dopamine on the dog's hemodynamics were less evident in endotoxin than in cardiogenic shock on account of the fact that in endotoxin shock, circulatory blood volume declines to a higher extent than in cardiogenic shock, and greater blood alterations develop, mainly acidosis. In such conditions, dopamine alone will not help the hemodynamic parameters return to normal levels. Lotto et al. reports that in shocked humans with serious metabolic acidosis, dopamine is effective only when bicarbonate solutions are infused to adjust blood PH.

  9. A peripherally restricted P2Y12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

    Directory of Open Access Journals (Sweden)

    David A. Brott

    2014-01-01

    Discussion: Similar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.

  10. Characterization of dopamine D1 receptor agonists in vivo- Implications for the treatment of schizophrenia and Parkinson s disease

    OpenAIRE

    Isacson, Ruben

    2008-01-01

    Dopamine is fundamental in human behavior for movement, cognition and reward. A dysfunctional dopamine system is implicated in several neurological and psychiatric disorders such as Parkinson s disease and schizophrenia. Dopamine mediates its effects through five receptors. Dopamine D2 receptors are well studied and successful drug targets in the treatment of Parkinson s disease and schizophrenia. The functional role of dopamine D1 receptors is not fully understood and the c...

  11. Comparison of two I-123 labeled SPECT probes, for the dopamine transporter in non-human primate brain

    Energy Technology Data Exchange (ETDEWEB)

    Gandelman, M.S.; Scanley, B.E.; Al-Tikrite, M.S. [Yale Univ., West Haven, CT (United States)] [and others

    1994-05-01

    A comparative SPECT evaluation of the regional uptake of 28-carboisopropoxy-3{beta}-(4-iodophenyl)tropane (IP-CIT) and 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ({beta}-CIT) was performed to assess the improved specificity of IP-CIT over {beta}-CIT for the dopamine (DE) transporter, as shown previously by in vitro studies (n=10), ranging from 7 to 10 hours with 6.9 to 15 mCi injected dose, were completed in 3 baboons. Peripheral metabolism of the two ligands were similar The SPECT images utilized ROIs over striatum (which reflect DA transporters), midbrain (previously shown for {beta}-CIT to reflect primarily serotonin transporters), and the occipital lobe (a region of non-specific uptake). The time to peak specific striatal uptake (striatal minus occipital activity) was similar for IP-CIT and {beta}-CIT (377{plus_minus}60 and 410{plus_minus}60 min, respectively); whereas midbrain peak activity occurred at a significantly earlier time for IP-CIT (21{plus_minus}4 min) as compared to {beta}-CIT (60{plus_minus}17 min). At time of peak specific striatal activity, striatal to occipital ratios were 2.7+0.6 for IP-CIT and 7.6{plus_minus}0.7 for {beta}-CIT, and at time of peak midbrain activity, midbrain to occipital ratios were 1.1{plus_minus}0.1 for IP-CIT, and 1.7{plus_minus}0.2 for {beta}-CIT. At peak specific striatal time, normalized regional uptake values ({mu}Ci/cc per {mu}Ci injected dose per g body mass) for the striatum were 4.9{plus_minus}1.1 IP-CIT and 5.2{plus_minus}0.7 {beta}-CIT, whereas for the occipital lobe normalized regional uptake values were 1.9{plus_minus}0.4 IP-CIT and 0.7{plus_minus}0.2 for {beta}-CIT. Similar regional kinetics in the striatum were observed, as both ligands demonstrate comparable peak striatal uptake and time to peak.

  12. The novel somatostatin receptor 2/dopamine type 2 receptor chimeric compound BIM-23A758 decreases the viability of human GOT1 midgut carcinoid cells.

    Science.gov (United States)

    Zitzmann, Kathrin; Andersen, Sandra; Vlotides, George; Spöttl, Gerald; Zhang, Shengwen; Datta, Rakesh; Culler, Michael; Göke, Burkhard; Auernhammer, Christoph J

    2013-01-01

    The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system coexpress somatostatin receptors (SSTRs) and dopamine type 2 receptors (D2R), thus providing a rationale for the use of novel SSTR2/D2R chimeric compounds in NET disease. Here we investigate the antitumor potential of the SSTR2/D2R chimeric compounds BIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonist BIM-23023 and the selective D2R agonist BIM-53097 on human NET cell lines of heterogeneous origin. While having only minor effects on human pancreatic and bronchus carcinoid cells (BON1 and NCI-H727), BIM-23A758 induced significant antitumor effects in human midgut carcinoid cells (GOT1). These effects involved apoptosis induction as well as inhibition of mitogen-activated protein kinase and Akt signaling. Consistent with their antitumor response to BIM-23A758, GOT1 cells showed relatively high expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cells highly express the short transcript variant of D2R. In contrast to BIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as the individual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097 induced no or only minor antitumor responses in the examined NET cell lines. Taken together, our findings suggest that the novel SSTR2/D2R chimeric compound BIM-23A758 might be a promising substance for the treatment of NETs highly expressing SSTR2 and D2R. In particular, a sufficient expression of the short transcript variant of DR2 might play a pivotal role for effective treatment.

  13. Regulation of blood pressure by dopamine receptors.

    Science.gov (United States)

    Jose, Pedro A; Eisner, Gilbert M; Felder, Robin A

    2003-01-01

    Dopamine is an important regulator of blood pressure. Its actions on renal hemodynamics, epithelial transport and humoral agents such as aldosterone, catecholamines, endothelin, prolactin, pro-opiomelanocortin, renin and vasopressin place it in central homeostatic position for regulation of extracellular fluid volume and blood pressure. Dopamine also modulates fluid and sodium intake via actions in the central nervous system and gastrointestinal tract, and by regulation of cardiovascular centers that control the functions of the heart, arteries and veins. Abnormalities in dopamine production and receptor function accompany a high percentage of human essential hypertension and several forms of rodent genetic hypertension. Some dopamine receptor genes and their regulators are in loci linked to hypertension in humans and in rodents. Furthermore, single nucleotide polymorphisms (SNPs) of genes that regulate dopamine receptors, alone or via the interaction with SNPs of genes that regulate the renin-angiotensin system, are associated with human essential hypertension. Each of the five dopamine receptor subtypes (D1, D2, D3, D4 and D5) participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors (D2 and D5) influence the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents (e.g., the D1, D3 and D4 receptors interact with the renin-angiotensin system). Modifications of the usual actions of the receptor can produce blood pressure changes. In addition, abnormal functioning of these dopamine receptor subtypes impairs their antioxidant function.

  14. The role of conditioning, learning and dopamine in sexual behavior: a narrative review of animal and human studies.

    Science.gov (United States)

    Brom, Mirte; Both, Stephanie; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip

    2014-01-01

    Many theories of human sexual behavior assume that sexual stimuli obtain arousing properties through associative learning processes. It is widely accepted that classical conditioning contributes to the etiology of both normal and maladaptive human behaviors. Despite the hypothesized importance of basic learning processes in sexual behavior, research on classical conditioning of the sexual response in humans is scarce. In the present paper, animal studies and studies in humans on the role of pavlovian conditioning on sexual responses are reviewed. Animal research shows robust, direct effects of conditioning processes on partner- and place preference. On the contrast, the empirical research with humans in this area is limited and earlier studies within this field are plagued by methodological confounds. Although recent experimental demonstrations of human sexual conditioning are neither numerous nor robust, sexual arousal showed to be conditionable in both men and women. The present paper serves to highlight the major empirical findings and to renew the insight in how stimuli can acquire sexually arousing value. Hereby also related neurobiological processes in reward learning are discussed. Finally, the connections between animal and human research on the conditionability of sexual responses are discussed, and suggestions for future directions in human research are given.

  15. Involvement of estrogen receptors in the resveratrol-mediated increase in dopamine transporter in human dopaminergic neurons and in striatum of female mice.

    Science.gov (United States)

    Di Liberto, Valentina; Mäkelä, Johanna; Korhonen, Laura; Olivieri, Melania; Tselykh, Timofey; Mälkiä, Annika; Do Thi, Hai; Belluardo, Natale; Lindholm, Dan; Mudò, Giuseppa

    2012-02-01

    Treatment with resveratrol (RSV) has been shown to protect vulnerable neurons after various brain injuries and in neurodegenerative diseases. The mechanisms for the effects of RSV in brain are not fully understood, but RSV may affect the expression of various gene products. RSV is structurally related to the synthetic estrogen, diethylstilbestrol so the effects of RSV may be gender-specific. Here we studied the role of RSV in the regulation of dopamine transporter (DAT) in the striatum using male and female mice. The basic levels of DAT in the striatum showed no sex difference, but the levels increased significantly by RSV (20 mg/kg i.p.) in female but not in male mice. Pretreatment of mice with the selective estrogen receptor (ER), ERα- and ERβ antagonist ICI 182,780, led to a complete block of RSV effect on DAT protein levels, suggesting that ERs are involved in the up-regulation of DAT by RSV. Similar data was also obtained in culture using human MESC2.10 and mouse SN4741 dopaminergic cells after treatment with RSV. Data further showed that RSV specifically induced gene transcription of DAT in the dopaminergic cells. These results show that estrogen receptors are involved in the up-regulation of DAT by RSV in the dopaminergic neurons, demonstrating a sex-dependent effect of RSV in the brain that may be of clinical importance. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  16. Dopamine D[sub 2]-receptors in human narcolepsy. A SPECT study with [sup 123]I-IB. [Single Photon Emission Computed Tomography. Iodobenzamide

    Energy Technology Data Exchange (ETDEWEB)

    Hublin, C. (Department of Ullanlinna Sleep Research Centre, Kivelae Hospital, Helsinki (Finland)); Launes, J. (Department of Neurology, Helsinki University Central Hospital (Finland)); Nikkinen, P. (Department of Clinical Chemistry, Division of Nuclear Medicine, Helsinki University Central Hospital (Finland)); Partinen, M. (Department of Neurological Unit of Kivelae Hospital, Helsinki (Finland))

    1994-09-01

    Increased dopamine D[sub 2] receptor binding in basal ganglia has been reported in human narcolepsy. These studies have been based on post-mortem material of 8 patients, most of them also medicated for narcolepsy. We studied six narcoleptics without stimulant or anticataplectic medication. The patients had an unambiguous history of cataplexy, and they were also studied polygraphically. Single photon emission computed tomography (SPECT) imaging was performed. The D[sub 2] receptor density wad determined by using [sup 123]I-iodobenzamide (IBZM). The control subjects were 8 unmedicated Parkinson patients with one-sided (hemiparkinsonian) clinical symptoms. The D[sub 2] receptor density in them is known to be normal or somewhat increased compared to healthy normals. The striatum/frontal D[sub 2] activity ratio was 1.331 [+-] 0.084 (with phantom study correction 2.101 [+-] 0.300) in the narcoleptic patients, and in the parkinsonian controls 1.321 [+-] 0.052 (2.067 [+-] 0.185) for the asymptomatic side and 1.335 [+-] 0.025 (2.117 [+-] 0.090) for the symptomatic side (i.e. contralateral to the side with the clinical extrapyramidal signs). There was no statistical difference between the groups or between the symptomatic and asymptomatic side in the Parkinson patients. Thus, our results differ from the earlier post-mortem studies. (au) (28 refs.).

  17. An evolutionary conserved region (ECR in the human dopamine receptor D4 gene supports reporter gene expression in primary cultures derived from the rat cortex

    Directory of Open Access Journals (Sweden)

    Haddley Kate

    2011-05-01

    Full Text Available Abstract Background Detecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours. At a molecular level, characterisation of variation in exons has been studied as they are easily identified in the current genome annotation although the functional consequences are less well understood; however, it has been difficult to prioritise regions of non-coding DNA in which genetic variation could also have significant functional consequences. Comparison of multiple vertebrate genomes has allowed the identification of non-coding evolutionary conserved regions (ECRs, in which the degree of conservation can be comparable with exonic regions suggesting functional significance. Results We identified ECRs at the dopamine receptor D4 gene locus, an important gene for human behaviours. The most conserved non-coding ECR (D4ECR1 supported high reporter gene expression in primary cultures derived from neonate rat frontal cortex. Computer aided analysis of the sequence of the D4ECR1 indicated the potential transcription factors that could modulate its function. D4ECR1 contained multiple consensus sequences for binding the transcription factor Sp1, a factor previously implicated in DRD4 expression. Co-transfection experiments demonstrated that overexpression of Sp1 significantly decreased the activity of the D4ECR1 in vitro. Conclusion Bioinformatic analysis complemented by functional analysis of the DRD4 gene locus has identified a a strong enhancer that functions in neurons and b a transcription factor that may modulate the function of that enhancer.

  18. Striatal dopamine release in reading and writing measured with [123I]iodobenzamide and single photon emission computed tomography in right handed human subjects.

    Science.gov (United States)

    Schommartz, B; Larisch, R; Vosberg, H; Müller-Gärtner, H M

    2000-09-29

    Competition between endogenous dopamine and a radioligand for postsynaptic dopamine D(2) receptor binding was examined in two groups of eight subjects each who had to read or write off a text, respectively, and in a control group. Single photon emission computed tomography (SPECT) and the ligand [(123)I]iodobenzamide (IBZM) were used for in vivo imaging. Subjects commenced reading or writing immediately before IBZM injection and continued for 30min thereafter. SPECT images were acquired 60min later. Striatum-to-parietal-cortex IBZM uptake ratios were lower in subjects who wrote off the text than in controls indicating competition of IBZM and dopamine. There was no difference between subjects who read the text and controls. Thus, dopamine release occurs as a consequence of the motoric activity involved in writing rather than of cognitive functions necessary for reading the text.

  19. Modafinil-Induced Increases in Brain Dopamine Levels

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-04-01

    Full Text Available The acute effects of modafinil on extracellular dopamine and on dopamine transporters in the male human brain were measured by PET study in 10 healthy subjects at Brookhaven National Laboratory and National Institute on Drug Abuse, Bethesda, MD.

  20. Reliance on habits at the expense of goal-directed control following dopamine precursor depletion

    NARCIS (Netherlands)

    de Wit, S.; Standing, H.R.; DeVito, E.E.; Robinson, O.J.; Ridderinkhof, K.R.; Robbins, T.W.; Sahakian, B.J.

    2012-01-01

    Rationale Dopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus-response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not

  1. PHARMACOLOGICAL ASPECTS OF R-(+)-7-OH-DPAT, A PUTATIVE DOPAMINE D-3 RECEPTOR-LIGAND

    NARCIS (Netherlands)

    DAMSMA, G; BOTTEMA, T; WESTERINK, BHC; TEPPER, PG; DIJKSTRA, D; PUGSLEY, TA; MACKENZIE, RG; HEFFNER, TG; WIKSTROM, H

    1993-01-01

    The R-(+)-isomer of 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) bound with a more than 200-fold higher affinity to cloned human dopamine D-3 receptors (K-i=0.57 nM) than to dopamine D-2 receptors; the corresponding S-(-)-enantiomer had considerably less affinity for both dopamine receptor

  2. Reward-based hypertension control by a synthetic brain–dopamine interface

    OpenAIRE

    Rossger, K.; Charpin-El Hamri, G.; Fussenegger, M

    2013-01-01

    Essential activities such as feeding and reproduction as well as social, emotional, and mental behavior are reinforced by the brain’s reward system. Pleasure status directly correlates with dopamine levels released in the brain. Because dopamine leaks into the bloodstream via the sympathetic nervous system, brain and blood dopamine levels are interrelated. We designed a synthetic dopamine sensor-effector device that enables engineered human cells, insulated by immunoprotective microcontainers...

  3. PARAMETRIC IMAGING AND TEST-RETEST VARIABILITY OF 11C-(+)-PHNO BINDING TO D2/D3 DOPAMINE RECEPTORS IN HUMANS ON THE HRRT PET SCANNER

    Science.gov (United States)

    Gallezot, Jean-Dominique; Zheng, Ming-Qiang; Lim, Keunpoong; Lin, Shu-fei; Labaree, David; Matuskey, David; Huang, Yiyun; Ding, Yu-Shin; Carson, Richard E.; Malison, Robert T.

    2014-01-01

    11C-(+)-PHNO is an agonist radioligand for imaging dopamine D2 and D3 receptors in the human brain with PET. In this study we evaluated the reproducibility of 11C-(+)-PHNO binding parameters using a within-day design and assessed parametric imaging methods. Methods Repeated studies were performed in eight subjects, with simultaneous measurement of the arterial input function and plasma free fraction. Two 11C-(+)-PHNO scans on the same subject were separated by 5.4±0.7 h. After evaluating compartment models, 11C-(+)-PHNO volumes of distribution VT and VT/fP and binding potentials BPND, BPP and BPF were quantified using the multilinear analysis MA1, with the cerebellum as reference region. Parametric images of BPND were also computed using SRTM and SRTM2. Results The test-retest variability of 11C-(+)-PHNO BPND was 9% in D2-rich regions (caudate and putamen). Among D3-rich regions, variability was low in pallidum (6%), but higher in substantia nigra (19%), thalamus (14%) and hypothalamus (21%). No significant mass carry-over effect was observed in D3-rich regions, although a trend in BPND was present in substantia nigra (−14±15%). Due to the relatively fast kinetics, low noise BPND parametric images were obtained with both SRTM and SRTM2 without spatial smoothing. Conclusion 11C-(+)-PHNO can be used to compute low noise parametric images in both D2 and D3 rich regions in humans. PMID:24732151

  4. Mesolimbic dopamine and its neuromodulators in obesity and binge eating.

    Science.gov (United States)

    Naef, Lindsay; Pitman, Kimberley A; Borgland, Stephanie L

    2015-12-01

    Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents.

  5. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    Dopamine is an endogenic catecholamine which, in addition to being the direct precursor of noradrenaline, has also an effect on peripheral dopaminergic receptors. These are localized mainly in the heart, splanchnic nerves and the kidneys. Dopamine is produced in the kidneys and the renal metaboli...... dialysis unnecessary in a number of patients on account of increased diuresis and natriuresis. The effect of GFR and the significance for the prognosis are not known....

  6. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-05-09

    Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

  7. The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-01-01

    Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

  8. Human neural stem cells survive long term in the midbrain of dopamine-depleted monkeys after GDNF overexpression and project neurites toward an appropriate target.

    Science.gov (United States)

    Wakeman, Dustin R; Redmond, D Eugene; Dodiya, Hemraj B; Sladek, John R; Leranth, Csaba; Teng, Yang D; Samulski, R Jude; Snyder, Evan Y

    2014-06-01

    Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%-5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression of a developmentally critical molecule, glial cell-derived neurotrophic factor (GDNF), in the host striatum could enhance DA differentiation of hfNSCs injected into the substantia nigra and elicit growth of their axons to the GDNF-expressing target. hfNSCs were transplanted into the midbrain of 10 green monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. GDNF was delivered concomitantly to the striatum via an adeno-associated virus serotype 5 vector, and the fate of grafted cells was assessed after 11 months. Donor cells remained predominantly within the midbrain at the injection site and sprouted numerous neurofilament-immunoreactive fibers that appeared to course rostrally toward the striatum in parallel with tyrosine hydroxylase-immunoreactive fibers from the host substantia nigra but did not mature into DA neurons. This work suggests that hfNSCs can generate neurons that project long fibers in the adult primate brain. However, in the absence of region-specific signals and despite GDNF overexpression, hfNSCs did not differentiate into mature DA neurons in large numbers. It is encouraging, however, that the adult primate brain appeared to retain axonal guidance cues. We believe that transplantation of stem cells, specifically instructed ex vivo to yield DA neurons, could lead to reconstruction of some portion of the nigrostriatal pathway and prove beneficial for the parkinsonian condition. ©AlphaMed Press.

  9. Regulation of blood pressure, oxidative stress and AT1R by high salt diet in mutant human dopamine D5 receptor transgenic mice.

    Science.gov (United States)

    Liu, Xing; Wang, Wenjie; Chen, Wei; Jiang, Xiaoliang; Zhang, Yanrong; Wang, Zihao; Yang, Jian; Jones, John E; Jose, Pedro A; Yang, Zhiwei

    2015-06-01

    Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished function. We generated hD5(F173L) cDNA that has a decreased response to D5R agonist-mediated increase in cAMP production and increased production of reactive oxygen species, relative to wild-type hD5R (hD5(WT)) cDNA expressed in Chinese hamster ovary cells. To investigate the role of hD5(F173L) in the pathogenesis of salt-sensitive hypertension, we generated transgenic mice overexpressing hD5(F173L) or hD5(WT) and fed them normal (0.8% NaCl) or high (4% NaCl) salt diet. On normal salt diet, the blood pressure, and renal NADPH oxidase activity and angiotensin type 1 receptor (AT1R) expression were higher in hD5(F173L) than hD5(WT) transgenic mice. After 2 weeks on high salt diet, the blood pressure and renal NADPH oxidase activity, but not AT1R expression, were increased in hD5(F173L) but not in hD5(WT) transgenic mice. Candesartan, an AT1R antagonist, decreased the blood pressure and NADPH oxidase activity in hD5(F173L) but not in hD5(WT) transgenic mice. We suggest that the ability of the hD5R to negatively regulate the renal NADPH oxidase activity and AT1R function may have important implications in the pathogenesis of salt-sensitive blood pressure. However, the mechanisms involved in regulating the balance of renal D5R and AT1R function in the oxidative stress-mediated salt-sensitive blood pressure remain to be determined.

  10. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy.

    Science.gov (United States)

    Tziortzi, Andri C; Searle, Graham E; Tzimopoulou, Sofia; Salinas, Cristian; Beaver, John D; Jenkinson, Mark; Laruelle, Marc; Rabiner, Eugenii A; Gunn, Roger N

    2011-01-01

    [(11)C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterisation of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [(11)C]-(+)-PHNO signal is a mixture of D3 and D2 components with the relative magnitude of each component determined by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal analysis of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [(11)C]-(+)-PHNO signal in each region into its D3 and D2 components and estimated the regional fraction of the D3 signal (f(PHNO)(D3)). In descending order of magnitude the following results for the f(PHNO)(D3) were obtained: hypothalamus=100%, substantia nigra=100%, ventral pallidum/substantia innominata=75%, globus pallidus=65%, thalamus=43%, ventral striatum=26% and precommissural-ventral putamen=6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.

  11. Cardiac safety profile of etamicastat, a novel peripheral selective dopamine-β-hydroxylase inhibitor in non-human primates, human young and elderly healthy volunteers and hypertensive patients

    Directory of Open Access Journals (Sweden)

    Manuel Vaz-da-Silva

    2015-06-01

    Full Text Available The aim of this work was to evaluate the cardiac risk for etamicastat, a peripheral reversible dopamine-β-hydroxylase inhibitor. Etamicastat blocked the hERG current amplitude with an IC50 value of 44 μg/ml. Etamicastat had no substantial effects on arterial blood pressure, heart rate and the PR interval in male Cynomolgus monkeys when administered orally up to 90 mg/kg. Administered orally at 15 and 45 mg/kg/day in female and male Cynomolgus monkey for 91 days, etamicastat had no effect on heart rate and the waveform or intervals of the electrocardiogram. At the highest dose level of 45 mg/kg, mean plasma concentrations of etamicastat ranged from 1875 to 3145 ng/ml on Day 1 and Day 91 of treatment, respectively. The effect of age on the tolerability and pharmacokinetics of etamicastat in elderly (≥65 years and young adult (18–45 years subjects showed that supine systolic (SBP and diastolic (DBP blood pressure, ECG heart rate, PR interval, QRS duration and QTcF interval were not affected following once-daily administration of 100 mg/day etamicastat for 7 days. In hypertensive patients the decrease of blood pressure tended to be more important in subjects who had received etamicastat (50, 100 and 200 mg than in subjects who had received placebo. No clinically significant out-of-range values in vital signs or ECG parameters, ECG heart rate, PR interval, QRS duration and QTcF interval were observed in hypertensive subjects following once-daily administration of etamicastat for 10 days. In conclusion, etamicastat is not likely to prolong the QT interval at therapeutic doses.

  12. Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [{sup 18}F]F-PHNO

    Energy Technology Data Exchange (ETDEWEB)

    Vasdev, Neil [PET Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T-1R8 (Canada) and Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada)]. E-mail: neil.vasdev@camhpet.ca; Seeman, Philip [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S-1A8 (Canada); Garcia, Armando [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Stableford, Winston T. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Nobrega, Jose N. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S-1A8 (Canada); Houle, Sylvain [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada); Wilson, Alan A. [PET Centre for Addiction and Mental Health, Toronto, Ontario, M5T-1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T-1R8 (Canada)

    2007-02-15

    Introduction: Carbon-11-labeled (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([{sup 11}C]-(+)-PHNO) is a dopamine D2/D3 agonist radioligand that is currently used to image the high-affinity state of dopamine receptors in humans with positron emission tomography (PET). The present study reports the preparation and evaluation of fluorinated (+)-PHNO derivatives. Methods: Five fluorinated (+)-PHNO derivatives were synthesized and tested in vitro for inhibition of binding of [{sup 3}H]domperidone in homogenates of rat striatum and inhibition of binding to [{sup 3}H]-(+)-PHNO in homogenates of human-cloned D2Long receptors in Chinese hamster ovary cells and rat striatum. Radiolabeling with fluorine-18 was carried out for the most promising candidate, N-fluoropropyl-(+)-HNO (F-PHNO), and ex vivo biodistribution and autoradiography studies with this radiopharmaceutical were performed in rodents. Results: (+)-PHNO and the fluorinated analogs inhibited binding of [{sup 3}H]domperidone and [{sup 3}H]-(+)-PHNO to the high- and low-affinity states of dopamine D2 receptors, consistent with D2 agonist behavior. The average dissociation constant at the high-affinity state of D2, K {sub i} {sup High}, was 0.4 nM for F-PHNO and proved to be equipotent with (+)-PHNO (0.7 nM). All other fluorinated derivatives were significantly less potent (K {sub i} {sup High}=2-102 nM). The most promising candidate, F-PHNO, was labeled with fluorine-18 in 5% uncorrected radiochemical yield, with respect to starting fluoride. Ex vivo biodistribution and autoradiography studies in rodents revealed that [{sup 18}F]F-PHNO rapidly enters the rodent brain. However, this radiotracer does not reveal specific binding in the brain and is rapidly cleared. Conclusions: Five novel dopamine D2/D3 agonists based on (+)-PHNO were synthesized and evaluated in vitro. F-PHNO was shown to behave as a potent D2 agonist in vitro and was therefore radiolabeled with fluorine-18. Despite the

  13. Osteogenesis of human adipose-derived stem cells on poly(dopamine)-coated electrospun poly(lactic acid) fiber mats.

    Science.gov (United States)

    Lin, Chi-Chang; Fu, Shu-Juan

    2016-01-01

    Electrospinning is a versatile technique to generate large quantities of micro- or nano-fibers from a wide variety of shapes and sizes of polymer. The aim of this study is to develop functionalized electrospun nano-fibers and use a mussel-inspired surface coating to regulate adhesion, proliferation and differentiation of human adipose-derived stem cells (hADSCs). We prepared poly(lactic acid) (PLA) fibers coated with polydopamine (PDA). The morphology, chemical composition, and surface properties of PDA/PLA were characterized by SEM and XPS. PDA/PLA modulated hADSCs' responses in several ways. Firstly, adhesion and proliferation of hADSCs cultured on PDA/PLA were significantly enhanced relative to those on PLA. Increased focal adhesion kinase (FAK) and collagen I levels and enhanced cell attachment and cell cycle progression were observed upon an increase in PDA content. In addition, the ALP activity and osteocalcin of hADSCs cultured on PDA/PLA were significantly higher than seen in those cultured on a pure PLA mat. Moreover, hADSCs cultured on PDA/PLA showed up-regulation of the ang-1 and vWF proteins associated with angiogenesis differentiation. Our results demonstrate that the bio-inspired coating synthetic degradable PLA polymer can be used as a simple technique to render the surfaces of synthetic biodegradable fibers, thus enabling them to direct the specific responses of hADSCs. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. The effects of Δ(9)-tetrahydrocannabinol on the dopamine system.

    Science.gov (United States)

    Bloomfield, Michael A P; Ashok, Abhishekh H; Volkow, Nora D; Howes, Oliver D

    2016-11-17

    The effects of Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

  15. Osteogenesis of human adipose-derived stem cells on poly(dopamine)-coated electrospun poly(lactic acid) fiber mats

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chi-Chang, E-mail: chichang31@thu.edu.tw; Fu, Shu-Juan

    2016-01-01

    Electrospinning is a versatile technique to generate large quantities of micro- or nano-fibers from a wide variety of shapes and sizes of polymer. The aim of this study is to develop functionalized electrospun nano-fibers and use a mussel-inspired surface coating to regulate adhesion, proliferation and differentiation of human adipose-derived stem cells (hADSCs). We prepared poly(lactic acid) (PLA) fibers coated with polydopamine (PDA). The morphology, chemical composition, and surface properties of PDA/PLA were characterized by SEM and XPS. PDA/PLA modulated hADSCs' responses in several ways. Firstly, adhesion and proliferation of hADSCs cultured on PDA/PLA were significantly enhanced relative to those on PLA. Increased focal adhesion kinase (FAK) and collagen I levels and enhanced cell attachment and cell cycle progression were observed upon an increase in PDA content. In addition, the ALP activity and osteocalcin of hADSCs cultured on PDA/PLA were significantly higher than seen in those cultured on a pure PLA mat. Moreover, hADSCs cultured on PDA/PLA showed up-regulation of the ang-1 and vWF proteins associated with angiogenesis differentiation. Our results demonstrate that the bio-inspired coating synthetic degradable PLA polymer can be used as a simple technique to render the surfaces of synthetic biodegradable fibers, thus enabling them to direct the specific responses of hADSCs. - Highlights: • A simple method of preparing electrospun poly(lactic acid) nanofibers coated with polydopamine • Enhanced adhesion and proliferation of hADSCs on a PDA/PLA mat • Increased focal adhesion kinase (FAK), collagen I levels, cell attachment and cell cycle progression with a high PDA content • Up-regulation of the Ang-1 and vWF proteins associated with angiogenesis differentiation of hADSCs is observed. • A promising method for bio-inspired surface modification on organic fiber substrates using PDA.

  16. Dopamine, T cells and multiple sclerosis (MS).

    Science.gov (United States)

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-03-10

    Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in

  17. Dopamine, hypertension and obesity.

    Science.gov (United States)

    Contreras, F; Fouillioux, C; Bolívar, A; Simonovis, N; Hernández-Hernández, R; Armas-Hernandez, M J; Velasco, M

    2002-03-01

    Dopamine, a neurotransmitter, precursor of noradrenaline, is responsible for cardiovascular and renal actions, such as increase in myocardial contractility and cardiac output, without changes in heart rate, producing passive and active vasodilatation, diuresis and natriuresis. These cardiovascular and renal actions take place through the interaction with dopamine receptors, D(1), D(2), D(3), D(4), and D(5). Recent findings point to the possibility of D(6) and D(7)receptors. Dopamine is known to influence the control of arterial pressure by influencing the central and peripheral nervous system and target organs such as kidneys and adrenal glands, in some types of hypertension. Although dopamine and its derivatives have been shown to have antihypertensive effects, these are still being studied; therefore it is important to explain some physiological and pharmacological aspects of dopamine, its receptors, and the clinical uses it could have in the treatment of arterial hypertension and more recently in obesity, based on evidence proving a clear association between obesity and the decrease in the expression of D(2) receptors in the brain of obese persons.

  18. A dopamine-secreting pheochromocytoma.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Minami, M; Kano, H; Ohhira, M; Nakamura, K; Yoshikawa, J

    2000-01-01

    We describe a patient with pheochromocytoma, which secretes dopamine. He was admitted to hospital because of chronic diarrhea. After surgical resection of the tumor, dramatic cessation of the diarrhea and blood pressure elevation were observed. Decreased expression of dopamine beta-hydroxylase in the tumor was considered a possible mechanism of producing a pathophysiological concentration of dopamine. This case shows that excessive excretion of dopamine, a vasodilative hormone, may affect blood pressure.

  19. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

    Science.gov (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing

    2014-07-01

    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

  20. Simultaneous voltammetric determination of dopamine and epinephrine in human body fluid samples using a glassy carbon electrode modified with nickel oxide nanoparticles and carbon nanotubes within a dihexadecylphosphate film.

    Science.gov (United States)

    Figueiredo-Filho, Luiz C S; Silva, Tiago A; Vicentini, Fernando C; Fatibello-Filho, Orlando

    2014-06-07

    A simple and highly selective electrochemical method was developed for the single or simultaneous determination of dopamine (DA) and epinephrine (EP) in human body fluids using a glassy carbon electrode modified with nickel oxide nanoparticles and carbon nanotubes within a dihexadecylphosphate film using square-wave voltammetry (SWV) or differential-pulse voltammetry (DPV). Using DPV with the proposed electrode, a separation of ca. 360 mV between the peak reduction potentials of DA and EP present in binary mixtures was obtained. The analytical curves for the simultaneous determination of dopamine and epinephrine showed an excellent linear response, ranging from 7.0 × 10(-8) to 4.8 × 10(-6) and 3.0 × 10(-7) to 9.5 × 10(-6) mol L(-1) for DA and EP, respectively. The detection limits for the simultaneous determination of DA and EP were 5.0 × 10(-8) mol L(-1) and 8.2 × 10(-8) mol L(-1), respectively. The proposed method was successfully applied in the simultaneous determination of these analytes in human body fluid samples of cerebrospinal fluid, human serum and lung fluid.

  1. Moderate alcohol exposure during the rat equivalent to the third trimester of human pregnancy alters dopamine regulation of GABAA receptor-mediated transmission in the basolateral amygdala

    Directory of Open Access Journals (Sweden)

    Marvin Rafael Diaz

    2014-05-01

    Full Text Available Fetal ethanol (EtOH exposure leads to a range of neurobehavioral alterations, including deficits in emotional processing. The basolateral amygdala (BLA plays a critical role in modulating emotional processing, in part, via dopamine (DA regulation of GABA transmission. This BLA modulatory system is acquired during the first two weeks of postnatal life in rodents (equivalent to the 3rd trimester of human pregnancy and we hypothesized that it could be altered by EtOH exposure during this period. We found that exposure of rats to moderate levels of EtOH vapor during the 3rd trimester-equivalent (postnatal days (P 2-12 alters DA modulation of GABAergic transmission in BLA pyramidal neurons during periadolescence. Specifically, D1R-mediated potentiation of spontaneous inhibitory postsynaptic currents (IPSCs was significantly attenuated in EtOH-exposed animals. However, this was associated with a compensatory decrease in D3R-mediated suppression of miniature IPSCs. Western blot analysis revealed that these effects were not a result of altered D1R or D3R levels. BLA samples from EtOH-exposed animals also had significantly lower levels of the DA precursor (L-3,4-dihydroxyphenylalanine but DA levels were not affected. This is likely a consequence of reduced catabolism of DA, as indicated by reduced levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the BLA samples. Anxiety-like behavior was not altered in EtOH-exposed animals. This is the first study to demonstrate that the modulatory actions of DA in the BLA are altered by developmental EtOH exposure. Although compensatory adaptations were engaged in our moderate EtOH exposure paradigm, it is possible that these are not able to restore homeostasis and correct anxiety-like behaviors under conditions of heavier EtOH exposure. Therefore, future studies should investigate the potential role of alterations in the modulatory actions of DA in the pathophysiology of fetal alcohol spectrum

  2. Dopamine D{sub 2} receptor occupancy in normal humans treated with a novel antipsychotic drug YKP1358 measured by PET and [11c]raclopride

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J. S.; Kim, S. J.; Lee, K. J.; Kim, E.; Yu, K. S.; Jang, I. J.; Kwon, J. S.; Kang, W. J.; Jeong, J. M.; Lee, D. S.; Chung, J. K.; Lee, M. C. [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    YKP1358 is a novel serotonin (5-HT{sub 2A}) and dopamine (D{sub 2}) antagonist, and fitted the general profile of an atypical neuroleptic agent in preclinical studies. The time course of D{sub 2} receptor occupancy in the brain of living human after a single oral dose of YKP1358 was measured using PET and related to the plasma drug levels. A single oral dose, dose escalation (100 mg, 200 mg, and 250 mg), open-label study was performed in 9 healthy male volunteers (3 per each dose) using the [{sup 11}C]raclopried PET. After the baseline scan, each subject was studied at 2, 5, and 10 hours after the single administration of YKP1358. Blood samples for evaluation of plasma concentration of YKP1358 were also taken at various time points (0-32 hours post-dose). Binding potential (BP) of [{sup 11}C]raclopride in the putamen was estimated with simplified reference tissue model and percent reduction of the BP was calculated to obtain the D{sub 2} receptor occupancy. BP parametric image was generated using a pixel-wise Logan noninvasive plot. T{sub max} of plasma concentration-time profiles was 0.67 hours, and elimination half-life was 5.71, 7.46, and 8.58 hours in 100 mg, 200 mg, and 250 mg dosing groups, respectively. D{sub 2} receptor occupancy of YKP1358 was 60 to 80% at 2 hours, 40 to 60% at 5 hours, and 20 to 50% at 10 hours. The relationship of plasma concentration and D{sub 2} receptor occupancy of YKP1358 was well predicted by Emax model, and Emax was 100 %, EC50 was 8.9 (=1.1) ng/mI, and Hills coefficient was 0.525. PK profile of YKP1358 showed individual variation, but the D{sub 2} receptor occupancy was less variable and well predicted by an Emax model. Since D{sub 2} antagonists show therapeutic effects at 50 to 80% D{sub 2} occupancy and the EC50 of YKP1358 is less than 10 ng/ml, doses of YKP1358 which maintain plasma concentrations above 10 ng/ml are expected to show therapeutic effects.

  3. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue.

    Science.gov (United States)

    Brisch, Ralf; Saniotis, Arthur; Wolf, Rainer; Bielau, Hendrik; Bernstein, Hans-Gert; Steiner, Johann; Bogerts, Bernhard; Braun, Katharina; Braun, Anna Katharina; Jankowski, Zbigniew; Kumaratilake, Jaliya; Kumaritlake, Jaliya; Henneberg, Maciej; Gos, Tomasz

    2014-01-01

    Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

  4. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue.

    Directory of Open Access Journals (Sweden)

    Ralf eBrisch

    2014-05-01

    Full Text Available Abstract: Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia.The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them, but also an outline of dopamine and it`s interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

  5. Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

    Science.gov (United States)

    Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

    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 non-exocytotic 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 two hours. 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, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-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 up-regulation 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

  6. Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release.

    Science.gov (United States)

    Cosi, Cristina; Carilla-Durand, Elisabeth; Assié, Marie Bernadette; Ormiere, Anne Marie; Maraval, Mireille; Leduc, Nathalie; Newman-Tancredi, Adrian

    2006-03-27

    Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [35S]-GTPgammaS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long (hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (pK(b) = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [35S]-GTPgammaS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 microM apomorphine (Emax = 100%). pEC50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only

  7. Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive, First-Episode Schizophrenia Patients

    DEFF Research Database (Denmark)

    Düring, Signe; Glenthøj, Birte Y; Andersen, Gitte Saltoft;

    2014-01-01

    , habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating......, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI...... deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may...

  8. The dopamine theory of addiction: 40 years of highs and lows.

    Science.gov (United States)

    Nutt, David J; Lingford-Hughes, Anne; Erritzoe, David; Stokes, Paul R A

    2015-05-01

    For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

  9. Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor.

    Science.gov (United States)

    Błasiak, Ewa; Łukasiewicz, Sylwia; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2017-04-01

    The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia. The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors. Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand. The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  10. Dopamine and anorexia nervosa.

    Science.gov (United States)

    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.

  11. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux

    DEFF Research Database (Denmark)

    Binda, Francesca; Dipace, Concetta; Bowton, Erica

    2008-01-01

    of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated...

  12. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

    DEFF Research Database (Denmark)

    Hamilton, P J; Campbell, N G; Sharma, S

    2013-01-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...... at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first...

  13. Dopamine Increases a Value-Independent Gambling Propensity

    OpenAIRE

    Rigoli, Francesco; Rutledge, Robb B.; Chew, Benjamin; Ousdal, Olga T; Dayan, Peter; Dolan, Raymond J.

    2016-01-01

    Although the impact of dopamine on reward learning is well documented, its influence on other aspects of behavior remains the subject of much ongoing work. Dopaminergic drugs are known to increase risk-taking behavior, but the underlying mechanisms for this effect are not clear. We probed dopamine's role by examining the effect of its precursor L-DOPA on the choices of healthy human participants in an experimental paradigm that allowed particular components of risk to be distinguished. We sho...

  14. Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

    Science.gov (United States)

    Hauck Newman, Amy; Katz, Jonathan L.

    The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

  15. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Emese Prandovszky

    Full Text Available 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.

  16. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

    Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1)

  17. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

    Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1) stim

  18. Turning skin into dopamine neurons

    Institute of Scientific and Technical Information of China (English)

    Malin Parmar; Johan Jakobsson

    2011-01-01

    The possibility to generate neurons from fibroblasts became a reality with the development of iPS technology a few years ago.By reprogramming somatic cells using transcription factor (TF) overexpression,it is possible to generate pluripotent stem cells that then can be differentiated into any somatic cell type including various subtypes of neurons.This raises the possibility of using donor-matched or even patientspecific cells for cell therapy of neurological disorders such as Parkinson's disease (PD),Huntington's disease and stroke.Supporting this idea,dopamine neurons,which are the cells dying in PD,derived from human iPS cells have been demonstrated to survive transplantation and reverse motor symptoms in animal models of PD [1].

  19. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice

    OpenAIRE

    Wang, Xiaoyan; Villar, Van Anthony M.; Armando, Ines; Eisner, Gilbert M.; Felder, Robin A.; Pedro A. Jose

    2008-01-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D1-like (D1, D5) and D2-like (D2, D3, D4) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models...

  20. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice.

    Science.gov (United States)

    Wang, Xiaoyan; Villar, Van Anthony M; Armando, Ines; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2008-12-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models and evaluates the impact of individual dopamine receptor subtypes on blood pressure regulation.

  1. Growth of dopamine crystals

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Vidya, E-mail: vidya.patil@ruparel.edu; Patki, Mugdha, E-mail: mugdha.patki@ruparel.edu [D. G. Ruparel College, Senapati Bapat Marg, Mahim, Mumbai – 400 016 (India)

    2016-05-06

    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. Growth of dopamine crystals

    Science.gov (United States)

    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.

  3. No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts.

    Science.gov (United States)

    Garcia-Miralles, Marta; Coomaraswamy, Janaky; Häbig, Karina; Herzig, Martin C; Funk, Natalja; Gillardon, Frank; Maisel, Martina; Jucker, Mathias; Gasser, Thomas; Galter, Dagmar; Biskup, Saskia

    2015-01-01

    Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion.

  4. No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts.

    Directory of Open Access Journals (Sweden)

    Marta Garcia-Miralles

    Full Text Available Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion.

  5. Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

    OpenAIRE

    Seiji Hayashizaki; Shinobu Hirai; Yumi Ito; Yoshiko Honda; Yosefu Arime; Ichiro Sora; Haruo Okado; Tohru Kodama; Masahiko Takada

    2013-01-01

    Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

  6. Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

    Science.gov (United States)

    Jääskeläinen, Satu K; Lindholm, Pauliina; Valmunen, Tanja; Pesonen, Ullamari; Taiminen, Tero; Virtanen, Arja; Lamusuo, Salla; Forssell, Heli; Hagelberg, Nora; Hietala, Jarmo; Pertovaara, Antti

    2014-10-01

    We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain.

  7. Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas.

    Science.gov (United States)

    Ben-Shlomo, Anat; Liu, Ning-Ai; Melmed, Shlomo

    2017-02-01

    Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are Gαi-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.

  8. Dopamine and glucose, obesity and Reward Deficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Kenneth eBlum

    2014-09-01

    Full Text Available Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1 brain dopamine (DA production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2 in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3 highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4 blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of

  9. Dopamine Oxidation and Autophagy

    Directory of Open Access Journals (Sweden)

    Patricia Muñoz

    2012-01-01

    Full Text Available The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic α-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i the formation of α-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii the formation of adducts with α- and β-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

  10. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of “unhealthy” foods

    NARCIS (Netherlands)

    Wallace, D.L.; Aarts, E.; d'Oleire Uquillas, F.; Dang, L.C.; Greer, S.M.; Jagust, W.J.; D'Esposito, M.

    2015-01-01

    The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene h

  11. Development and function of the midbrain dopamine system: what we know and what we need to.

    Science.gov (United States)

    Bissonette, G B; Roesch, M R

    2016-01-01

    The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  12. Interindividual variability in the dose-specific effect of dopamine on carotid chemoreceptor sensitivity to hypoxia.

    Science.gov (United States)

    Limberg, Jacqueline K; Johnson, Blair D; Holbein, Walter W; Ranadive, Sushant M; Mozer, Michael T; Joyner, Michael J

    2016-01-15

    Human studies use varying levels of low-dose (1-4 μg·kg(-1)·min(-1)) dopamine to examine peripheral chemosensitivity, based on its known ability to blunt carotid body responsiveness to hypoxia. However, the effect of dopamine on the ventilatory responses to hypoxia is highly variable between individuals. Thus we sought to determine 1) the dose response relationship between dopamine and peripheral chemosensitivity as assessed by the ventilatory response to hypoxia in a cohort of healthy adults, and 2) potential confounding cardiovascular responses at variable low doses of dopamine. Young, healthy adults (n = 30, age = 32 ± 1, 24 male/6 female) were given intravenous (iv) saline and a range of iv dopamine doses (1-4 μg·kg(-1)·min(-1)) prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects initially received iv saline, and after each HVR the dopamine infusion rate was increased by 1 μg·kg(-1)·min(-1). Tidal volume, respiratory rate, heart rate, blood pressure, and oxygen saturation were continuously measured. Dopamine significantly reduced HVR at all doses (P high (n = 13) and low (n = 17) baseline chemosensitivity, dopamine infusion (when assessed by dose) reduced HVR in the high group only (P dopamine on HVR in the low group (P > 0.05). Dopamine infusion also resulted in a reduction in blood pressure (3 μg·kg(-1)·min(-1)) and total peripheral resistance (1-4 μg·kg(-1)·min(-1)), driven primarily by subjects with low baseline chemosensitivity. In conclusion, we did not find a single dose of dopamine that elicited a nadir HVR in all subjects. Additionally, potential confounding cardiovascular responses occur with dopamine infusion, which may limit its usage.

  13. Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease.

    Science.gov (United States)

    Reyes, Stefanie; Fu, Yuhong; Double, Kay L; Cottam, Veronica; Thompson, Lachlan H; Kirik, Deniz; Paxinos, George; Watson, Charles; Cooper, Helen M; Halliday, Glenda M

    2013-03-01

    Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors pituitary homeobox 3 (Pitx3) and orthodenticle homeobox 2 (Otx2) and the trophic factor receptor deleted in colorectal cancer (DCC), but there is limited information on their expression and localization in adult humans. Pitx3, Otx2, and DCC were immunohistochemically localized in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterized vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons.

  14. Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [(11)C]-(+)-PHNO.

    Science.gov (United States)

    Caravaggio, Fernando; Chung, Jun Ku; Gerretsen, Philip; Fervaha, Gagan; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2017-04-01

    Differences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D2/3 receptor (D2/3R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D2/3R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D2/3R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [(11)C]-(+)-PHNO. Surprisingly, more social attachment-as measured by the attachment subscale of the temperament and character inventory-was related to less [(11)C]-(+)-PHNO binding in the VS (r(30) = -.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BPND in the dorsal striatum or D3R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D2/3R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment.

  15. Automated preparation of the dopamine D{sub 2/3} receptor agonist ligand [{sup 11}C]-(+)-PHNO for human PET imaging studies

    Energy Technology Data Exchange (ETDEWEB)

    Plisson, Christophe, E-mail: Christophe.2.plisson@gsk.com [GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London W12 0NN (United Kingdom); Huiban, Mickael; Pampols-Maso, Sabina; Singleton, Goerkem; Hill, Samuel P.; Passchier, Jan [GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London W12 0NN (United Kingdom)

    2012-02-15

    Carbon-11 labelled (+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([{sup 11}C]-(+)-PHNO) is used as a high-affinity state, dopamine D{sub 2/3} receptor ligand in clinical PET studies. To facilitate its use, robust, rapid, efficient and GMP compliant methods are required for the manufacturing and QC testing processes. Additionally, to allow for full quantification of the resulting signal in the CNS, a reliable method is required to establish the parent plasma concentration over the course of the scan. This paper provides high-quality methods to support clinical application of [{sup 11}C]-(+)-PHNO. - Highlights: Black-Right-Pointing-Pointer Fully automated synthesis of [{sup 11}C]-(+)-PHNO. Black-Right-Pointing-Pointer Rapid multi-step synthesis and QC analysis. Black-Right-Pointing-Pointer Reproducible synthesis process typically yielding more than 3 GBq of [{sup 11}C]-(+)-PHNO. Black-Right-Pointing-Pointer Very low failure rate.

  16. Addiction: Beyond dopamine reward circuitry

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. Neuropharmacology of novel dopamine modulators

    NARCIS (Netherlands)

    Beek, Erik Tomas te

    2014-01-01

    De neurotransmitter dopamine speelt een essentiële rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de ziekte van Parkinson, schizofrenie, drugsverslaving en hyperprolactinemie. De huidige

  18. Dopamine, the Kidney, and Hypertension

    OpenAIRE

    Raymond C. Harris; Zhang, Ming-Zhi

    2012-01-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal mo...

  19. Interval timing, dopamine, and motivation

    OpenAIRE

    Balcı, Fuat

    2014-01-01

    The dopamine clock hypothesis suggests that the dopamine level determines the speed of the hypothetical internal clock. However, dopaminergic function has also been implicated for motivation and thus the effect of dopaminergic manipulations on timing behavior might also be independently mediated by altered motivational state. Studies that investigated the effect of motivational manipulations on peak responding are reviewed in this paper. The majority of these studies show that a higher reward...

  20. Dopamine, Affordance and Active Inference

    Science.gov (United States)

    Friston, Karl J.; Shiner, Tamara; FitzGerald, Thomas; Galea, Joseph M.; Adams, Rick; Brown, Harriet; Dolan, Raymond J.; Moran, Rosalyn; Stephan, Klaas Enno; Bestmann, Sven

    2012-01-01

    The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. PMID:22241972

  1. Dopamine, affordance and active inference.

    Directory of Open Access Journals (Sweden)

    Karl J Friston

    2012-01-01

    Full Text Available The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order in which cues are presented. These simulations provide a (Bayes-optimal model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

  2. Reward-based hypertension control by a synthetic brain-dopamine interface.

    Science.gov (United States)

    Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

    2013-11-05

    Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

  3. Dynamic Nigrostriatal Dopamine Biases Action Selection.

    Science.gov (United States)

    Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

    2017-03-22

    Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

  5. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism

    Science.gov (United States)

    The common parasite Toxoplasma gondii induces behavioral alterations in its hosts including phenotypes increasing the likelihood of its transmission in rodents and reports of psychobehavioral alterations in humans. We have found that elevated levels of dopamine are associated with the encysted stage...

  6. Orbitofrontal connectivity with resting-state networks is associated with midbrain dopamine D3 receptor availability

    NARCIS (Netherlands)

    Cole, D.M.; Beckmann, C.F.; Searle, G.E.; Pisson, C.; Tziortzi, A.C.; Nichols, T.E.; Gunn, R.N.; Matthews, P.M.; Rabiner, E.A.; Beaver, J.D.

    2012-01-01

    Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed

  7. Dopamine and Huntington's disease.

    Science.gov (United States)

    Schwab, Laetitia C; Garas, Shady N; Garas, Shaady N; Drouin-Ouellet, Janelle; Mason, Sarah L; Stott, Simon R; Barker, Roger A

    2015-04-01

    Huntington's disease (HD) is an incurable, inherited, progressive neurodegenerative disorder that is defined by a combination of motor, cognitive and psychiatric features. Pre-clinical and clinical studies have demonstrated an important role for the dopamine (DA) system in HD with dopaminergic dysfunction at the level of both DA release and DA receptors. It is, therefore, not surprising that the drug treatments most commonly used in HD are anti-dopaminergic agents. Their use is based primarily on the belief that the characteristic motor impairments are a result of overactivation of the central dopaminergic pathways. While this is a useful starting place, it is clear that the behavior of the central dopaminergic pathways is not fully understood in this condition and may change as a function of disease stage. In addition, how abnormalities in dopaminergic systems may underlie some of the non-motor features of HD has also been poorly investigated and this is especially important given the greater burden these place on the patients' and families' quality of life. In this review, we discuss what is known about central dopaminergic pathways in HD and how this informs us about the mechanisms of action of the dopaminergic therapies used to treat it. By doing so, we will highlight some of the paradoxes that exist and how solving them may reveal new insights for improved treatment of this currently incurable condition, including the possibility that such drugs may even have effects on disease progression and pathogenesis.

  8. PET neuroimaging of extrastriatal dopamine receptors and prefrontal cortex functions.

    Science.gov (United States)

    Takahashi, Hidehiko

    2013-12-01

    The role of prefrontal dopamine D1 receptors in prefrontal cortex (PFC) functions, including working memory, is widely investigated. However, human (healthy volunteers and schizophrenia patients) positron emission tomography (PET) studies about the relationship between prefrontal D1 receptors and PFC functions are somewhat inconsistent. We argued that several factors including an inverted U-shaped relationship between prefrontal D1 receptors and PFC functions might be responsible for these inconsistencies. In contrast to D1 receptors, relatively less attention has been paid to the role of D2 receptors in PFC functions. Several animal and human pharmacological studies have reported that the systemic administration of D2 receptor agonist/antagonist modulates PFC functions, although those studies do not tell us which region(s) is responsible for the effect. Furthermore, while prefrontal D1 receptors are primarily involved in working memory, other PFC functions such as set-shifting seem to be differentially modulated by dopamine. PET studies of extrastriatal D2 receptors including ours suggested that orchestration of prefrontal dopamine transmission and hippocampal dopamine transmission might be necessary for a broad range of normal PFC functions. In order to understand the complex effects of dopamine signaling on PFC functions, measuring a single index related to basic dopamine tone is not sufficient. For a better understanding of the meanings of PET indices related to neurotransmitters, comprehensive information (presynaptic, postsynaptic, and beyond receptor signaling) will be required. Still, an interdisciplinary approach combining molecular imaging techniques with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders and their innovative drug developments.

  9. MR-DTI and PET multimodal imaging of dopamine release within subdivisions of basal ganglia

    Science.gov (United States)

    Tziortzi, A.; Searle, G.; Tsoumpas, C.; Long, C.; Shotbolt, P.; Rabiner, E.; Jenkinson, M.; Gunn, R. N.

    2011-09-01

    The basal ganglia is a group of anatomical nuclei, functionally organised into limbic, associative and sensorimotor regions, which plays a central role in dopamine related neurological and psychiatric disorders. In this study, we combine two imaging modalities to enable the measurement of dopamine release in functionally related subdivisions of the basal ganglia. [11C]-(+)-PHNO Positron Emission Tomography (PET) measurements in the living human brain pre- and post-administration of amphetamine allow for the estimation of regional dopamine release. Combined Magnetic Resonance Diffusion Tensor Imaging (MR-DTI) data allows for the definition of functional territories of the basal ganglia from connectivity information. The results suggest that there is a difference in dopamine release among the connectivity derived functional subdivisions. Dopamine release is highest in the limbic area followed by the sensorimotor and then the associative area with this pattern reflected in both striatum and pallidum.

  10. Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors.

    Science.gov (United States)

    Mikelman, Sarah R; Guptaroy, Bipasha; Gnegy, Margaret E

    2017-04-01

    As one of the primary mechanisms by which dopamine signaling is regulated, the dopamine transporter (DAT) is an attractive pharmacological target for the treatment of diseases based in dopaminergic dysfunction. In this work we demonstrate for the first time that the commonly prescribed breast cancer therapeutic tamoxifen and its major metabolites, 4-hydroxytamoxifen and endoxifen, inhibit DAT function. Tamoxifen inhibits [(3) H]dopamine uptake into human DAT (hDAT)-N2A cells via an uncompetitive or mixed mechanism. Endoxifen, an active metabolite of tamoxifen, asymmetrically inhibits DAT function in hDAT-N2A cells, showing a preference for the inhibition of amphetamine-stimulated dopamine efflux as compared to dopamine uptake. Importantly, we demonstrate that the effects of tamoxifen and its metabolites on the DAT occur independently of its activity as selective estrogen receptor modulators. This work suggests that tamoxifen is inhibiting DAT function through a previously unidentified mechanism. © 2017 International Society for Neurochemistry.

  11. Test-retest reproducibility of dopamine D{sub 2/3} receptor binding in human brain measured by PET with [{sup 11}C]MNPA and [{sup 11}C]raclopride

    Energy Technology Data Exchange (ETDEWEB)

    Kodaka, Fumitoshi [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); Jikei University School of Medicine, Department of Psychiatry, Tokyo (Japan); Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Kimura, Yasuyuki; Fujie, Saori; Takano, Harumasa; Fujiwara, Hironobu; Sasaki, Takeshi; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); Nakayama, Kazuhiko [Jikei University School of Medicine, Department of Psychiatry, Tokyo (Japan); Halldin, Christer; Farde, Lars [Karolinska Institutet, Department of Clinical Neuroscience, Stockholm (Sweden)

    2013-04-15

    Dopamine D{sub 2/3} receptors (D{sub 2/3}Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D{sub 2/3} {sup HIGH}), which has a high affinity for endogenous dopamine, and low-affinity state (D{sub 2/3} {sup LOW}). The density of D{sub 2/3} {sup HIGH} can be measured with (R)-2-{sup 11}CH{sub 3}O-N-n-propylnorapomorphine ([{sup 11}C]MNPA), while total density of D{sub 2/3} {sup HIGH} and D{sub 2/3} {sup LOW} (D{sub 2/3}Rs) can be measured with [{sup 11}C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [{sup 11}C]MNPA to that of [{sup 11}C]raclopride ([{sup 11}C]MNPA/[{sup 11}C]raclopride) may reflect the proportion of the density of D{sub 2/3} {sup HIGH} to that of D{sub 2/3}Rs. In the caudate and putamen, [{sup 11}C]MNPA/[{sup 11}C]raclopride reflects the proportion of the density of D{sub 2} {sup HIGH} to that of D{sub 2}Rs. To evaluate the reliability of the PET paradigm with [{sup 11}C]MNPA and [{sup 11}C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP{sub ND}) measured with [{sup 11}C]MNPA and of [{sup 11}C]MNPA/[{sup 11}C]raclopride in healthy humans. Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [{sup 11}C]MNPA and [{sup 11}C]raclopride scans. BP{sub ND} values in the caudate and putamen were calculated. Test-retest reproducibility of BP{sub ND} of [{sup 11}C]MNPA and [{sup 11}C]MNPA/[{sup 11}C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). The absolute variability of [{sup 11}C]MNPA BP{sub ND} was 5.30 {+-} 3.96 % and 12.3 {+-} 7.95 % and the ICC values of [{sup 11}C]MNPA BP{sub ND} were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [{sup 11}C]MNPA/[{sup 11}C]raclopride was 6.11 {+-} 3.68 % and 11.60 {+-} 5.70 % and the ICC values of [{sup

  12. Loss of dopamine neuron terminals in antipsychotic-treated schizophrenia; relation to tardive dyskinesia.

    Science.gov (United States)

    Seeman, Philip; Tinazzi, Michele

    2013-07-01

    The in vivo labeling and brain imaging of dopamine transporters measure the density of dopamine neuron terminals in the human caudate/putamen. A review of such studies shows that the long-term use of antipsychotics had no major effect on the density of the dopamine terminals in individuals who had no tardive dyskinesia, but had reduced the density in those patients with tardive dyskinesia. In addition, the normal loss of dopamine terminals in healthy individuals was approximately 5% per decade. However, this rate of cell loss was apparently increased by approximately three-fold, to about 15% per decade, in schizophrenia patients using antipsychotics on a long-term basis, as measured by the in vivo imaging of the dopamine transporters in the dopamine neuron terminals. While an apparent reduction in dopamine transporters may result from reduced expression of the transporters secondary to antipsychotic treatment, the seemingly increased loss rate is consistent with the accumulation of antipsychotics in the neuromelanin of the substantia nigra, subsequent injury to the dopamine-containing neurons, and the development of extrapyramidal motor disturbances such as tardive dyskinesia or Parkinson's disease.

  13. Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI

    Science.gov (United States)

    Lohani, Sweyta; Poplawsky, Alexander John; Kim, Seong-Gi; Moghaddam, Bita

    2016-01-01

    Dopamine neurons in the ventral tegmental area (VTA) are strongly implicated in cognitive and affective processing as well as in psychiatric disorders including schizophrenia, ADHD and substance abuse disorders. In human studies, dopamine-related functions are routinely assessed using functional magnetic resonance imaging (fMRI) measures of blood oxygenation-level dependent (BOLD) signals during the performance of dopamine-dependent tasks. There is, however, a critical void in our knowledge about if and how activation of VTA dopamine neurons specifically influences regional or global fMRI signals. Here we used optogenetics in Th::Cre rats to selectively stimulate VTA dopamine neurons while simultaneously measuring global hemodynamic changes using BOLD and cerebral blood volume-weighted (CBVw) fMRI. Phasic activation of VTA dopamine neurons increased BOLD and CBVw fMRI signals in VTA-innervated limbic regions, including the ventral striatum (nucleus accumbens). Surprisingly, basal ganglia regions that receive sparse or no VTA dopaminergic innervation, including the dorsal striatum and the globus pallidus, were also activated. In fact, the most prominent fMRI signal increase in the forebrain was observed in the dorsal striatum that is not traditionally associated with VTA dopamine neurotransmission. These data establish causation between phasic activation of VTA dopamine neurons and global fMRI signals. They further suggest that mesolimbic and non-limbic basal ganglia dopamine circuits are functionally connected and, thus, provide a potential novel framework for understanding dopamine-dependent functions and interpreting data obtained from human fMRI studies. PMID:27457809

  14. Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI.

    Science.gov (United States)

    Lohani, S; Poplawsky, A J; Kim, S-G; Moghaddam, B

    2017-04-01

    Dopamine neurons in the ventral tegmental area (VTA) are strongly implicated in cognitive and affective processing as well as in psychiatric disorders, including schizophrenia, depression, attention-deficit hyperactivity disorder and substance abuse disorders. In human studies, dopamine-related functions are routinely assessed using functional magnetic resonance imaging (fMRI) measures of blood oxygenation-level-dependent (BOLD) signals during the performance of dopamine-dependent tasks. There is, however, a critical void in our knowledge about whether and how activation of VTA dopamine neurons specifically influences regional or global fMRI signals. Here, we used optogenetics in Th::Cre rats to selectively stimulate VTA dopamine neurons while simultaneously measuring global hemodynamic changes using BOLD and cerebral blood volume-weighted (CBVw) fMRI. Phasic activation of VTA dopamine neurons increased BOLD and CBVw fMRI signals in VTA-innervated limbic regions, including the ventral striatum (nucleus accumbens). Surprisingly, basal ganglia regions that receive sparse or no VTA dopaminergic innervation, including the dorsal striatum and the globus pallidus, were also activated. In fact, the most prominent fMRI signal increase in the forebrain was observed in the dorsal striatum that is not traditionally associated with VTA dopamine neurotransmission. These data establish causation between phasic activation of VTA dopamine neurons and global fMRI signals. They further suggest that mesolimbic and non-limbic basal ganglia dopamine circuits are functionally connected and thus provide a potential novel framework for understanding dopamine-dependent functions and interpreting data obtained from human fMRI studies.

  15. NOVEL FLUORESCENT PROBES FOR THE DOPAMINE TRANSPORTER

    DEFF Research Database (Denmark)

    Cha, J; Vægter, Christian Bjerggaard; Adkins, Erica

    To enable visualization of the dopamine transporter (DAT) through fluorescence technologies we have synthesized a novel series of fluorescently tagged analogs of cocaine. Previous structure-activity relationship (SAR) studies have demonstrated that the dopamine transporter (DAT) can tolerate...

  16. Dopamine regulates body size in Caenorhabditis elegans.

    Science.gov (United States)

    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.

  17. Dopamine, reward learning, and active inference

    Directory of Open Access Journals (Sweden)

    Thomas eFitzgerald

    2015-11-01

    Full Text Available Temporal difference learning models propose phasic dopamine signalling 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 behaviour. 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.

  18. NOVEL FLUORESCENT PROBES FOR THE DOPAMINE TRANSPORTER

    DEFF Research Database (Denmark)

    Cha, J; Vægter, Christian Bjerggaard; Adkins, Erica

    To enable visualization of the dopamine transporter (DAT) through fluorescence technologies we have synthesized a novel series of fluorescently tagged analogs of cocaine. Previous structure-activity relationship (SAR) studies have demonstrated that the dopamine transporter (DAT) can tolerate...

  19. Behavioural effects of chemogenetic dopamine neuron activation

    NARCIS (Netherlands)

    Boekhoudt, L

    2016-01-01

    Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific p

  20. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.

    Science.gov (United States)

    Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András

    2011-04-08

    Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

  1. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence

    Directory of Open Access Journals (Sweden)

    Pierre eTrifilieff

    2013-06-01

    Full Text Available Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the Positron Emission Tomography (PET imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.

  2. Dopamine agents for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...... therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS: Trials were identified through the Cochrane...... of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy...

  3. Chaotic behavior in dopamine neurodynamics.

    Science.gov (United States)

    King, R; Barchas, J D; Huberman, B A

    1984-02-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of mood in some patients with an affective disorder. Moreover our hypothesis offers specific results concerning the appearance or disappearance of erratic solutions as a function of k and the external input to the dopamine neuronal system.

  4. Generation of an activating Zn(2+) switch in the dopamine transporter

    DEFF Research Database (Denmark)

    Loland, Claus Juul; Norregaard, Lene; Litman, Thomas

    2002-01-01

    Binding of Zn(2+) to the endogenous Zn(2+) binding site in the human dopamine transporter leads to potent inhibition of [(3)H]dopamine uptake. Here we show that mutation of an intracellular tyrosine to alanine (Y335A) converts this inhibitory Zn(2+) switch into an activating Zn(2+) switch, allowing......-type levels of surface expression, Y335A displayed a dramatic decrease in [(3)H]dopamine uptake velocity (V(max)) to less than 1% of the wild type. In addition, Y335A showed up to 150-fold decreases in the apparent affinity for cocaine, mazindol, and related inhibitors whereas the apparent affinity...

  5. Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

    Science.gov (United States)

    Narayanaswami, V; Thompson, A C; Cassis, L A; Bardo, M T; Dwoskin, L P

    2013-08-01

    A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that

  6. Dopamine Receptor Availability in ADHD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-01-01

    Full Text Available Striatal dopamine (D2 receptor availability was determined by iodobenzamide brain SPECT, before and 3 months after methylphenidate (MPH therapy, in 9 children (mean age, 9.8 years with attention deficit hyperactivity disorder (ADHD examined at Gazi University, Ankara, Turkey.

  7. The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review.

    Science.gov (United States)

    Caravaggio, Fernando; Nakajima, Shinichiro; Plitman, Eric; Gerretsen, Philip; Chung, Jun Ku; Iwata, Yusuke; Graff-Guerrero, Ariel

    2016-02-04

    Understanding the interplay between the neurotransmitters dopamine and glutamate in the striatum has become the highlight of several theories of neuropsychiatric illnesses, such as schizophrenia. Using in vivo brain imaging in humans, alterations in dopamine and glutamate concentrations have been observed in several neuropsychiatric disorders. However, it is unclear a priori how alterations in striatal dopamine should modulate glutamate concentrations in the basal ganglia. In this selective mini-review, we examine the consequence of reducing striatal dopamine functioning on glutamate concentrations in the striatum and cortex; regions of interest heavily examined in the human brain imaging studies. We examine the predictions of the classical model of the basal ganglia, and contrast it with findings in humans and animals. The review concludes that chronic dopamine depletion (>4months) produces decreases in striatal glutamate levels which are consistent with the classical model of the basal ganglia. However, acute alterations in striatal dopamine functioning, specifically at the D2 receptors, may produce opposite affects. This has important implications for models of the basal ganglia and theorizing about neurochemical alterations in neuropsychiatric diseases. Moreover, these findings may help guide a priori hypotheses for (1)H-MRS studies measuring glutamate changes given alterations in dopaminergic functioning in humans.

  8. Developmental imaging genetics: linking dopamine function to adolescent behavior.

    Science.gov (United States)

    Padmanabhan, Aarthi; Luna, Beatriz

    2014-08-01

    Adolescence is a period of development characterized by numerous neurobiological changes that significantly influence behavior and brain function. Adolescence is of particular interest due to the alarming statistics indicating that mortality rates increase two to three-fold during this time compared to childhood, due largely to a peak in risk-taking behaviors resulting from increased impulsivity and sensation seeking. Furthermore, there exists large unexplained variability in these behaviors that are in part mediated by biological factors. Recent advances in molecular genetics and functional neuroimaging have provided a unique and exciting opportunity to non-invasively study the influence of genetic factors on brain function in humans. While genes do not code for specific behaviors, they do determine the structure and function of proteins that are essential to the neuronal processes that underlie behavior. Therefore, studying the interaction of genotype with measures of brain function over development could shed light on critical time points when biologically mediated individual differences in complex behaviors emerge. Here we review animal and human literature examining the neurobiological basis of adolescent development related to dopamine neurotransmission. Dopamine is of critical importance because of (1) its role in cognitive and affective behaviors, (2) its role in the pathogenesis of major psychopathology, and (3) the protracted development of dopamine signaling pathways over adolescence. We will then focus on current research examining the role of dopamine-related genes on brain function. We propose the use of imaging genetics to examine the influence of genetically mediated dopamine variability on brain function during adolescence, keeping in mind the limitations of this approach. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Developmental imaging genetics: linking dopamine function to adolescent behavior

    Science.gov (United States)

    Padmanabhan, Aarthi; Luna, Beatriz

    2014-01-01

    Adolescence is a period of development characterized by numerous neurobiological changes that significantly influence behavior and brain function. Adolescence is of particular interest due to the alarming statistics indicating that mortality rates increase two to three-fold during this time compared to childhood, due largely to a peak in risk-taking behaviors resulting from increased impulsivity and sensation seeking. Furthermore, there exists large unexplained variability in these behaviors that are in part mediated by biological factors. Recent advances in molecular genetics and functional neuroimaging have provided a unique and exciting opportunity to noninvasively study the influence of genetic factors on brain function in humans. While genes do not code for specific behaviors, they do determine the structure and function of proteins that are essential to the neuronal processes that underlie behavior. Therefore, studying the interaction of genotype with measures of brain function over development could shed light on critical time points when biologically mediated individual differences in complex behaviors emerge. Here we review animal and human literature examining the neurobiological basis of adolescent development related to dopamine neurotransmission. Dopamine is of critical importance because of (1) its role in cognitive and affective behaviors, (2) its role in the pathogenesis of major psychopathology, and (3) the protracted development of dopamine signaling pathways over adolescence. We will then focus on current research examining the role of dopamine-related genes on brain function. We propose the use of imaging genetics to examine the influence of genetically mediated dopamine variability on brain function during adolescence, keeping in mind the limitations of this approach. PMID:24139694

  10. Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

    Science.gov (United States)

    Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

    2014-06-05

    Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. A Role for D1 Dopamine Receptors in Striatal Methamphetamine-Induced Neurotoxicity

    OpenAIRE

    Friend, Danielle M.; Keefe, Kristen A

    2013-01-01

    Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Import...

  12. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    OpenAIRE

    Siciliano, Cody A.; Fordahl, Steve C.; Jones, Sara R.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Her...

  13. The potential role of dopamine D₃ receptor neurotransmission in cognition.

    Science.gov (United States)

    Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

    2013-08-01

    Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D₃ receptors in cognition, and propose dopamine D₃ receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D₃ receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D₃ receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D₃ receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D₃ receptor blockade appears to enhance while D₃ receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D₃ receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D₃ receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.

  14. Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice.

    Science.gov (United States)

    Stout, Kristen A; Dunn, Amy R; Lohr, Kelly M; Alter, Shawn P; Cliburn, Rachel A; Guillot, Thomas S; Miller, Gary W

    2016-10-19

    Drugs of abuse induce sensitization, which is defined as enhanced response to additional drug following a period of withdrawal. Sensitization occurs in both humans and animal models of drug reinforcement and contributes substantially to the addictive nature of drugs of abuse, because it is thought to represent enhanced motivational wanting for drug. The ventral pallidum, a key member of the reward pathway, contributes to behaviors associated with reward, such as sensitization. Dopamine inputs to the ventral pallidum have not been directly characterized. Here we provide anatomical, neurochemical, and behavioral evidence demonstrating that dopamine terminals in the ventral pallidum contribute to reward in mice. We report subregional differences in dopamine release, measured by ex vivo fast-scan cyclic voltammetry: rostral ventral pallidum exhibits increased dopamine release and uptake compared with caudal ventral pallidum, which is correlated with tissue expression of dopaminergic proteins. We then subjected mice to a methamphetamine-sensitization protocol to investigate the contribution of dopaminergic projections to the region in reward related behavior. Methamphetamine-sensitized animals displayed a 508% and 307% increase in baseline dopamine release in the rostral and caudal ventral pallidum, respectively. Augmented dopamine release in the rostral ventral pallidum was significantly correlated with sensitized locomotor activity. Moreover, this presynaptic dopaminergic plasticity occurred only in the ventral pallidum and not in the ventral or dorsal striatum, suggesting that dopamine release in the ventral pallidum may be integrally important to drug-induced sensitization.

  15. Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans.

    Science.gov (United States)

    Kuwahara, Tomoki; Koyama, Akihiko; Gengyo-Ando, Keiko; Masuda, Mayumi; Kowa, Hisatomo; Tsunoda, Makoto; Mitani, Shohei; Iwatsubo, Takeshi

    2006-01-06

    Mutations in alpha-synuclein gene cause familial form of Parkinson disease, and deposition of wild-type alpha-synuclein as Lewy bodies occurs as a hallmark lesion of sporadic Parkinson disease and dementia with Lewy bodies, implicating alpha-synuclein in the pathogenesis of Parkinson disease and related neurodegenerative diseases. Dopamine neurons in substantia nigra are the major site of neurodegeneration associated with alpha-synuclein deposition in Parkinson disease. Here we establish transgenic Caenorhabditis elegans (TG worms) that overexpresses wild-type or familial Parkinson mutant human alpha-synuclein in dopamine neurons. The TG worms exhibit accumulation of alpha-synuclein in the cell bodies and neurites of dopamine neurons, and EGFP labeling of dendrites is often diminished in TG worms expressing familial Parkinson disease-linked A30P or A53T mutant alpha-synuclein, without overt loss of neuronal cell bodies. Notably, TG worms expressing A30P or A53T mutant alpha-synuclein show failure in modulation of locomotory rate in response to food, which has been attributed to the function of dopamine neurons. This behavioral abnormality was accompanied by a reduction in neuronal dopamine content and was treatable by administration of dopamine. These phenotypes were not seen upon expression of beta-synuclein. The present TG worms exhibit dopamine neuron-specific dysfunction caused by accumulation of alpha-synuclein, which would be relevant to the genetic and compound screenings aiming at the elucidation of pathological cascade and therapeutic strategies for Parkinson disease.

  16. Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.

    Science.gov (United States)

    Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

    2011-09-14

    Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing.

  17. Antiferroptotic activity of non-oxidative dopamine.

    Science.gov (United States)

    Wang, Ding; Peng, Yingpeng; Xie, Yangchun; Zhou, Borong; Sun, Xiaofang; Kang, Rui; Tang, Daolin

    2016-11-25

    Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Dopamine plasma clearance is increased in piglets compared to neonates during continuous dopamine infusion

    DEFF Research Database (Denmark)

    Rasmussen, Martin B; Gramsbergen, Jan Bert; Eriksen, Vibeke R

    2017-01-01

    AIM: Piglets models have often been used to study the effects of dopamine infusion on hypotension in neonates. However, piglets need higher doses of dopamine than neonates to increase blood pressure. We investigated whether this difference was due to interspecific difference in dopamine...... pharmacokinetics. METHODS: Arterial blood samples were drawn from six neonates admitted to the neonatal intensive care unit of Copenhagen University Hospital and 20 newborn piglets during continuous dopamine infusion. Furthermore, to estimate the piglet plasma dopamine half-life, blood samples were drawn at 2.......5-minute intervals after the dopamine infusion was discontinued. The plasma dopamine content was analysed by high-performance liquid chromatography with electrochemical detection. RESULTS: The dopamine displayed first-order kinetics in piglets and had a half-life of 2.5 minutes, while the median plasma...

  19. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    Science.gov (United States)

    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

  20. Chaotic behavior in dopamine neurodynamics.

    OpenAIRE

    King, R; Barchas, J.D.; Huberman, B A

    1984-01-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of moo...

  1. Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

    OpenAIRE

    Stamford, J. A.; Kruk, Z L; Millar, J.

    1988-01-01

    1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (c...

  2. Dopamine and glucose, obesity, and reward deficiency syndrome.

    Science.gov (United States)

    Blum, Kenneth; Thanos, Panayotis K; Gold, Mark S

    2014-01-01

    Obesity as a result of overeating as well as a number of well described eating disorders has been accurately considered to be a world-wide epidemic. Recently a number of theories backed by a plethora of scientifically sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Our laboratory has published on the concept known as Reward Deficiency Syndrome (RDS) which is a genetic and epigenetic phenomena leading to impairment of the brain reward circuitry resulting in a hypo-dopaminergic function. RDS involves the interactions of powerful neurotransmitters and results in abnormal craving behavior. A number of important facts which could help translate to potential therapeutic targets espoused in this focused review include: (1) consumption of alcohol in large quantities or carbohydrates binging stimulates the brain's production of and utilization of dopamine; (2) in the meso-limbic system the enkephalinergic neurons are in close proximity, to glucose receptors; (3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; (4) a significant correlation between blood glucose and cerebrospinal fluid concentrations of homovanillic acid the dopamine metabolite; (5) 2-deoxyglucose (2DG), the glucose analog, in pharmacological doses is associated with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and fMRI in humans support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and for the most part, implicate the involvement of DA-modulated reward circuits in pathologic eating behaviors. Based on a consensus of neuroscience research treatment of both glucose and drug like cocaine, opiates should incorporate dopamine agonist therapy in contrast to current theories and practices that utilizes dopamine antagonistic therapy. Considering that up until now clinical utilization

  3. Dopamine Modulates the Functional Organization of the Orbitofrontal Cortex.

    Science.gov (United States)

    Kahnt, Thorsten; Tobler, Philippe N

    2017-02-08

    Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D2 receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks.SIGNIFICANCE STATEMENT A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D2 receptors has profound effects on the functional connectivity patterns of

  4. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion.

    Science.gov (United States)

    Rubí, Blanca; Ljubicic, Sanda; Pournourmohammadi, Shirin; Carobbio, Stefania; Armanet, Mathieu; Bartley, Clarissa; Maechler, Pierre

    2005-11-04

    Dopamine signaling is mediated by five cloned receptors, grouped into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families. We identified by reverse transcription-PCR the presence of dopamine receptors from both families in INS-1E insulin-secreting cells as well as in rodent and human isolated islets. D2 receptor expression was confirmed by immunodetection revealing localization on insulin secretory granules of INS-1E and primary rodent and human beta cells. We then tested potential effects mediated by the identified receptors on beta cell function. Dopamine (10 microM) and the D2-like receptor agonist quinpirole (5 microM) inhibited glucose-stimulated insulin secretion tested in several models, i.e. INS-1E beta cells, fluorescence-activated cell-sorted primary rat beta cells, and pancreatic islets of rat, mouse, and human origin. Insulin exocytosis is controlled by metabolism coupled to cytosolic calcium changes. Measurements of glucose-induced mitochondrial hyperpolarization and ATP generation showed that dopamine and D2-like agonists did not inhibit glucose metabolism. On the other hand, dopamine decreased cell membrane depolarization as well as cytosolic calcium increases evoked by glucose stimulation in INS-1E beta cells. These results show for the first time that dopamine receptors are expressed in pancreatic beta cells. Dopamine inhibited glucose-stimulated insulin secretion, an effect that could be ascribed to D2-like receptors. Regarding the molecular mechanisms implicated in dopamine-mediated inhibition of insulin release, our results point to distal steps in metabolism-secretion coupling. Thus, the role played by dopamine in glucose homeostasis might involve dopamine receptors, expressed in pancreatic beta cells, modulating insulin release.

  5. Dopamine Modulates the Neural Representation of Subjective Value of Food in Hungry Subjects

    Science.gov (United States)

    Ziauddeen, Hisham; Vestergaard, Martin D.; Henning, Elana; Schultz, Wolfram; Farooqi, I. Sadaf; Fletcher, Paul C.

    2014-01-01

    Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels. PMID:25505337

  6. 5-HT6/7 receptor antagonists facilitate dopamine release in the cochlea via a GABAergic disinhibitory mechanism

    NARCIS (Netherlands)

    Doleviczenyi, Zoltan; Vizi, E. Sylvester; Gacsalyi, Istvan; Pallagi, Katalin; Volk, Balazs; Harsing, Laszlo G.; Halmos, Gyorgy; Lendvai, Balazs; Zelles, Tibor

    2008-01-01

    In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve dendrites, controls auditory nerve activation and

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

    Science.gov (United States)

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

    2010-02-09

    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.

  8. [{sup 11}]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, Joanna S. E-mail: fowler@bnl.gov; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-07-01

    Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [{sup 11}C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [{sup 11}C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [{sup 11}C]cocaine.

  9. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

    DEFF Research Database (Denmark)

    Decressac, M; Mattsson, Bente; Lundblad, M

    2012-01-01

    Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far...... have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α......-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine...

  10. Using gold nanostars modified pencil graphite electrode as a novel substrate for design a sensitive and selective Dopamine aptasensor.

    Science.gov (United States)

    Talemi, Rasoul Pourtaghavi; Mousavi, Seyed Mehdi; Afruzi, Hossein

    2017-04-01

    For the first time, gold nanostars (GNS) were applied for electrostatic and covalent immobilizing a thiol modified Dopamine aptamer on the pencil graphite electrode and signal amplification. Dopamine aptamer was immobilized on the gold nanostars through electrostatic interaction between negatively charged phosphate groups of aptamer and positively charged gold nanostars and AuS well known covalent interaction. In the presence of Dopamine in the test solution, the charge transfer resistance (RCT) on the electrode surface increased with the increase of the Dopamine concentration due to specific interaction between Dopamine aptamer and Dopamine molecules, which made a barrier for electrons and inhibited the electron-transfer. So, the proposed approach showed a high sensitivity and a wide linearity to Dopamine in the range from 1.0 (±0.1) to 100.0 (±0.3) ngL(-1) (ppt) with detection and quantification limits of 0.29 (±0.10) and 0.90 (±0.08) ngL(-1) (ppt), respectively. Finally, the sensor was successfully used for determination of Dopamine in biological (human blood plasma and urine) samples. The results open up the path for manufacturing cost effective aptasensors for other biomedical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Neurobehavioral evidence for changes in dopamine system activity during adolescence.

    Science.gov (United States)

    Wahlstrom, Dustin; White, Tonya; Luciana, Monica

    2010-04-01

    Human adolescence has been characterized by increases in risk-taking, emotional lability, and deficient patterns of behavioral regulation. These behaviors have often been attributed to changes in brain structure that occur during this developmental period, notably alterations in gray and white matter that impact synaptic architecture in frontal, limbic, and striatal regions. In this review, we provide a rationale for considering that these behaviors may be due to changes in dopamine system activity, particularly overactivity, during adolescence relative to either childhood or adulthood. This rationale relies on animal data due to limitations in assessing neurochemical activity more directly in juveniles. Accordingly, we also present a strategy that incorporates molecular genetic techniques to infer the status of the underlying tone of the dopamine system across developmental groups. Implications for the understanding of adolescent behavioral development are discussed.

  12. Computational systems analysis of dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Zhen Qi

    Full Text Available A prominent feature of Parkinson's disease (PD is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

  13. Going for broke: dopamine influences risky choice.

    Science.gov (United States)

    Moschak, Travis M; Carelli, Regina M

    2014-10-01

    Dopamine neurons track reward by increasing or decreasing their firing rate when a reward is present or absent. In this issue of Neuron, Stopper et al. (2014) demonstrate that artificially eliminating these dopamine bursts or dips can alter risky decision-making.

  14. Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis.

    Science.gov (United States)

    Andreou, Dimitrios; Söderman, Erik; Axelsson, Tomas; Sedvall, Göran C; Terenius, Lars; Agartz, Ingrid; Jönsson, Erik G

    2016-04-21

    Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

  15. Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity

    Science.gov (United States)

    Rieckmann, Anna; Hedden, Trey; Younger, Alayna P.; Sperling, Reisa A.; Johnson, Keith A.; Buckner, Randy L.

    2016-01-01

    Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65–87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, mirroring the established association between cardiovascular health and white matter integrity. Dopamine transporter availability was not associated with the presence of amyloid burden. Neurobiological correlates of dopamine transporter measures in aging are therefore likely unrelated to Alzheimer’s disease but are aligned with white matter integrity and cardiovascular risk. More generally, these results suggest that two common imaging markers of the aging brain that are typically investigated separately do not reflect independent neurobiological processes. PMID:26542307

  16. Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity.

    Science.gov (United States)

    Rieckmann, Anna; Hedden, Trey; Younger, Alayna P; Sperling, Reisa A; Johnson, Keith A; Buckner, Randy L

    2016-02-01

    Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, mirroring the established association between cardiovascular health and white matter integrity. Dopamine transporter availability was not associated with the presence of amyloid burden. Neurobiological correlates of dopamine transporter measures in aging are therefore likely unrelated to Alzheimer's disease but are aligned with white matter integrity and cardiovascular risk. More generally, these results suggest that two common imaging markers of the aging brain that are typically investigated separately do not reflect independent neurobiological processes. Hum Brain Mapp 37:621-631, 2016. © 2015 Wiley Periodicals, Inc.

  17. Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study.

    Science.gov (United States)

    Florio, Tullio; Barbieri, Federica; Spaziante, Renato; Zona, Gianluigi; Hofland, Leo J; van Koetsveld, Peter M; Feelders, Richard A; Stalla, Günter K; Theodoropoulou, Marily; Culler, Michael D; Dong, Jesse; Taylor, John E; Moreau, Jacques-Pierre; Saveanu, Alexandru; Gunz, Ginette; Dufour, Henry; Jaquet, Philippe

    2008-06-01

    Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

  18. A cytoarchitectonic and chemoarchitectonic analysis of the dopamine cell groups in the substantia nigra, ventral tegmental area, and retrorubral field in the mouse.

    Science.gov (United States)

    Fu, Yuhong; Yuan, Yuan; Halliday, Glenda; Rusznák, Zoltán; Watson, Charles; Paxinos, George

    2012-04-01

    The three main dopamine cell groups of the brain are located in the substantia nigra (A9), ventral tegmental area (A10), and retrorubral field (A8). Several subdivisions of these cell groups have been identified in rats and humans but have not been well described in mice, despite the increasing use of mice in neurodegenerative models designed to selectively damage A9 dopamine neurons. The aim of this study was to determine whether typical subdivisions of these dopamine cell groups are present in mice. The dopamine neuron groups were analysed in 15 adult C57BL/6J mice by anatomically localising tyrosine hydroxylase (TH), dopamine transporter protein (DAT), calbindin, and the G-protein-activated inward rectifier potassium channel 2 (GIRK2) proteins. Measurements of the labeling intensity, neuronal morphology, and the proportion of neurons double-labeled with TH, DAT, calbindin, or GIRK2 were used to differentiate subregions. Coronal maps were prepared and reconstructed in 3D. The A8 cell group had the largest dopamine neurons. Five subregions of A9 were identified: the reticular part with few dopamine neurons, the larger dorsal and smaller ventral dopamine tiers, and the medial and lateral parts of A9. The latter has groups containing some calbindin-immunoreactive dopamine neurons. The greatest diversity of dopamine cell types was identified in the seven subregions of A10. The main dopamine cell groups in the mouse brain are similar in terms of diversity to those observed in rats and humans. These findings are relevant to models using mice to analyse the selective vulnerability of different types of dopamine neurons.

  19. Affinities and intrinsic activities of dopamine receptor agonists for the hD(21) and hD(4.4) receptors

    NARCIS (Netherlands)

    Lahti, RA; Mutin, A; Cochrane, EV; Tepper, PG; Dijkstra, D; Wikstrom, H; Tamminga, CA

    1996-01-01

    The affinity and intrinsic activity of dopamine receptor agonists were determined at the human dopamine hD(21) and hD(4.4) receptors. (-)-3-Hydroxy-N-n-propylpiperidine ((-)3-PPP) had an intrinsic activity of 46% and 83%, whereas (+)-N-propylnorapomorphine ((+)-NPA) had intrinsic activities of 61%

  20. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel

    2006-03-01

    Full Text Available Abstract 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.

  1. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  2. Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis.

    Science.gov (United States)

    Glimcher, Paul W

    2011-09-13

    A number of recent advances have been achieved in the study of midbrain dopaminergic neurons. Understanding these advances and how they relate to one another requires a deep understanding of the computational models that serve as an explanatory framework and guide ongoing experimental inquiry. This intertwining of theory and experiment now suggests very clearly that the phasic activity of the midbrain dopamine neurons provides a global mechanism for synaptic modification. These synaptic modifications, in turn, provide the mechanistic underpinning for a specific class of reinforcement learning mechanisms that now seem to underlie much of human and animal behavior. This review describes both the critical empirical findings that are at the root of this conclusion and the fantastic theoretical advances from which this conclusion is drawn.

  3. Hypoximimetic activity of N-acyl-dopamines. N-arachidonoyl-dopamine stabilizes HIF-1α protein through a SIAH2-dependent pathway.

    Science.gov (United States)

    Soler-Torronteras, Rafael; Lara-Chica, Maribel; García, Victor; Calzado, Marco A; Muñoz, Eduardo

    2014-11-01

    The N-acyl conjugates of amino acids and neurotransmitters (NAANs) are a class of endogenous lipid messengers that are expressed in the mammalian central and peripheral nervous system. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia, and hypoxic preconditioning through HIF-1α has been shown to be neuroprotective in ischemic models. This study showed that N-acyl-dopamines induce HIF-1α stabilization on human primary astrocytes and neurons as well as in transformed cell lines. N-arachidonoyl-dopamine (NADA)-induced HIF-1α stabilization depends on the dopamine moiety of the molecule and is independent of cannabinoid receptor-1 (CB1) and transient receptor potential vanilloid type I (TRPV1) activation. NADA increases the activity of the E3 ubiquitin ligase seven in absentia homolog-2 (SIAH2), inhibits prolyl-hydroxylase-3 (PHD3) and stabilizes HIF-1α. NADA enhances angiogenesis in endothelial vascular cells and promotes the expression of genes such as erythropoietin (EPO), vascular endothelial growth factor A (VEGFA), heme oxygenase 1 (HMOX-1), hexokinase 2 (HK2) and Bcl-2/E1B-nineteen kiloDalton interacting protein (BNIP3) in primary astrocytes. These findings indicate a link between N-acyl-dopamines and hypoxic preconditioning and suggest that modulation of the N-acyl-dopamine metabolism might prove useful for prevention against hypoxic diseases.

  4. Phasic dopamine neuron activity elicits unique mesofrontal plasticity in adolescence.

    Science.gov (United States)

    Mastwal, Surjeet; Ye, Yizhou; Ren, Ming; Jimenez, Dennisse V; Martinowich, Keri; Gerfen, Charles R; Wang, Kuan Hong

    2014-07-16

    The mesofrontal dopaminergic circuit, which connects the midbrain motivation center to the cortical executive center, is engaged in control of motivated behaviors. In addition, deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans. Developmental studies suggest that the mesofrontal circuit exhibits a protracted maturation through adolescence. However, whether the structure and function of this circuit are modifiable by activity in dopaminergic neurons during adolescence remains unknown. Using optogenetic stimulation and in vivo two-photon imaging in adolescent mice, we found that phasic, but not tonic, dopamine neuron activity induces the formation of mesofrontal axonal boutons. In contrast, in adult mice, the effect of phasic activity diminishes. Furthermore, our results showed that dopaminergic and glutamatergic transmission regulate this axonal plasticity in adolescence and inhibition of dopamine D2-type receptors restores this plasticity in adulthood. Finally, we found that phasic activation of dopamine neurons also induces greater changes in mesofrontal circuit activity and psychomotor response in adolescent mice than in adult mice. Together, our findings demonstrate that the structure and function of the mesofrontal circuit are modifiable by phasic activity in dopaminergic neurons during adolescence and suggest that the greater plasticity in adolescence may facilitate activity-dependent strengthening of dopaminergic input and improvement in behavioral control.

  5. Dopamine enhances duodenal epithelial permeability via the dopamine D5 receptor in rodent.

    Science.gov (United States)

    Feng, X-Y; Zhang, D-N; Wang, Y-A; Fan, R-F; Hong, F; Zhang, Y; Li, Y; Zhu, J-X

    2017-05-01

    The intestinal barrier is made up of epithelial cells and intercellular junctional complexes to regulate epithelial ion transport and permeability. Dopamine (DA) is able to promote duodenal epithelial ion transport through D1-like receptors, which includes subtypes of D1 (D1 R) and D5 (D5 R), but whether D1-like receptors influence the duodenal permeability is unclear. FITC-dextran permeability, short-circuit current (ISC ), Western blot, immunohistochemistry and ELISA were used in human D5 R transgenic mice and hyperendogenous enteric DA (HEnD) rats in this study. Dopamine induced a downward deflection in ISC and an increase in FITC-dextran permeability of control rat duodenum, which were inhibited by the D1-like receptor antagonist, SCH-23390. However, DA decreased duodenal transepithelial resistance (TER), an effect also reversed by SCH-23390. A strong immunofluorescence signal for D5 R, but not D1 R, was observed in the duodenum of control rat. In human D5 R knock-in transgenic mice, duodenal mucosa displayed an increased basal ISC with high FITC-dextran permeability and decreased TER with a lowered expression of tight junction proteins, suggesting attenuated duodenal barrier function in these transgenic mice. D5 R knock-down transgenic mice manifested a decreased basal ISC with lowered FITC-dextran permeability. Moreover, an increased FITC-dextran permeability combined with decreased TER and tight junction protein expression in duodenal mucosa were also observed in HEnD rats. This study demonstrates, for the first time, that DA enhances duodenal permeability of control rat via D5 R, which provides new experimental and theoretical evidence for the influence of DA on duodenal epithelial barrier function. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  6. Dopamine-Secreting Paraganglioma in the Retroperitoneum.

    Science.gov (United States)

    Matsuda, Yusuke; Kimura, Noriko; Yoshimoto, Takanobu; Sekiguchi, Yoshihiro; Tomoishi, Junzo; Kasahara, Ichiro; Hara, Yoshihito; Ogawa, Yoshihiro

    2017-03-01

    Pheochromocytomas and paragangliomas, which exclusively produce dopamine, are very rare. Herein, we report for the first time a Japanese case of an exclusively dopamine-producing paraganglioma accompanied by detailed immunohistochemical analyses. A 70-year-old Japanese woman was referred to our hospital for functional examination of her left retroperitoneal mass. Her adrenal functions were normal, except for excessive dopamine secretion. After the tumorectomy, her dopamine level normalized. The histopathological diagnosis of the tumor was paraganglioma; this was confirmed by positive immunostaining of chromogranin A (CgA), tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and succinate dehydrogenase gene subunit B (SDHB). However, the immunostaining of CgA in the tumor cells showed peculiar dot-like staining located corresponding to Golgi complex in the perinuclear area, rather than the diffuse cytoplasmic staining usually observed in epinephrine- or norepinephrine-producing functional pheochromocytomas and paragangliomas. The immunohistochemical results suggested that the tumor cells had sparse neuroendocrine granules in the cytoplasm, resulting in inhibition of catecholamine synthesis from dopamine to norepinephrine in neurosecretory granules. This may be the mechanism responsible for exclusive dopamine secretion in the present case.

  7. Insulin resistance impairs nigrostriatal dopamine function.

    Science.gov (United States)

    Morris, J K; Bomhoff, G L; Gorres, B K; Davis, V A; Kim, J; Lee, P-P; Brooks, W M; Gerhardt, G A; Geiger, P C; Stanford, J A

    2011-09-01

    Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF

    Science.gov (United States)

    Nam, Jin H.; Park, Eun S.; Won, So-Yoon; Lee, Yu A.; Kim, Kyoung I.; Jeong, Jae Y.; Baek, Jeong Y.; Cho, Eun J.; Jin, Minyoung; Chung, Young C.; Lee, Byoung D.; Kim, Sung Hyun; Kim, Eung-Gook; Byun, Kyunghee; Lee, Bonghee; Woo, Dong Ho; Lee, C. Justin; Kim, Sang R.; Bok, Eugene; Kim, Yoon-Seong; Ahn, Tae-Beom; Ko, Hyuk Wan; Brahmachari, Saurav; Pletinkova, Olga; Troconso, Juan C.; Dawson, Valina L.; Dawson, Ted M.

    2015-01-01

    Currently there is no neuroprotective or neurorestorative therapy for Parkinson’s disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP+-lesioned or adeno-associated virus α-synuclein rat models of Parkinson’s disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson’s disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson’s disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson’s disease. PMID:26490328

  9. Cellular regulation of the dopamine transporter

    DEFF Research Database (Denmark)

    Eriksen, Jacob

    2010-01-01

    The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. DAT and its trafficking...... in heterologous cells and in cultured DA neurons. DAT has been shown to be regulated by the dopamine D2 receptor (D2R), the primary target foranti-psychotics, through a direct interaction. D2R is among other places expressed as an autoreceptor in DA neurons. Transient over-expression of DAT with D2R in HEK293...

  10. Incorporation of the dopamine D2L receptor and bacteriorhodopsin within bicontinuous cubic lipid phases. 2. Relevance to in meso crystallization of integral membrane proteins in novel lipid systems

    Energy Technology Data Exchange (ETDEWEB)

    Conn, Charlotte E.; Darmanin, Connie; Sagnella, Sharon M.; Mulet, Xavier; Greaves, Tamar L.; Varghese, Joseph N.; Drummond, Calum J.

    2014-09-24

    The dopamine D2 long (D2L) receptor and bacteriorhodopsin (bR), which are integral membraneproteins, have been incorporated within bicontinuous cubic mesophases formed by the lipids anandamide and H-farnesoyl monoethanolamide, which have been specifically investigated by us for use as in mesocrystallization media. We show that the incorporated membraneprotein affects the structure of the cubic phases with the particular effect observed dependent on the geometry of the underlying cubic phase. The results are complementary to those obtained in Part 1 of this series, where we demonstrated that the structural effects observed depend on the structure of the membraneprotein. Importantly protein concentrations commonly used for crystallization can destroy the cubic phase matrix, particularly where there is a large discrepancy between the hydrophilic and the hydrophobic spans of the membraneprotein, and the hydrophilic and hydrophobic domain sizes of the cubic phase.

  11. Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo.

    Science.gov (United States)

    Kang, Xinjiang; Xu, Huadong; Teng, Sasa; Zhang, Xiaoyu; Deng, Zijun; Zhou, Li; Zuo, Panli; Liu, Bing; Liu, Bin; Wu, Qihui; Wang, Li; Hu, Meiqin; Dou, Haiqiang; Liu, Wei; Zhu, Feipeng; Li, Qing; Guo, Shu; Gu, Jingli; Lei, Qian; Lü, Jing; Mu, Yu; Jin, Mu; Wang, Shirong; Jiang, Wei; Liu, Kun; Wang, Changhe; Li, Wenlin; Zhang, Kang; Zhou, Zhuan

    2014-11-04

    Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson's disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopamine-like neurons (pNSC-DAn) in culture. Here, we showed that after the striatal transplantation of pNSC-DAn, (i) pNSC-DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; (ii) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and (iii) the rescued dopamine was released directly from the grafted pNSC-DAn (and not from injured original cells). Thus, pNSC-DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation.

  12. Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling

    DEFF Research Database (Denmark)

    Klewe, Ib V; Nielsen, Søren M; Tarpø, Louise

    2008-01-01

    Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment...... of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit...... marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole...

  13. Maternal neglect: oxytocin, dopamine and the neurobiology of attachment.

    Science.gov (United States)

    Strathearn, L

    2011-11-01

    Maternal neglect, including physical and emotional neglect, is a pervasive public health challenge with serious long-term effects on child health and development. I provide an overview of the neurobiological basis of maternal caregiving, aiming to better understand how to prevent and respond to maternal neglect. Drawing from both animal and human studies, key biological systems are identified that contribute to maternal caregiving behaviour, focusing on the oxytocinergic and dopaminergic systems. Mesocorticolimbic and nigrostriatal dopamine pathways contribute to the processing of infant-related sensory cues leading to a behavioural response. Oxytocin may activate the dopaminergic reward pathways in response to social cues. Human neuroimaging studies are summarised that demonstrate parallels between animal and human maternal caregiving responses in the brain. By comparing different patterns of human adult attachment, we gain a clearer understanding of how differences in maternal brain and endocrine responses may contribute to maternal neglect. For example, in insecure/dismissing attachment, which may be associated with emotional neglect, we see reduced activation of the mesocorticolimbic dopamine reward system in response to infant face cues, as well as decreased peripheral oxytocin response to mother-infant contact. We are currently testing whether the administration of intranasal oxytocin, as part of a randomised placebo controlled trial, may reverse some of these neurological differences, and potentially augment psychosocial and behavioural interventions for maternal neglect.

  14. Involvement of dopamine loss in extrastriatal basal ganglia nuclei in the pathophysiology of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Abdelhamid eBenazzouz

    2014-05-01

    Full Text Available Parkinson’s disease is a neurological disorder characterized by the manifestation of motor symptoms, such as akinesia, muscle rigidity and tremor at rest. These symptoms are classically attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra (SNc, which results in a marked dopamine depletion in the striatum. It is well established that dopamine neurons in the SNc innervate not only the striatum, which is the main target, but also other basal ganglia nuclei including the two segments of globus pallidus and the subthalamic nucleus. The role of dopamine and its depletion in the striatum is well known, however, the role of dopamine depletion in the pallidal complex and the subthalamic nucleus in the genesis of their abnormal neuronal activity and in parkinsonian motor deficits is still not clearly determined. Based on recent experimental data from animal models of Parkinson's disease in rodents and non-human primates and also from parkinsonian patients, this review summarizes current knowledge on the role of dopamine in the modulation of basal ganglia neuronal activity and also the role of dopamine depletion in these nuclei in the pathophysiology of Parkinson's disease.

  15. DOPA, norepinephrine, and dopamine in rat tissues

    DEFF Research Database (Denmark)

    Eldrup, E; Richter, Erik; Christensen, N J

    1989-01-01

    We studied the effect of unilateral sympathectomy on rat quadriceps and gastrocnemius muscle concentrations of endogenous dihydroxyphenylalanine (DOPA), dopamine (DA), and norepinephrine (NE) and assessed the relationships between these catecholamines in several rat tissues. Catecholamines were...

  16. Dopamine system, cerebellum, and nucleus ruber in fish and mammals.

    Science.gov (United States)

    Matsui, Hideaki

    2017-05-01

    Small teleost fish including zebrafish and medaka have been used as animal models for research because of their small body size, vast amounts of eggs produced, their rapid development, low husbandry costs, and transparency during embryogenesis. Although the body size and appearance seem different, fish and mammals including human still possess anatomical and functional similarities in their brains. This review summarizes the similarities of brain structures and functions between teleost fish and mammalian brains, focusing on the dopamine system, functional regionalization of the cerebellum, and presence of the nucleus ruber. © 2017 Japanese Society of Developmental Biologists.

  17. Circuit Analysis of a Drosophila Dopamine Type 2 Receptor That Supports Anesthesia-Resistant Memory.

    Science.gov (United States)

    Scholz-Kornehl, Sabrina; Schwärzel, Martin

    2016-07-27

    Dopamine is central to reinforcement processing and exerts this function in species ranging from humans to fruit flies. It can do so via two different types of receptors (i.e., D1 or D2) that mediate either augmentation or abatement of cellular cAMP levels. Whereas D1 receptors are known to contribute to Drosophila aversive odor learning per se, we here show that D2 receptors are specific for support of a consolidated form of odor memory known as anesthesia-resistant memory. By means of genetic mosaicism, we localize this function to Kenyon cells, the mushroom body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes, suggesting that consolidated anesthesia-resistant memory requires widespread dopaminergic modulation within the olfactory circuit. Additionally, dopaminergic neurons themselves require D2R, suggesting a critical role in dopamine release via its recognized autoreceptor function. Considering the dual role of dopamine in balancing memory acquisition (proactive function of dopamine) and its "forgetting" (retroactive function of dopamine), our analysis suggests D2R as central player of either process. Dopamine provides different information; while it mediates reinforcement during the learning act (proactive function), it balances memory performance between two antithetic processes thereafter (retroactive function) (i.e., forgetting and augmentation). Such bidirectional design can also be found at level of dopamine receptors, where augmenting D1 and abating D2 receptors are engaged to balance cellular cAMP levels. Here, we report that consolidated anesthesia-resistant memory (ARM), but not other concomitant memory phases, are sensitive to bidirectional dopaminergic signals. By means of genetic mosaicism, we identified widespread dopaminergic modulation within the olfactory circuit that suggests nonredundant and reiterating functions of D2R in support of ARM. Our results oppose ARM to its concomitant memory phases

  18. MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway

    Science.gov (United States)

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Karuppagounder, Senthilkumar S.; Talbot, C. Conover; Dawson, Valina L.; Dawson, Ted M.; Yolken, Robert H.

    2014-01-01

    Congenital toxoplasmosis and toxoplasmic encephalitis can be associated with severe neuropsychiatric symptoms. However, which host cell processes are regulated and how Toxoplasma gondii affects these changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of over 1000 miRNAs in human neuroepithelioma cells in response to infection with Toxoplasma. MiR-132, a cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma. To identify cellular pathways regulated by miR-132, we performed target prediction followed by pathway enrichment analysis in the transcriptome of Toxoplasma-infected mice. This led us to identify 20 genes and dopamine receptor signaling was their strongest associated pathway. We then examined myriad aspects of the dopamine pathway in the striatum of Toxoplasma infected mice 5 days after infection. Here we report decreased expression of D1-like dopamine receptors (DRD1, DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated with the transduction of dopamine-mediated signaling (DARPP-32 phosphorylation at Thr34 and Ser97). Increased concentrations of dopamine and its metabolites, serotonin and 5-hydroxyindoleacetic acid were documented by HPLC analysis; however, the metabolism of dopamine was decreased and serotonin metabolism was unchanged. Our data show that miR-132 is upregulated following infection with Toxoplasma and is associated with changes in dopamine receptor signaling. Our findings provide a possible mechanism for how the parasite contributes to the neuropathology of infection. PMID:24657774

  19. Aberrant reward processing in Parkinson's disease is associated with dopamine cell loss.

    Science.gov (United States)

    Aarts, Esther; Helmich, Rick C; Janssen, Marcel J R; Oyen, Wim J G; Bloem, Bastiaan R; Cools, Roshan

    2012-02-15

    Dopamine has been implicated in reward-related impulsivity, but the exact relationship between dopamine, reward and impulsivity in humans remains unknown. We address this question in Parkinson's disease (PD), which is characterized by severe dopamine depletion. PD is associated primarily with motor and cognitive inflexibility, but can also be accompanied by reward-related impulsivity. This paradoxical symptom of PD has often been attributed to dopaminergic overstimulation by antiparkinson medication, which is necessary to relieve the motor and cognitive inflexibility. However, factors other than medication may also contribute to aberrant impact of reward. Here we assess whether cognitive inflexibility and aberrant reward impact in PD are two sides of the same coin, namely dopamine cell loss. To measure dopamine cell loss, we employed (123)I-FP-CIT Single Photon Emission Computed Tomography (SPECT) in 32 PD patients (10 never-medicated patients and 22 patients after withdrawal of all medication for >12h) and related the values to behavior on a rewarded task-switching paradigm. Dopamine cell loss was associated not only with cognitive inflexibility (under low reward), but also with aberrant impact of reward. These effects could not be attributed to medication use. Relative to controls (n=26), aberrant reward processing in PD was particularly expressed as reduced capacity to maintain (i.e., repeat) the current task-set under high reward. Our findings demonstrate that factors intrinsically related to PD may underlie the paradoxical symptoms of inflexibility and reward-related impulsivity in PD. The present results concur with observations that low baseline dopamine states predispose to drug and other addictions.

  20. Dopamine versus noradrenaline in septic shock

    Directory of Open Access Journals (Sweden)

    Bo Xu

    2011-10-01

    Full Text Available BackgroundThe ‘Surviving Sepsis’ Campaign guidelines recommend theuse of dopamine or noradrenaline as the first vasopressor inseptic shock. However, information that guides clinicians inchoosing between dopamine and noradrenaline as the firstvasopressor in patients with septic shock is limited.ObjectiveThis article presents a review of the literature regarding theuse of dopamine versus noradrenaline in patients with septicshock.ResultsTwo randomised controlled trials (RCT and two largeprospective cohort studies were analysed. RCT data showeddopamine was associated with increased arrhythmic events.One cohort study found dopamine was associated with higher30-day mortality. The other cohort study found noradrenalinewas associated with higher 28-day mortality.DiscussionData on the use of dopamine versus noradrenaline in patientswith septic shock is limited. Following the recent SOAP IIstudy, there is now strong evidence that the use of dopaminein septic shock is associated with significantly morecardiovascular adverse events, compared tonoradrenaline.ConclusionNoradrenaline should be used as the initial vasopressor inseptic shock to avoid the arrhythmic events associatedwith dopamine.

  1. Metabolism of N-acylated-dopamine.

    Directory of Open Access Journals (Sweden)

    Dominika Zajac

    Full Text Available N-oleoyl-dopamine (OLDA is a novel lipid derivative of dopamine. Its biological action includes the interaction with dopamine and the transient receptor potential vanilloid (TRPV1 receptors. It seems to be synthesized in a dopamine-like manner, but there has been no information on its degradation. The aim of the study was, therefore, to determine whether OLDA metabolism proceeds the way dopamine proper does. We addressed the issue by examining the occurrence of O-methylation of exogenously supplemented OLDA via catechol-O-methyltransferase (COMT under in vitro, ex vivo, and in vivo conditions using rat brain tissue. The results show that OLDA was methylated by COMT in all conditions studied, yielding the O-methylated derivative. The methylation was reversed by tolcapone, a potent COMT inhibitor, in a dose-dependent manner. We conclude that OLDA enters the metabolic pathway of dopamine. Methylation of OLDA may enhance its bioactive properties, such as the ability to interact with TRPV1 receptors.

  2. Selegiline increases heme oxygenase-1 expression and the cytotoxicity produced by dopamine treatment of neuroblastoma SK-N-SH cells

    Directory of Open Access Journals (Sweden)

    Rieder C.R.M.

    2004-01-01

    Full Text Available Increased dopamine catabolism may be associated with oxidative stress and neuronal cell death in Parkinson's disease. The present study was carried out to examine the effect of dopamine on the expression of heme oxygenase-1 and -2 (HO-1 and HO-2 in human neuroblastomas (SK-N-SH cell line and the effects of selegiline and antioxidants on this expression. Cells were kept with close control of pH and were incubated with varying concentrations of dopamine (0.1-100 µM for 24 h. HO-1 and HO-2 cDNA probes were prepared by reverse transcription-polymerase chain reaction amplification. The mRNA expression of HO-1 and HO-2 was measured by Northern blot analysis. The levels of HO-1 mRNA increased after dopamine treatment, in a dose-dependent manner, in all cell lines studied, whereas levels of the two HO-2 transcripts did not. The HO-1 and HO-2 protein expression was analyzed by Western blotting. HO-1 protein was undetectable in untreated SK-N-SH cells and increased after treatment with dopamine. In contrast, the HO-2 protein (36 kDa was detected in untreated cells and the levels did not change as a result of treatment. alpha-Tocopherol (10-100 µM and ascorbic acid (100 µM did not attenuate the effects of dopamine. Selegiline (10 µM produced significant increase (P < 0.01 in the induction of HO-1 by dopamine (more than six times the control values. The increased expression of HO-1 following dopamine treatment indicates that dopamine produces oxidative stress in this cell line.

  3. Molecular profiling of midbrain dopamine regions in cocaine overdose victims.

    Science.gov (United States)

    Tang, Wen-Xue; Fasulo, Wendy H; Mash, Deborah C; Hemby, Scott E

    2003-05-01

    Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in brain regions associated with drug reinforcement. To evaluate whether the alterations in gene expression in cocaine overdose victims are associated with specific dopamine populations in the midbrain, cDNA arrays and western blotting were used to compare gene and protein expression patterns between cocaine overdose victims and age-matched controls in the ventral tegmental area (VTA) and lateral substantia nigra (l-SN). Array analysis revealed significant up-regulation of numerous transcripts in the VTA, but not in the l-SN, of cocaine overdose victims including NMDAR1, GluR2, GluR5 and KA2 receptor mRNA (p overdose victims and controls were observed for GluR1, R3 or R4 mRNA levels. Correspondingly, western blot analysis revealed VTA-selective up-regulation of CREB (p cocaine overdose victims. The present results indicate that selective alterations of CREB and certain ionotropic glutamate receptor (iGluR) subtypes appear to be associated with chronic cocaine use in humans in a region-specific manner. Moreover, as subunit composition determines the functional properties of iGluRs, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine in humans.

  4. DELINEATING THE MOLECULAR BASIS FOR CONSTITUTIVE INTERNALIZATION AND DEGRADATION OF THE DOPAMINE TRANSPORTER

    DEFF Research Database (Denmark)

    Fog, Jacob; (Vægter), Christian Bjerggaard; Gether, Ulrik;

    The human dopamine transporter (hDAT) was transiently expressed in N2A neuroblastoma cells. Confocal fluorescence microscopy revealed efficient surface targeting of the transporter in undifferentiated cells as well as in differentiated cells. In the differentiated cells the hDAT displayed...

  5. Dopamine Receptor D4 Gene Variation Predicts Preschoolers' Developing Theory of Mind

    Science.gov (United States)

    Lackner, Christine; Sabbagh, Mark A.; Hallinan, Elizabeth; Liu, Xudong; Holden, Jeanette J. A.

    2012-01-01

    Individual differences in preschoolers' understanding that human action is caused by internal mental states, or representational theory of mind (RTM), are heritable, as are developmental disorders such as autism in which RTM is particularly impaired. We investigated whether polymorphisms of genes affecting dopamine (DA) utilization and metabolism…

  6. Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity

    NARCIS (Netherlands)

    Colzato, L.S.; van den Wildenberg, W.P.M.; van der Does, A.J.W.; Hommel, B.

    2010-01-01

    Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsiv

  7. Enhanced dopamine-dependent hippocampal plasticity after single MK-801 application.

    NARCIS (Netherlands)

    Bartsch, J.C.; Fidzinski, P.; Huck, J.H.; Hortnagl, H.; Kovacs, R.; Liotta, A.; Priller, J.; Wozny, C.; Behr, J.

    2015-01-01

    Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippo

  8. Dopamine Receptor D4 Gene Variation Predicts Preschoolers' Developing Theory of Mind

    Science.gov (United States)

    Lackner, Christine; Sabbagh, Mark A.; Hallinan, Elizabeth; Liu, Xudong; Holden, Jeanette J. A.

    2012-01-01

    Individual differences in preschoolers' understanding that human action is caused by internal mental states, or representational theory of mind (RTM), are heritable, as are developmental disorders such as autism in which RTM is particularly impaired. We investigated whether polymorphisms of genes affecting dopamine (DA) utilization and metabolism…

  9. Central serotonin and dopamine transporters in overeating, obesity and insulin resistance

    NARCIS (Netherlands)

    Koopman, K.E.M.

    2014-01-01

    The objectives of this thesis were to study cerebral serotonin transporters (SERT) in the diencephalon and striatal dopamine transporters (DAT) in humans in different metabolic conditions (i.e. lean, obese and insulin resistant state) in relation to feeding behavior and to investigate the early cons

  10. Elevated dopamine D1 receptor availability in striatum of Göttingen minipigs after electroconvulsive therapy

    DEFF Research Database (Denmark)

    Landau, Anne M.; Alstrup, Aage Kristian Olsen; Audrain, Héléne

    2017-01-01

    established a novel model of brain stimulation in Göttingen minipigs based on the protocol of ECT applied in humans. With positron emission tomography (PET), we determined a measure of dopaminergic neurotransmission with the dopamine D1 receptor antagonist [11C]SCH23390. Seven minipigs were anesthetized......, binding returned towards baseline at 8-10 days. Increased binding was observed in inverse proportion to baseline binding rates. Increased binding to dopamine D1 receptors suggests facilitation of dopaminergic neurotransmission, which may contribute to the therapeutic effects of ECT. Importantly...

  11. Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Owens, WA; Winkler, Marie-Therese

    2013-01-01

    The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate...

  12. Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

    Science.gov (United States)

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

    2015-02-01

    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.

  13. Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass

    Directory of Open Access Journals (Sweden)

    Daisuke Sakano

    2016-07-01

    Full Text Available Understanding the molecular mechanisms that regulate β cell mass and proliferation is important for the treatment of diabetes. Here, we identified domperidone (DPD, a dopamine D2 receptor (DRD2 antagonist that enhances β cell mass. Over time, islet β cell loss occurs in dissociation cultures, and this was inhibited by DPD. DPD increased proliferation and decreased apoptosis of β cells through increasing intracellular cAMP. DPD prevented β cell dedifferentiation, which together highly contributed to the increased β cell mass. DRD2 knockdown phenocopied the effects of domperidone and increased the number of β cells. Drd2 overexpression sensitized the dopamine responsiveness of β cells and increased apoptosis. Further analysis revealed that the adenosine agonist 5′-N-ethylcarboxamidoadenosine, a previously identified promoter of β cell proliferation, acted with DPD to increase the number of β cells. In humans, dopamine also modulates β cell mass through DRD2 and exerts an inhibitory effect on adenosine signaling.

  14. Dopamine, behavioral economics, and effort

    Directory of Open Access Journals (Sweden)

    John D Salamone

    2009-09-01

    Full Text Available Abstract. 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.

  15. Immunomodulatory Effects Mediated by Dopamine

    Science.gov (United States)

    Alvarez-Herrera, Samantha; Pérez-Sánchez, Gilberto; Becerril-Villanueva, Enrique; Cruz-Fuentes, Carlos; Flores-Gutierrez, Enrique Octavio; Quintero-Fabián, Saray

    2016-01-01

    Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers. PMID:27795960

  16. Dopamine, behavioral economics, and effort.

    Science.gov (United States)

    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.

  17. Vascular dopamine-I receptors.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Yokokawa, K; Horio, T; Kano, H; Takeda, T

    1995-06-01

    The modulation of dopamine DA1 receptors of cultured rat renal arterial smooth muscle cells by phorbol ester, glucocorticoid and sodium chloride was studied. The extent of [3H]Sch-23390 binding to phorbol ester-treated cell was increased without any change in the dissociation constant (Kd). At a concentration of 10 nmol/l, the synthetic glucocorticoid dexamethasone increased maximum receptor binding (Bmax) but had no effect on the Kd. 100 mmol/l sodium chloride did not change Bmax, but increased the Kd for DA1 receptor. The production of cAMP in response to DA1 receptor stimulation was enhanced without any change of the adenylate cyclase activity. The glucocorticoid effect on DA1 of arterial smooth muscle cells became apparent after hours of incubation in the presence of the steroid and was significantly inhibited by cycloheximide (10 micrograms/ml) and by the glucocorticoid receptor antagonist RU-38486, indicating that the effect required protein synthesis through glucocorticoid receptors. Treatment of cells with 1 mumol/l dexamethasone for 24 h increased basal and DA1-stimulated adenylate cyclase activity. Basal adenylate cyclase was decreased by sodium chloride in a dose-dependent manner. These results suggest differential control of DA1 receptors on vascular smooth muscle cells by protein kinase C, glucocorticoid or sodium chloride.

  18. Immunomodulatory Effects Mediated by Dopamine

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2016-01-01

    Full Text Available Dopamine (DA, a neurotransmitter in the central nervous system (CNS, has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R and D2-like receptors (D2R, D3R, and D4R. The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS, there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

  19. Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.

    Science.gov (United States)

    Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu; Yang, Jian; Asico, Laureano D; Chen, Wei; Felder, Robin A; Armando, Ines; Jose, Pedro A; Yang, Zhiwei

    2017-01-01

    Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. Copyright © 2017 the American Physiological Society.

  20. Discovery of antagonists of tick dopamine receptors via chemical library screening and comparative pharmacological analyses.

    Science.gov (United States)

    Ejendal, Karin F K; Meyer, Jason M; Brust, Tarsis F; Avramova, Larisa V; Hill, Catherine A; Watts, Val J

    2012-11-01

    Ticks transmit a wide variety of disease causing pathogens to humans and animals. Considering the global health impact of tick-borne diseases, there is a pressing need to develop new methods for vector control. We are exploring arthropod dopamine receptors as novel targets for insecticide/acaricide development because of their integral roles in neurobiology. Herein, we developed a screening assay for dopamine receptor antagonists to further characterize the pharmacological properties of the two D₁-like dopamine receptors (Isdop1 and Isdop2) identified in the Lyme disease vector, Ixodes scapularis, and develop a screening assay for receptor antagonists. A cell-based, cyclic AMP luciferase reporter assay platform was implemented to screen the LOPAC(1280) small molecule library for Isdop2 receptor antagonists, representing the first reported chemical library screen for any tick G protein-coupled receptor. Screening resulted in the identification of 85 "hit" compounds with antagonist activity at the Isdop2 receptor. Eight of these chemistries were selected for confirmation assays using a direct measurement of cAMP, and the effects on both Isdop1 and Isdop2 were studied for comparison. Each of these eight compounds showed antagonistic activity at both Isdop1 and Isdop2, although differences were observed regarding their relative potencies. Furthermore, comparison of the pharmacological properties of the tick dopamine receptors with that of the AaDOP2 receptor from the yellow fever mosquito and the human dopamine D₁ receptor (hD₁) revealed species-specific pharmacological profiles of these receptors. Compounds influencing dopaminergic functioning, such as the dopamine receptor antagonists discovered here, may provide lead chemistries for discovery of novel acaricides useful for vector control

  1. Guidelines for Homology Modeling of Dopamine, Norepinephrine, and Serotonin Transporters.

    Science.gov (United States)

    Haddad, Yazan; Heger, Zbynek; Adam, Vojtech

    2016-11-16

    The human dopamine, norepinephrine, and serotonin transporters (hDAT, hNET, and hSERT) are carriers of neurotransmitters and targets for many drugs. Pioneering works in the past three years to elucidate experimental models of the Drosophila dDAT and human hSERT structures will rapidly impact the field of neuroscience. Here, we evaluated automated homology-based human models of these transporters, employing systematic physics-based, knowledge-based, and empirical-based check. Modeling guidelines were conveyed with attention to the central binding site (S1), secondary binding site (S2), and the extracellular loops EL2 and EL4. Application of new experimental models (dDAT and hSERT) will improve the accuracy of homology models, previously utilizing prokaryotic leucine transporter (LeuT) structure, and provide better predictions of ligand interactions, which is required for understanding of cellular mechanisms and for development of novel therapeutics.

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

    Science.gov (United States)

    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...

  3. Role of dopamine in distal retina.

    Science.gov (United States)

    Popova, E

    2014-05-01

    Dopamine is the most abundant catecholamine in the vertebrate retina. Despite the description of retinal dopaminergic cells three decades ago, many aspects of their function in the retina remain unclear. There is no consensus among the authors about the stimulus conditions for dopamine release (darkness, steady or flickering light) as well as about its action upon the various types of retinal cells. Many contradictory results exist concerning the dopamine effect on the gross electrical activity of the retina [reflected in electroretinogram (ERG)] and the receptors involved in its action. This review summarized current knowledge about the types of the dopaminergic neurons and receptors in the retina as well as the effects of dopamine receptor agonists and antagonists on the light responses of photoreceptors, horizontal and bipolar cells in both nonmammalian and mammalian retina. Special focus of interest concerns their effects upon the diffuse ERG as a useful tool for assessment of the overall function of the distal retina. An attempt is made to reveal some differences between the dopamine actions upon the activity of the ON versus OFF channel in the distal retina. The author has included her own results demonstrating such differences.

  4. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    OpenAIRE

    Tulen, Joke; Man in't Veld, A.; Mechelse, Karel; Boomsma, Frans

    1990-01-01

    textabstractSleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine and its metabolites are elevated. The relative importance of noradrenaline deficit in the face of dopamine excess for sleep-regulatory mechanisms can be inferred from the sleep pattern of these patie...

  5. Cerebral vascular effects of hypovolemia and dopamine infusions

    DEFF Research Database (Denmark)

    Holst Hahn, Gitte; Heiring, Christian; Pryds, Ole

    2012-01-01

    Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature.......Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature....

  6. Differential dopamine function in fibromyalgia.

    Science.gov (United States)

    Albrecht, Daniel S; MacKie, Palmer J; Kareken, David A; Hutchins, Gary D; Chumin, Evgeny J; Christian, Bradley T; Yoder, Karmen K

    2016-09-01

    Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.

  7. Dopamine, vesicular transporters, and dopamine receptor expression in rat major salivary glands.

    Science.gov (United States)

    Tomassoni, Daniele; Traini, Enea; Mancini, Manuele; Bramanti, Vincenzo; Mahdi, Syed Sarosh; Amenta, Francesco

    2015-09-01

    The localization of dopamine stores and the expression and localization of dopamine (DAT) and vesicular monoamine transporters (VMAT) type-1 and -2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat submandibular, sublingual, and parotid salivary glands by HPLC with electrochemical detection, as well as immunochemical and immunohistochemical techniques. Male Wistar rats of 2 mo of age were used. The highest dopamine levels were measured in the parotid gland, followed by the submandibular and sublingual glands. Western blot analysis revealed DAT, VMAT-1, VMAT-2, and dopamine receptors immunoreactivity in membrane preparations obtained from the three glands investigated. Immunostaining for dopamine and transporters was developed within striated ducts. Salivary glands processed for dopamine receptors immunohistochemistry developed an immunoreaction primarily in striated and excretory ducts. In the submandibular gland, acinar cells displayed strong immunoreactivity for the D2 receptor, while cells of the convoluted granular tubules were negative for both D1-like and D2-like receptors. Parotid glands acinar cells displayed the highest immunoreactivity for both D1 and D2 receptors compared with other salivary glands. The above localization of dopamine and dopaminergic markers investigated did not correspond closely with neuron-specific enolase (NSE) localization. This indicates that at least in part, catecholamine stores and dopaminergic markers are independent from glandular innervation. These findings suggest that rat major salivary glands express a dopaminergic system probably involved in salivary secretion. The stronger immunoreactivity for dopamine transporters and receptors in striated duct cells suggests that the dopaminergic system could regulate not only quality, but also volume and ionic concentration of saliva.

  8. Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake.

    Science.gov (United States)

    Wheeler, Daniel S; Ebben, Amanda L; Kurtoglu, Beliz; Lovell, Marissa E; Bohn, Austin T; Jasek, Isabella A; Baker, David A; Mantsch, John R; Gasser, Paul J; Wheeler, Robert A

    2017-10-01

    Stressful and aversive events promote maladaptive reward-seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our lab and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast-scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally-occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    NARCIS (Netherlands)

    J.H.M. Tulen (Joke); A.J. Man in't Veld (A.); K. Mechelse (Karel); F. Boomsma (Frans)

    1990-01-01

    textabstractSleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine an

  10. ORAL IBOPAMINE SUBSTITUTION IN PATIENTS WITH INTRAVENOUS DOPAMINE DEPENDENCE

    NARCIS (Netherlands)

    GIRBES, ARJ; MILNER, AR; MCCLOSKEY, BV; ZWAVELING, JH; VANVELDHUISEN, DJ; ZIJLSTRA, JG; LIE, KI

    1995-01-01

    In a prospective open study we evaluated whether intravenous dopamine infusions can be safely switched to enterally administered ibopamine in dopamine-dependent patients. Six patients defined as being clinically stable, normovolaemic, but dopamine dependent, i.e. with repeated inability to stop

  11. The binding sites for cocaine and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L

    2008-01-01

    Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... inhibition of dopamine transport by cocaine....

  12. Renal Dopamine Receptors, Oxidative Stress, and Hypertension

    OpenAIRE

    Ines Armando; Van Anthony Villar; Pedro A. Jose; Santiago Cuevas

    2013-01-01

    Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxi...

  13. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Directory of Open Access Journals (Sweden)

    Argel Aguilar-Valles

    Full Text Available Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  14. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Science.gov (United States)

    Aguilar-Valles, Argel; Flores, Cecilia; Luheshi, Giamal N

    2010-06-04

    Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  15. Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

    Science.gov (United States)

    Zisapel, N

    2001-12-01

    To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.

  16. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

  17. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine.

    NARCIS (Netherlands)

    Watanabe, S.; Aono, Y.; Fusa, K.; Takada, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally

  18. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopami

  19. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine.

    NARCIS (Netherlands)

    Watanabe, S.; Aono, Y.; Fusa, K.; Takada, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally ad

  20. D5 dopamine receptor knockout mice and hypertension.

    Science.gov (United States)

    Yang, Zhiwei; Sibley, David R; Jose, Pedro A

    2004-08-01

    Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.

  1. The effects of dopamine synthesis inhibitors and dopamine antagonists on regeneration in the hydra Hydra attenuata.

    Science.gov (United States)

    Ostroumova, T V; Markova, L N

    2002-01-01

    The effects of catecholamine synthesis inhibitors (alpha-methyltyrosine, 3-iodotyrosine, and alpha-methyl-DOPA) and dopamine receptor blockers (haloperidol and spiperone) on the regeneration of apical, gastral, and basal fragments of the hydra Hydra attenuata were studied. These experiments showed that alpha-methyltyrosine and 3-iodotyrosine significantly inhibited regeneration but did not produce morphological anomalies. Alpha-Methyl-DOPA produce less inhibition of regeneration, but induced ectopic tentacles and outgrowths in gastral regenerates. Haloperidol and spiperone had no significant effect on the rate of regeneration but induced significant numbers of morphogenetic anomalies in gastral regenerates. Apical and basal regenerates, which retained their natural organizers (the head and base respectively) never yielded morphogenetic anomalies in the presence of either dopamine receptor blockers or dopamine synthesis inhibitors. The possible role of neurotransmitters. particularly dopamine, in morphogenesis in hydras is discussed.

  2. Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens.

    Science.gov (United States)

    Yorgason, Jordan T; Zeppenfeld, Douglas M; Williams, John T

    2017-02-22

    The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met(5)]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study

  3. The role of dopamine in the pursuit of nutritional value.

    Science.gov (United States)

    McCutcheon, James Edgar

    2015-12-01

    Acquiring enough food to meet energy expenditure is fundamental for all organisms. Thus, mechanisms have evolved to allow foods with high nutritional value to be readily detected, consumed, and remembered. Although taste is often involved in these processes, there is a wealth of evidence supporting the existence of taste-independent nutrient sensing. In particular, post-ingestive mechanisms arising from the arrival of nutrients in the gut are able to drive food intake and behavioural conditioning. The physiological mechanisms underlying these effects are complex but are believed to converge on mesolimbic dopamine signalling to translate post-ingestive sensing of nutrients into reward and reinforcement value. Discerning the role of nutrition is often difficult because food stimulates sensory systems and post-ingestive pathways in concert. In this mini-review, I discuss the various methods that may be used to study post-ingestive processes in isolation including sham-feeding, non-nutritive sweeteners, post-ingestive infusions, and pharmacological and genetic methods. Using this structure, I present the evidence that dopamine is sensitive to nutritional value of certain foods and examine how this affects learning about food, the role of taste, and the implications for human obesity.

  4. Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    BACKGROUND: For the normal resolution of an acute inflammatory response, neutrophil (PMN) apoptosis is essential to maintain immune homeostasis and to limit inappropriate host tissue damage. A delay in PMN apoptosis has been implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS). Dopamine, a biogenic amine with known cardiovascular and neurotransmitter properties, is used in patients with SIRS to maintain hemodynamic stability. We sought to determine whether dopamine may also have immunoregulatory properties capable of influencing PMN apoptosis, function, and activation state in patients with SIRS. METHODS: PMNs were isolated from healthy volunteers and patients with SIRS and treated with varying doses of dopamine and a dopamine D-1 receptor agonist, fenoldopam. PMN apoptosis was assessed every 6 hours with use of propidium iodide DNA staining and PMN function was assessed with use of respiratory burst activity, phagocytosis ability, and CD11a, CD11b, and CD18 receptor expression as functional markers. RESULTS: There was a significant delay in PMN apotosis in patients with SIRS compared with controls. Treatment of isolated PMNs from both healthy controls and patients with SIRS with 10 and 100 mumol\\/L dopamine induced apoptosis. PMN ingestive and cytocidal capacity were both decreased in patients with SIRS compared with controls. Treatment with dopamine significantly increased phagocytic function. Fenoldopam did not induce PMN apoptosis. CONCLUSION: Our data demonstrate for the first time that dopamine induces PMN apoptosis and modulates PMN function both in healthy controls and in patients with SIRS. These results indicate that dopamine may be beneficial during SIRS through a nonhemodynamic PMN-dependent proapoptotic mechanism.

  5. Tranylcypromine substituted cis-hydroxycyclobutylnaphthamides as potent and selective dopamine D₃ receptor antagonists.

    Science.gov (United States)

    Chen, Jianyong; Levant, Beth; Jiang, Cheng; Keck, Thomas M; Newman, Amy Hauck; Wang, Shaomeng

    2014-06-12

    We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (K(i) = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K(i) values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor.

  6. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

    Directory of Open Access Journals (Sweden)

    N. L. Rukavina Mikusic

    2016-01-01

    Full Text Available Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP and Ang-(1-7 may regulate renal dopamine availability in tubular cells, contributing to Na+, K+-ATPase inhibition. Present results show that CNP did not affect either 3H-dopamine uptake in renal tissue or Na+, K+-ATPase activity; meanwhile, Ang-(1-7 was able to increase 3H-dopamine uptake and decreased Na+, K+-ATPase activity in renal cortex. Ang-(1-7 and dopamine together decreased further Na+, K+-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7 stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide did not modify CNP effects on 3H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7 on 3H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7 was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7 on AT1 receptors on 3H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7 enhances Na+, K+-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  7. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney.

    Science.gov (United States)

    Rukavina Mikusic, N L; Kouyoumdzian, N M; Rouvier, E; Gironacci, M M; Toblli, J E; Fernández, B E; Choi, M R

    2016-01-01

    Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP) and Ang-(1-7) may regulate renal dopamine availability in tubular cells, contributing to Na(+), K(+)-ATPase inhibition. Present results show that CNP did not affect either (3)H-dopamine uptake in renal tissue or Na(+), K(+)-ATPase activity; meanwhile, Ang-(1-7) was able to increase (3)H-dopamine uptake and decreased Na(+), K(+)-ATPase activity in renal cortex. Ang-(1-7) and dopamine together decreased further Na(+), K(+)-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7)-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7) stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide) did not modify CNP effects on (3)H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7) on (3)H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7) was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7) on AT1 receptors on (3)H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7) enhances Na(+), K(+)-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  8. Dopamine-melanin nanofilms for biomimetic structural coloration.

    Science.gov (United States)

    Wu, Tong-Fei; Hong, Jong-Dal

    2015-02-09

    This article describes the formation of dopamine-melanin thin films (50-200 nm thick) at an air/dopamine solution interface under static conditions. Beneath these films, spherical melanin granules formed in bulk liquid phase. The thickness of dopamine-melanin films at the interface relied mainly on the concentration of dopamine solution and the reaction time. A plausible mechanism underlining dopamine-melanin thin film formation was proposed based on the hydrophobicity of dopamine-melanin aggregates and the mass transport of the aggregates to the air/solution interface as a result of convective flow. The thickness of the interfacial films increased linearly with the dopamine concentration and the reaction time. The dopamine-melanin thin film and granules (formed in bulk liquid phase) with a double-layered structure were transferred onto a solid substrate to mimic the (keratin layer)/(melanin granules) structure present in bird plumage, thereby preparing full dopamine-melanin thin-film reflectors. The reflected color of the thin-film reflectors depended on the film thickness, which could be adjusted according to the dopamine concentration. The reflectance of the resulted reflectors exhibited a maximal reflectance value of 8-11%, comparable to that of bird plumage (∼11%). This study provides a useful, simple, and low-cost approach to the fabrication of biomimetic thin-film reflectors using full dopamine-melanin materials.

  9. Dopamine in heart failure and critical care

    NARCIS (Netherlands)

    Smit, AJ

    Dopamine is widely used in critical care to prevent renal function loss. Nevertheless sufficient evidence is still lacking of reduction in end points like mortality or renal replacement therapy. Dopaminergic treatment in chronic heart failure (CHF) has provided an example of unexpected adverse

  10. Dopamine in heart failure and critical care

    NARCIS (Netherlands)

    Smit, AJ

    2000-01-01

    Dopamine is widely used in critical care to prevent renal function loss. Nevertheless sufficient evidence is still lacking of reduction in end points like mortality or renal replacement therapy. Dopaminergic treatment in chronic heart failure (CHF) has provided an example of unexpected adverse outco

  11. Molecular model of the neural dopamine transporter

    Science.gov (United States)

    Ravna, Aina Westrheim; Sylte, Ingebrigt; Dahl, Svein G.

    2003-05-01

    The dopamine transporter (DAT) regulates the action of dopamine by reuptake of the neurotransmitter into presynaptic neurons, and is the main molecular target of amphetamines and cocaine. DAT and the Na+/H+ antiporter (NhaA) are secondary transporter proteins that carry small molecules across a cell membrane against a concentration gradient, using ion gradients as energy source. A 3-dimensional projection map of the E. coli NhaA has confirmed a topology of 12 membrane spanning domains, and was previously used to construct a 3-dimensional NhaA model with 12 trans-membrane α-helices (TMHs). The NhaA model, and site directed mutagenesis data on DAT, were used to construct a detailed 3-dimensional DAT model using interactive molecular graphics and empiric force field calculations. The model proposes a dopamine transport mechanism involving TMHs 1, 3, 4, 5, 7 and 11. Asp79, Tyr252 and Tyr274 were the primary cocaine binding residues. Binding of cocaine or its analogue, (-)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (CFT), seemed to lock the transporter in an inactive state, and thus inhibit dopamine transport. The present model may be used to design further experimental studies of the molecular structure and mechanisms of DAT and other secondary transporter proteins.

  12. Oscillating from Neurosecretion to Multitasking Dopamine Neurons

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    David R. Grattan

    2016-04-01

    Full Text Available In this issue of Cell Reports, Stagkourakis et al. (2016 report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits.

  13. Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans.

    Science.gov (United States)

    Reckziegel, Patrícia; Chen, Pan; Caito, Sam; Gubert, Priscila; Soares, Félix Alexandre Antunes; Fachinetto, Roselei; Aschner, Michael

    2016-03-01

    Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.

  14. Dopamine receptor in anterior byssus retractor muscle of Mytilus edulis.

    Science.gov (United States)

    Takayanagi, I; Murakami, H; Iwayama, Y; Yoshida, Y; Miki, S

    1981-04-01

    Effects of dopamine, N-methyl-, ethyl- and propyl-derivatives of dopamine, and alpha- and beta-adrenoceptor stimulants on catch contraction of anterior byssus retractor muscle of Mytilus edulis were tested. The test drugs except the beta-adrenoceptor stimulants relaxed catch contraction. Dopamine was most active and substitution of amino group in dopamine with ethyl and propyl decreased activity considerably. The concentration-curves of dopamine, its derivatives and norepinephrine shifted in parallel with application of haloperidol but were not influenced by the alpha- and beta-adrenoceptor antagonists. These results suggest that relaxation of catch contraction by catecholamines is mediated through a dopamine receptor. This muscle is considered to be suitable for a study of the dopamine receptor.

  15. Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand.

    Science.gov (United States)

    Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle; Neve, Kim A; Mach, Robert H; Luedtke, Robert R

    2014-11-01

    LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki  > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [(3) H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37°C) and binds with high affinity to both human (Kd  = 0.06 ± 0.01 nM) and rat (Kd  = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [(3) H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [(3) H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.

  16. Love to win or hate to lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward vs. punishment

    Science.gov (United States)

    Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T; Fox, Andrew S; King, Carlye R; Murali, Dhanabalan; Gluck, Mark A; Davidson, Richard J

    2014-01-01

    Humans show consistent differences in the extent to which their behavior reflects a bias towards appetitive approach-related behavior or avoidance of aversive stimuli (Elliot, 2008). We examined the hypothesis that in healthy subjects this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding , we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward vs. punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition. PMID:24345165

  17. Renal Dopamine Receptors, Oxidative Stress, and Hypertension

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    Ines Armando

    2013-08-01

    Full Text Available Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1, paraoxonase 2 (PON2, and heme oxygenase 2 (HO-2, all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.

  18. Renal dopamine receptors, oxidative stress, and hypertension.

    Science.gov (United States)

    Cuevas, Santiago; Villar, Van Anthony; Jose, Pedro A; Armando, Ines

    2013-08-27

    Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.

  19. Over-Expression of Dopamine D2 Receptor and Inwardly Rectifying Potassium Channel Genes in Drug-Naive Schizophrenic Peripheral Blood Lymphocytes as Potential Diagnostic Markers

    OpenAIRE

    Ágnes Zvara; György Szekeres; Zoltán Janka; Kelemen, János Z.; Csongor Cimmer; Miklós Sántha; Puskás, László G.

    2005-01-01

    Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-exp...

  20. Association of dopamine D(3) receptors with actin-binding protein 280 (ABP-280).

    Science.gov (United States)

    Li, Ming; Li, Chuanyu; Weingarten, Paul; Bunzow, James R; Grandy, David K; Zhou, Qun Yong

    2002-03-01

    Proteins that bind to G protein-coupled receptors have been identified as regulators of receptor localization and signaling. In our previous studies, a cytoskeletal protein, actin-binding protein 280 (ABP-280), was found to associate with the third cytoplasmic loop of dopamine D(2) receptors. In this study, we demonstrate that ABP-280 also interacts with dopamine D(3) receptors, but not with D(4) receptors. Similar to the dopamine D(2) receptor, the D(3)/ABP-280 association is of signaling importance. In human melanoma M2 cells lacking ABP-280, D(3) receptors were unable to inhibit forskolin-stimulated cyclic AMP (cAMP) production significantly. D(4) receptors, however, exhibited a similar degree of inhibition of forskolin-stimulated cAMP production in ABP-280-deficient M2 cells and ABP-280-replent M2 subclones (A7 cells). Further experiments revealed that the D(3)/ABP-280 interaction was critically dependent upon a 36 amino acid carboxyl domain of the D(3) receptor third loop, which is conserved in the D(2) receptor but not in the D(4) receptor. Our results demonstrate a subtype-specific regulation of dopamine D(2)-family receptor signaling by the cytoskeletal protein ABP-280.

  1. Preparation of Pd/Bacterial Cellulose Hybrid Nanofibers for Dopamine Detection

    Directory of Open Access Journals (Sweden)

    Dawei Li

    2016-05-01

    Full Text Available Palladium nanoparticle-bacterial cellulose (PdBC hybrid nanofibers were synthesized by in-situ chemical reduction method. The obtained PdBC nanofibers were characterized by a series of analytical techniques. The results revealed that Pd nanoparticles were evenly dispersed on the surfaces of BC nanofibers. Then, the as-prepared PdBC nanofibers were mixed with laccase (Lac and Nafion to obtain mixture suspension, which was further modified on electrode surface to construct novel biosensing platform. Finally, the prepared electrochemical biosensor was employed to detect dopamine. The analysis result was satisfactory, the sensor showed excellent electrocatalysis towards dopamine with high sensitivity (38.4 µA·mM−1, low detection limit (1.26 µM, and wide linear range (5–167 µM. Moreover, the biosensor also showed good repeatability, reproducibility, selectivity and stability and was successfully used in the detection of dopamine in human urine, thus providing a promising method for dopamine analysis in clinical application.

  2. Striatal dopamine release and biphasic pattern of locomotor and motor activity under gas narcosis.

    Science.gov (United States)

    Balon, Norbert; Risso, Jean-Jacques; Blanc, François; Rostain, Jean-Claude; Weiss, Michel

    2003-05-02

    Inert gas narcosis is a neurological syndrome appearing when humans or animals are exposed to hyperbaric inert gases (nitrogen, argon) composed by motor and cognitive impairments. Inert gas narcosis induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity. We have investigated, in freely moving rats exposed to different narcotic conditions, the relationship between the locomotor and motor activity and the striatal dopamine release, using respectively a computerized device that enables a quantitative analysis of this behavioural disturbance and voltammetry. The use of 3 MPa of nitrogen, 2 MPa of argon and 0.1 MPa of nitrous oxide, revealed after a transient phase of hyperactivity, a lower level of the locomotor and motor activity, in relation with the decrease of the striatal dopamine release. It is concluded that the striatal dopamine decrease could be related to the decrease of the locomotor and motor hyperactivity, but that other(s) neurotransmitter(s) could be primarily involved in the behavioural motor disturbances induced by narcotics. This biphasic effect could be of major importance for future pharmacological investigations, and motor categorization, on the basic mechanisms of inert gas at pressure.

  3. The potential role of dopamine D3 receptor neurotransmission in cognition

    Science.gov (United States)

    Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

    2013-01-01

    Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. PMID:23791072

  4. Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles.

    Science.gov (United States)

    Abdul-Majeed, Shakila; Nauli, Surya M

    2011-08-01

    Polycystic kidney disease is characterized by cardiovascular irregularities, including hypertension. Dopamine, a circulating hormone, is implicated in essential hypertension in humans and animal models. Vascular endothelial primary cilia are known to function as mechano-sensory organelles. Although both primary cilia and dopamine receptors play important roles in vascular hypertension, their relationship has never been explored. To determine the roles of the dopaminergic system and mechano-sensory cilia, we studied the effects of dopamine on ciliary length and function in wild-type and mechano-insensitive polycystic mutant cells (Pkd1(-/)(-) and Tg737(orpk/orpk)). We show for the first time that mouse vascular endothelia exhibit dopamine receptor-type 5 (DR5), which colocalizes to primary cilia in cultured cells and mouse arteries in vivo. DR5 activation increases cilia length in arteries and endothelial cells through cofilin and actin polymerization. DR5 activation also restores cilia function in the mutant cells. In addition, silencing DR5 completely abolishes mechano-ciliary function in WT cells. We found that DR5 plays very important roles in ciliary length and function. Furthermore, the chemo-sensory function of cilia can alter the mechano-sensory function through changes in sensitivity to fluid-shear stress. We propose that ciliary DR5 has functional chemo- and mechano-sensory roles in endothelial cells.

  5. Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation.

    Science.gov (United States)

    de Jong, Johannes W; Roelofs, Theresia J M; Mol, Frédérique M U; Hillen, Anne E J; Meijboom, Katharina E; Luijendijk, Mieneke C M; van der Eerden, Harrie A M; Garner, Keith M; Vanderschuren, Louk J M J; Adan, Roger A H

    2015-08-01

    Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

  6. α-Synuclein overexpression increases dopamine toxicity in BE(2-M17 cells

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    Miller David W

    2010-03-01

    Full Text Available Abstract Background Oxidative stress has been proposed to be involved in the pathogenesis of Parkinson's disease (PD. A plausible source of oxidative stress in nigral dopaminergic neurons is the redox reactions that specifically involve dopamine and produce various toxic molecules, i.e., free radicals and quinone species. α-Synuclein, a protein found in Lewy bodies characteristic of PD, is also thought to be involved in the pathogenesis of PD and point mutations and multiplications in the gene coding for α-synuclein have been found in familial forms of PD. Results We used dopaminergic human neuroblastoma BE(2-M17 cell lines stably transfected with WT or A30P mutant α-synuclein to characterize the effect of α-synuclein on dopamine toxicity. Cellular toxicity was analyzed by lactate dehydrogenase assay and by fluorescence-activated cell sorter analysis. Increased expression of either wild-type or mutant α-synuclein enhances the cellular toxicity induced by the accumulation of intracellular dopamine or DOPA. Conclusions Our results suggest that an interplay between dopamine and α-synuclein can cause cell death in a neuron-like background. The data presented here are compatible with several models of cytotoxicity, including the formation of α-synuclein oligomers and impairment of the lysosomal degradation.

  7. Intermittent-access binge consumption of sweet high-fat liquid does not require opioid or dopamine receptors in the nucleus accumbens.

    Science.gov (United States)

    Lardeux, Sylvie; Kim, James J; Nicola, Saleem M

    2015-10-01

    Binge eating disorders are characterized by episodes of intense consumption of high-calorie food. In recently developed animal models of binge eating, rats given intermittent access to such food escalate their consumption over time. Consumption of calorie-dense food is associated with neurochemical changes in the nucleus accumbens, including dopamine release and alterations in dopamine and opioid receptor expression. Therefore, we hypothesized that binge-like consumption on intermittent access schedules is dependent on opioid and/or dopamine neurotransmission in the accumbens. To test this hypothesis, we asked whether injection of dopamine and opioid receptor antagonists into the core and shell of the accumbens reduced consumption of a sweet high-fat liquid in rats with and without a history of intermittent binge access to the liquid. Although injection of a μ opioid agonist increased consumption, none of the antagonists (including μ opioid, δ opioid, κ opioid, D1 dopamine and D2 dopamine receptor antagonists, as well as the broad-spectrum opioid receptor antagonist naltrexone) reduced consumption, and this was the case whether or not the animals had a prior history of intermittent access. These results suggest that consumption of sweet, fatty food does not require opioid or dopamine receptor activation in the accumbens even under intermittent access conditions that resemble human binge episodes.

  8. Depression of vitamin B6 levels due to dopamine.

    Science.gov (United States)

    Weir, M R; Keniston, R C; Enriquez, J I; McNamee, G A

    1991-04-01

    Dopamine is a commonly used pressor agent. Frequently recognized side effects other than occasional reports of pedal gangrene respond to reduction of dose. Because a number of compounds interfere with vitamin B6 and dopamine toxicity in animals is modified by B6, we studied the dopamine-vitamin B6 interaction in rabbits. Six animals received 40 mg dopamine/kg and 10 mg pyridoxine injections; 6 received dopamine and saline. Dopamine administration led to an average fall of 20% (p = 0.04) in plasma pyridoxal 5'-phosphate (PLP) levels, which declined 42% by day 5. Three days later, a 25% decrease persisted (p = 0.03). Dopamine with pyridoxine caused a PLP rise of 65% (p = 0.007), but the post-study level was 28% lower than baseline (p = 0.04). We interpret our data to mean that dopamine reduced PLP levels during and 3 days after the study, and that dopamine appeared to increase the requirements for B6. We worry that dopamine given with other drugs, ie gentamicin, digoxin and theophylline which are frequently used in critical care settings, could aggravate alterations of requirements for or body stores of vitamin B6, creating B6 deficiency.

  9. Optical suppression of drug-evoked phasic dopamine release.

    Science.gov (United States)

    McCutcheon, James E; Cone, Jackson J; Sinon, Christopher G; Fortin, Samantha M; Kantak, Pranish A; Witten, Ilana B; Deisseroth, Karl; Stuber, Garret D; Roitman, Mitchell F

    2014-01-01

    Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

  10. Optical suppression of drug-evoked phasic dopamine release

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2014-09-01

    Full Text Available Brief fluctuations in dopamine concentration (dopamine transients play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc of urethane-anesthetized rats. We targeted halorhodopsin (NpHR specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats. Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

  11. Dopamine-mediated oxidation of methionine 127 in α-synuclein causes cytotoxicity and oligomerization of α-synuclein.

    Directory of Open Access Journals (Sweden)

    Kazuhiro Nakaso

    Full Text Available Parkinson's disease (PD is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. Many recent studies focused on the interaction between α-synuclein (α-syn and dopamine in the pathogenesis of PD, and fluorescent anisotropy suggested that the C-terminal region of α-syn may be a target for modification by dopamine. However, it is not well understood why PD-related pathogenesis occurs selectively in dopaminergic neurons. We investigated the interaction between dopamine and α-syn with regard to cytotoxicity. A soluble oligomer was formed by co-incubating α-syn and dopamine in vitro. To clarify the effect of dopamine on α-syn in cells, we generated PC12 cells expressing human α-syn, as well as the α-syn mutants, M116A, Y125D, M127A, S129A, and M116A/M127A, in a tetracycline-inducible manner (PC12-TetOFF-α-syn. Overexpression of wildtype α-syn in catecholaminergic PC12 cells decreased cell viability in long-term cultures, while a competitive inhibitor of tyrosine hydroxylase blocked this vulnerability, suggesting that α-syn-related cytotoxicity is associated with dopamine metabolism. The vulnerabilities of all mutant cell lines were lower than that of wildtype α-syn-expressing cells. Moreover, α-syn containing dopamine-mediated oxidized methionine (Met(O was detected in PC12-TetOFF-α-syn. Met(O was lower in methionine mutant cells, especially in the M127A or M116A/M127A mutants, but also in the Y125D and S129A mutants. Co-incubation of dopamine and the 125YEMPS129 peptide enhanced the production of H2O2, which may oxidize methionine residues and convert them to Met(O. Y125- or S129-lacking peptides did not enhance the dopamine-related production of H2O2. Our results suggest that M127 is the major target for oxidative modification by dopamine, and that Y125 and S129 may act as enhancers of this modification. These results may describe a mechanism of dopaminergic neuron

  12. Serotonin transporter and dopamine transporter imaging in the canine brain

    Energy Technology Data Exchange (ETDEWEB)

    Peremans, Kathelijne [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Goethals, Ingeborg [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); De Vos, Filip [Laboratory of Radiopharmacy, Pharmaceutical Sciences, Ghent University, B-9000 Ghent (Belgium); Dobbeleir, A. [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Ham, Hamphrey [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); Van Bree, Henri [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Heeringen, Cees van [Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium); Audenaert, Kurt [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium) and Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium)]. E-mail: kurt.audenaert@ugent.be

    2006-10-15

    The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [{sup 123}I]-{beta}-CIT and [{sup 123}I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models.

  13. Dopamine restores reward prediction errors in old age.

    Science.gov (United States)

    Chowdhury, Rumana; Guitart-Masip, Marc; Lambert, Christian; Dayan, Peter; Huys, Quentin; Düzel, Emrah; Dolan, Raymond J

    2013-05-01

    Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA.

  14. Dopamine, fronto-striato-thalamic circuits and risk for psychosis.

    Science.gov (United States)

    Dandash, Orwa; Pantelis, Christos; Fornito, Alex

    2017-02-01

    A series of parallel, integrated circuits link distinct regions of prefrontal cortex with specific nuclei of the striatum and thalamus. Dysfunction of these fronto-striato-thalamic systems is thought to play a major role in the pathogenesis of psychosis. In this review, we examine evidence from human and animal investigations that dysfunction of a specific dorsal fronto-striato-thalamic circuit, linking the dorsolateral prefrontal cortex, dorsal (associative) striatum, and mediodorsal nucleus of the thalamus, is apparent across different stages of psychosis, including prior to the onset of a first episode, suggesting that it represents a candidate risk biomarker. We consider how abnormalities at distinct points in the circuit may give rise to the pattern of findings seen in patient populations, and how these changes relate to disruptions in dopamine, glutamate and GABA signaling. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    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.

  16. A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake.

    Directory of Open Access Journals (Sweden)

    Beryl Luk

    Full Text Available The regulation of the dopamine transporter (DAT impacts extracellular dopamine levels after release from dopaminergic neurons. Furthermore, a variety of protein partners have been identified that can interact with and modulate DAT function. In this study we show that DJ-1 can potentially modulate DAT function. Co-expression of DAT and DJ-1 in HEK-293T cells leads to an increase in [3H] dopamine uptake that does not appear to be mediated by increased total DAT expression but rather through an increase in DAT cell surface localization. In addition, through a series of GST affinity purifications and co-immunoprecipitations, we provide evidence that the DAT can be found in a complex with DJ-1, which involve distinct regions within both DAT and DJ-1. Using in vitro binding experiments we also show that this complex can be formed in part by a direct interaction between DAT and DJ-1. Co-expression of a mini-gene that can disrupt the DAT/DJ-1 complex appears to block the increase in [3H] dopamine uptake by DJ-1. Mutations in DJ-1 have been linked to familial forms of Parkinson's disease, yet the normal physiological function of DJ-1 remains unclear. Our study suggests that DJ-1 may also play a role in regulating dopamine levels by modifying DAT activity.

  17. Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice

    OpenAIRE

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear con...

  18. The Roles of Dopamine D2 Receptor in the Social Hierarchy of Rodents and Primates

    OpenAIRE

    Yoshie Yamaguchi; Young-A. Lee; Akemi Kato; Emanuel Jas; Yukiori Goto

    2017-01-01

    Dopamine (DA) plays significant roles in regulation of social behavior. In social groups of humans and other animals, social hierarchy exists, which is determined by several behavioral characteristics such as aggression and impulsivity as well as social affiliations. In this study, we investigated the effects of pharmacological blockade of DA D2 receptor on social hierarchy of Japanese macaque and mouse social groups. We found acute administration of the D2 antagonist, sulpiride, in socially ...

  19. Effects of oral exposure to mining waste on in vivo dopamine release from rat striatum.

    OpenAIRE

    1998-01-01

    Several single components of mining waste (arsenic, manganese, lead, cadmium) to which humans are exposed at the mining area of Villa de la Paz, Mexico, are known to provoke alterations of striatal dopaminergic parameters. In this study we used an animal model to examine neurochemical changes resulting from exposure to a metal mixture. We used microdialysis to compare in vivo dopamine release from adult rats subchronically exposed to a mining waste by oral route with those from a control grou...

  20. [Effect of dopamine on the portal pressure].

    Science.gov (United States)

    Benko, H; Peschl, L; Schüller, J; Neumayr, A

    1975-01-01

    1. An infusion of 3 gamma/kg/min dopamine causes a significant increase in the renal plasma flow and the glomerulum filtration rate. This dosage does not cause a change of the mean systolic and arterial pressure. This effect may also be observed in patients with hepatic cirrhosis. 2. The wedged hepatic vein pressure, an indicator for the portal pressure, only shows a slight increase (9,46 +/- 9,41%) as compared to the initial pressure produced by the mentioned dose. Measurements of the spleen pulpa pressure, which likewise indicates the portal pressure, showed an increase of pressure up to 100% due to pressing or coughing. 3. If in the case of bleeding oesophageal varices acute renal failure might develop, the advantage of the effect of dopamine in stimulating the blood flow through the kidneys may be considered more important than the minute danger of a slight increase of the portal pressure, which might provoke haemorrhage.

  1. Cellular regulation of the dopamine transporter

    DEFF Research Database (Denmark)

    Eriksen, Jacob

    2010-01-01

    -membrane spanning protein Tac, thereby creating an extracellular antibody epitope. Upon expression in HEK293 cells this TacDAT fusion protein displayed functional properties similar to the wild type transporter. In an ELISA based internalization assay, TacDAT intracellular accumulation was increased by inhibitors......The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. DAT and its trafficking...... to natively expressed transporter, DAT was visualized directly in cultured DA neurons using the fluorescent cocaine analog JHC 1-64. These data showed pronounced colocalization upon constitutive internalization with Lysotracker, a late endosomal/lysosomal marker; however only little cololization was observed...

  2. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear......]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  3. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  4. Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

    Science.gov (United States)

    Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana; Karam, Caline S; Farino, Zachary J; Sonders, Mark S; Choi, Se Joon; Grygoruk, Anna; Zhang, Yuchao; Cela, Carolina; Choi, Ben Jiwon; Flores, Jorge; Freyberg, Robin J; McCabe, Brian D; Mosharov, Eugene V; Krantz, David E; Javitch, Jonathan A; Sulzer, David; Sames, Dalibor; Rayport, Stephen; Freyberg, Zachary

    2017-08-30

    The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  6. Dopamine in motivational control: rewarding, aversive, and alerting.

    Science.gov (United States)

    Bromberg-Martin, Ethan S; Matsumoto, Masayuki; Hikosaka, Okihide

    2010-12-09

    Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior.

  7. Dopamine neurons share common response function for reward prediction error.

    Science.gov (United States)

    Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

    2016-03-01

    Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found marked homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we were able to describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal.

  8. Dopamine Dysfunction in DYT1 Dystonia

    Science.gov (United States)

    2015-07-01

    brains removed. Frontal cortex, caudate-putamen and ventral midbrain were micro- dissected based on anatomical landmarks. Samples of each region from the...is linked to DYT1 dystonia [6]. TorsinA is a member of AAA + ATPase superfamily [6], associated with chaperone like functions in multiple processes...mRNA and protein expression for the same receptor may not correlate with each other), it appears that dopamine receptor expression and function undergo

  9. Vascular dopamine-I receptors and atherosclerosis.

    Science.gov (United States)

    Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J

    1997-01-01

    Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.

  10. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.

    Science.gov (United States)

    Binda, Francesca; Dipace, Concetta; Bowton, Erica; Robertson, Sabrina D; Lute, Brandon J; Fog, Jacob U; Zhang, Minjia; Sen, Namita; Colbran, Roger J; Gnegy, Margaret E; Gether, Ulrik; Javitch, Jonathan A; Erreger, Kevin; Galli, Aurelio

    2008-10-01

    The soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein syntaxin 1A (SYN1A) interacts with and regulates the function of transmembrane proteins, including ion channels and neurotransmitter transporters. Here, we define the first 33 amino acids of the N terminus of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated fraction shows that the AMPH-induced increase in DAT/SYN1A association occurs at the plasma membrane. In a superfusion assay of DA efflux, cells overexpressing SYN1A exhibited significantly greater AMPH-induced DA release with respect to control cells. By combining the patch-clamp technique with amperometry, we measured DA release under voltage clamp. At -60 mV, a physiological resting potential, AMPH did not induce DA efflux in hDAT cells and DA neurons. In contrast, perfusion of exogenous SYN1A (3 microM) into the cell with the whole-cell pipette enabled AMPH-induced DA efflux at -60 mV in both hDAT cells and DA neurons. It has been shown recently that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by AMPH and regulates AMPH-induced DA efflux. Here, we show that AMPH-induced association between DAT and SYN1A requires CaMKII activity and that inhibition of CaMKII blocks the ability of exogenous SYN1A to promote DA efflux. These data suggest that AMPH activation of CaMKII supports DAT/SYN1A association, resulting in a mode of DAT capable of DA efflux.

  11. Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis

    Science.gov (United States)

    Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modula...

  12. The (B)link Between Creativity and Dopamine: Spontaneous Eye Blink Rates Predict and Dissociate Divergent and Convergent Thinking

    Science.gov (United States)

    Chermahini, Soghra Akbari; Hommel, Bernhard

    2010-01-01

    Human creativity has been claimed to rely on the neurotransmitter dopamine, but evidence is still sparse. We studied whether individual performance (N=117) in divergent thinking (alternative uses task) and convergent thinking (remote association task) can be predicted by the individual spontaneous eye blink rate (EBR), a clinical marker of…

  13. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance

    Directory of Open Access Journals (Sweden)

    Andrii eDomanskyi

    2014-09-01

    Full Text Available The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson’s disease (PD. Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT promoter (DATCreERT2. The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1 protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc of aged cFoxa1/2-/- mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  14. Effects of aging and dopamine genotypes on the emergence of explicit memory during sequence learning.

    Science.gov (United States)

    Schuck, Nicolas W; Frensch, Peter A; Schjeide, Brit-Maren M; Schröder, Julia; Bertram, Lars; Li, Shu-Chen

    2013-11-01

    The striatum and medial temporal lobe play important roles in implicit and explicit memory, respectively. Furthermore, recent studies have linked striatal dopamine modulation to both implicit as well as explicit sequence learning and suggested a potential role of the striatum in the emergence of explicit memory during sequence learning. With respect to aging, previous findings indicated that implicit memory is less impaired than explicit memory in older adults and that genetic effects on cognition are magnified by aging. To understand the links between these findings, we investigated effects of aging and genotypes relevant for striatal dopamine on the implicit and explicit components of sequence learning. Reaction time (RT) and error data from 80 younger (20-30 years) and 70 older adults (60-71 years) during a serial reaction time task showed that age differences in learning-related reduction of RTs emerged gradually over the course of learning. Verbal recall and measures derived from the process-dissociation procedure revealed that younger adults acquired more explicit memory about the sequence than older adults, potentially causing age differences in RT gains in later stages of learning. Of specific interest, polymorphisms of the dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32, rs907094) and dopamine transporter (DAT, VNTR) genes showed interactive effects on overall RTs and verbal recall of the sequence in older but not in younger adults. Together our findings show that variations in genotypes relevant for dopamine functions are associated more with aging-related impairments in the explicit than the implicit component of sequence learning, providing support for theories emphasizing the role of dopaminergic modulation in cognitive aging and the magnification of genetic effects in human aging. © 2013 Elsevier Ltd. All rights reserved.

  15. Safety out of control: dopamine and defence.

    Science.gov (United States)

    Lloyd, Kevin; Dayan, Peter

    2016-05-23

    We enjoy a sophisticated understanding of how animals learn to predict appetitive outcomes and direct their behaviour accordingly. This encompasses well-defined learning algorithms and details of how these might be implemented in the brain. Dopamine has played an important part in this unfolding story, appearing to embody a learning signal for predicting rewards and stamping in useful actions, while also being a modulator of behavioural vigour. By contrast, although choosing correct actions and executing them vigorously in the face of adversity is at least as important, our understanding of learning and behaviour in aversive settings is less well developed. We examine aversive processing through the medium of the role of dopamine and targets such as D2 receptors in the striatum. We consider critical factors such as the degree of control that an animal believes it exerts over key aspects of its environment, the distinction between 'better' and 'good' actual or predicted future states, and the potential requirement for a particular form of opponent to dopamine to ensure proper calibration of state values.

  16. Transdermal delivery of dopamine receptor agonists.

    Science.gov (United States)

    Reichmann, Heinz

    2009-12-01

    Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. Copyright 2009 Elsevier Ltd. All rights reserved.

  17. Linking unfounded beliefs to genetic dopamine availability

    Science.gov (United States)

    Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

    2015-01-01

    Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

  18. Linking unfounded beliefs to genetic dopamine availability

    Directory of Open Access Journals (Sweden)

    Katharina eSchmack

    2015-09-01

    Full Text Available Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity towards unfounded beliefs. 109 healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818 and rs4680, also known as val158met that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioural experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity towards unfounded beliefs, and that this effect was mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world.

  19. The Effects of Dopamine and Estrogen upon Cortical Parvalbumin Expression

    Science.gov (United States)

    2001-10-01

    positive interneurons because studies indicate that the parvalbumin containing subclass of GABAergic neurons are contacted by mesocortical dopamine fibers...that both dopamine and estrogen enhance the maturation of cortical interneurons that express the calcium binding protein, parvalbumin , in the developing... parvalbumin expression in the deep cortical layers in the in vivo model. Dopamine D1 and D2 receptors are located on parvalbumin containing interneurons

  20. Dopamine and vascular dynamics control: present status and future perspectives.

    Science.gov (United States)

    Tayebati, Seyed Khosrow; Lokhandwala, Mustafa F; Amenta, Francesco

    2011-08-01

    The catecholamine dopamine is a precursors in the biosynthesis of norepinephrine and epinephrine as well as a neurotransmitter in the central nervous system. Besides of its well known role of brain neurotransmitter, dopamine exerts specific functions at the periphery, being those at the level of the cardiovascular system and the kidney the most relevant. In fact it plays a role of modulator of blood pressure, sodium balance, and renal and adrenal functions through an independent peripheral dopaminergic system. In vivo administration or in vitro application of dopamine or of dopamine receptor agonists induce vasodilatation in the cerebral, coronary, renal and mesenteric vascular beds and cause hypotension. Moreover, dopamine stimulates cardiac contractility and induces diuresis and natriuresis. Dopamine probably plays a role in the pathogenesis of arterial hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin-angiotensin and sympathetic nervous systems. Dopamine exerts its actions via a class of cell surface receptors belonging to the rhodopsin-like family of G-protein coupled receptors. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3 and D4) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes can participate in the regulation of blood pressure by specific mechanisms. Some receptors regulate blood pressure by influencing the central and/or autonomic nervous system; others influence epithelial transport and regulate the secretion and receptors of several humeral agents. This paper outlines the biochemistry, anatomical localization and physiology of the different dopamine receptors involved in the regulation of blood pressure, the relationship between dopamine receptor subtypes and hypertension and possibilities of modulating pharmacologically vascular dopamine receptor function.

  1. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  2. The binding sites for benztropines and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Jensen, Heidi Bisgaard; Larsen, M Andreas B; Mazier, Sonia

    2011-01-01

    Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational...... the pocket, including(2) Val152(3.46) to Ala or Ile, Ser422(8.60) to Ala and Asn157(3.51) to Cys or Ala, resulted in decreased affinity for BZT and the analog JHW007, as assessed in [(3)H]dopamine uptake inhibition assays and/or [(3)H]CFT competition binding assay. A putative polar interaction of one...... with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine....

  3. Effect of blood transfusion, dopamine, or normal saline on neurogenic shock secondary to acutely raised intracranial pressure.

    Science.gov (United States)

    Rahimifar, M; Tator, C H; Shanlin, R J; Sole, M J

    1989-06-01

    An experimental model to simulate acutely raised intracranial pressure due to a rapidly expanding intracranial space-occupying lesion was used to produce neurogenic shock. Forty-one rats in neurogenic shock (defined as a mean systemic arterial pressure (SAP) of less than 60 mm Hg) were subjected to various treatments to increase the mean SAP to a level of more than 80 mm Hg. The control group with neurogenic shock received no treatment, and the six treatment groups received infusions of: whole blood, packed cells, plasma, normal saline, dopamine, or a combination of dopamine and saline. Detrimental effects were observed after transfusion of packed cells or whole blood, which caused further deterioration of mean SAP. Although dopamine or the combination of dopamine and saline were both effective (p = 0.0001) for reversing hypotension, the combination was the most effective. If this rat paradigm correlates with human disease, these results indicate that, in the absence of hypovolemia, neurogenic shock due to acute intracranial hypertension should be treated with a combined transfusion of dopamine and normal saline, but not blood since the latter could have a detrimental effect.

  4. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  5. Reinforcement signalling in Drosophila; dopamine does it all after all.

    Science.gov (United States)

    Waddell, Scott

    2013-06-01

    Reinforcement systems are believed to drive synaptic plasticity within neural circuits that store memories. Recent evidence from the fruit fly suggests that anatomically distinct dopaminergic neurons ultimately provide the key instructive signals for both appetitive and aversive learning. This dual role for dopamine overturns the previous model that octopamine signalled reward and dopamine punishment. More importantly, this anatomically segregated double role for dopamine in reward and aversion mirrors that emerging in mammals. Therefore, an antagonistic organization of distinct reinforcing dopaminegic neurons is a conserved feature of brains. It now seems crucial to understand how the dopaminergic neurons are controlled and what the released dopamine does to the underlying circuits to convey opposite valence.

  6. Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice.

    Science.gov (United States)

    Zeng, Chunyu; Armando, Ines; Luo, Yingjin; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2008-02-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3), and D(4)) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.

  7. Carbon dots prepared by hydrothermal treatment of dopamine as an effective fluorescent sensing platform for the label-free detection of iron(III) ions and dopamine.

    Science.gov (United States)

    Qu, Konggang; Wang, Jiasi; Ren, Jinsong; Qu, Xiaogang

    2013-05-27

    A facile, economic and green one-step hydrothermal synthesis route using dopamine as source towards photoluminescent carbon nanoparticles (CNPs) is proposed. The as-prepared CNPs have an average size about 3.8 nm. The emission spectra of the CNPs are broad, ranging from approximately 380 (purple) to approximately 525 nm (green), depending on the excitation wavelengths. Due to the favorable optical properties, the CNPs can readily enter into A549 cells and has been used for multicolor biolabeling and bioimaging. Most importantly, the as-prepared CNPs contain distinctive catechol groups on their surfaces. Due to the special response of catechol groups to Fe(3+) ions, we further demonstrate that such wholly new CNPs can serve as a very effective fluorescent sensing platform for label-free sensitive and selective detection of Fe(3+) ions and dopamine with a detection limit as low as 0.32 μM and 68 nM, respectively. The new "mix-and-detect" strategy is simple, green, and exhibits high sensitivity and selectivity. The present method was also applied to the determination of Fe(3+) ions in real water samples and dopamine in human urine and serum samples successfully. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Monitoring Dopamine Quinone-Induced Dopaminergic Neurotoxicity Using Dopamine Functionalized Quantum Dots.

    Science.gov (United States)

    Ma, Wei; Liu, Hui-Ting; Long, Yi-Tao

    2015-07-08

    Dopamine (DA) quinone-induced dopaminergic neurotoxicity is known to occur due to the interaction between DA quinone and cysteine (Cys) residue, and it may play an important a role in pathological processes associated with neurodegeneration. In this study, we monitored the interaction process of DA to form DA quinone and the subsequent Cys residue using dopamine functionalized quantum dots (QDs). The fluorescence (FL) of the QD bioconjugates changes as a function of the structure transformation during the interaction process, providing a potential FL tool for monitoring dopaminergic neurotoxicity.

  9. Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Directory of Open Access Journals (Sweden)

    Javier A Urra

    Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  10. Presence and function of dopamine transporter (DAT) in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Science.gov (United States)

    Urra, Javier A; Villaroel-Espíndola, Franz; Covarrubias, Alejandra A; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I

    2014-01-01

    Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP(+)), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  11. Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning.

    Science.gov (United States)

    Parker, Jones G; Zweifel, Larry S; Clark, Jeremy J; Evans, Scott B; Phillips, Paul E M; Palmiter, Richard D

    2010-07-27

    During Pavlovian conditioning, phasic dopamine (DA) responses emerge to reward-predictive stimuli as the subject learns to anticipate reward delivery. This observation has led to the hypothesis that phasic dopamine signaling is important for learning. To assess the ability of mice to develop anticipatory behavior and to characterize the contribution of dopamine, we used a food-reinforced Pavlovian conditioning paradigm. As mice learned the cue-reward association, they increased their head entries to the food receptacle in a pattern that was consistent with conditioned anticipatory behavior. D1-receptor knockout (D1R-KO) mice had impaired acquisition, and systemic administration of a D1R antagonist blocked both the acquisition and expression of conditioned approach in wild-type mice. To assess the specific contribution of phasic dopamine transmission, we tested mice lacking NMDA-type glutamate receptors (NMDARs) exclusively in dopamine neurons (NR1-KO mice). Surprisingly, NR1-KO mice learned at the same rate as their littermate controls. To evaluate the contribution of NMDARs to phasic dopamine release in this paradigm, we performed fast-scan cyclic voltammetry in the nucleus accumbens of awake mice. Despite having significantly attenuated phasic dopamine release following reward delivery, KO mice developed cue-evoked dopamine release at the same rate as controls. We conclude that NMDARs in dopamine neurons enhance but are not critical for phasic dopamine release to behaviorally relevant stimuli; furthermore, their contribution to phasic dopamine signaling is not necessary for the development of cue-evoked dopamine or anticipatory activity in a D1R-dependent Pavlovian conditioning paradigm.

  12. Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings.

    Science.gov (United States)

    Le Foll, Bernard; Collo, Ginetta; Rabiner, Eugenii A; Boileau, Isabelle; Merlo Pich, Emilio; Sokoloff, Pierre

    2014-01-01

    The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction.

  13. Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

    Science.gov (United States)

    2012-01-01

    We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10- to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying several analogues that also exhibit D2 vs D3 dopamine receptor binding selectivity. These studies further characterize the intrinsic efficacy of the compound with the greatest binding selectivity from each chemical class, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s), using an adenylyl cyclase inhibition assay, a G-protein-coupled inward-rectifying potassium (GIRK) channel activation assay, and a cell based phospho-MAPK (pERK1/2) assay. SV 293 was found to be a neutral antagonist at D2 dopamine receptors using all three assays. SV-III-130s is a partial agonist using an adenylyl cyclase inhibition assay but an antagonist in the GIRK and phospho ERK1/2 assays. To define the molecular basis for the binding selectivity, the affinity of these two compounds was evaluated using (a) wild type human D2 and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors. Computer-assisted modeling techniques were used to dock these compounds to the human D2 and D3 dopamine receptor subtypes. It is hoped that these studies on D2 receptor selective ligands will be useful in the future design of (a) receptor selective ligands used to define the function of D2-like receptor subtypes, (b) novel pharmacotherapeutic agents, and/or (c) in vitro and in vivo imaging agents. PMID:23259040

  14. Facilitatory effect of dopamine on neuromuscular transmission mediated via dopamine D1-like receptors and prospective interaction with nicotine.

    Science.gov (United States)

    AlQot, H E; Elnozahi, N A; Mohy El-Din, M M; Bistawroos, A E; Abou Zeit-Har, M S

    2015-10-15

    The objective of this study is to probe the effects of dopamine and potential interactions with nicotine at the motor end plate. To accomplish this, we measured the amplitude of nerve-evoked muscle twitches of the isolated rat phrenic hemi-diaphragm preparation. Dopamine potentiated indirect muscle twitches in normal and gallamine-presensitized preparations amounting to a maximum of 31.14±0.71% and 69.23±1.96%, respectively. The dopamine-induced facilitation was well maintained in presence of 10 µM propranolol but greatly reduced in presence of 6 µM SCH 23390 or 3 µM dantrolene. In addition, SKF 81297 attained a plateau at 16 µM as opposed to 64 µM dopamine, with a percentage potentiation of 69.47±1.76. The facilitatory effect of dopamine was potentiated in nicotine treated rats. This study revealed for the first time that the facilitatory effect exerted by dopamine on neuromuscular transmission is mediated via the dopamine D1-like receptors. In addition, it highlighted the possible dependency of dopamine effects on intracellular calcium and signified potential interaction among dopamine and nicotine. Clinically, the findings generated by this study reveal potential targets for approaching motor deficit syndromes.

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

    Science.gov (United States)

    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.

  16. Dopamine attenuates the chemoattractant effect of interleukin-8: a novel role in the systemic inflammatory response syndrome.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    Activated neutrophil (PMN) adherence to vascular endothelium comprises a key step for both transendothelial migration and initiation of potentially deleterious release of PMN products. The biogenic amine, dopamine (DA), has been used for several decades in patients to maintain hemodynamic stability. The effect of dopamine on PMN transendothelial migration and adhesion receptor expression and on the endothelial molecules, E-selectin and ICAM-1, was evaluated. PMN were isolated from healthy controls, stimulated with lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) and treated with dopamine. CD 11b and CD 18 PMN adhesion receptor expression were assessed flow cytometrically. In a separate experiment, the chemoattractant peptide, IL-8, was placed in the lower chamber of transwells, and PMN migration was assessed. Human umbilical vein endothelial cells (HUVEC) were stimulated with LPS\\/TNF-alpha and incubated with dopamine. ICAM-1 and E-selectin endothelial molecule expression were assessed flow cytometrically. There was a significant increase in transendothelial migration in stimulated PMN compared with normal PMN (40 vs. 14%, P < 0.001). In addition, PMN CD11b\\/CD18 was significantly upregulated in stimulated PMN compared with normal PMN (252.4\\/352.4 vs. 76.7\\/139.4, P < 0.001) as were endothelial E-selectin\\/ICAM-1 expression compared with normal EC (8.1\\/9 vs. 3.9\\/3.8, P < 0.05). After treatment with dopamine, PMN transmigration was significantly decreased compared with stimulated PMN (8% vs. 40%, P < 0.001). Furthermore, dopamine also attenuated PMN CD11b\\/CD18 and the endothelial molecules E-selectin and ICAM-1 compared with stimulated PMN\\/EC that were not treated dopamine (174\\/240 vs. 252\\/352, P < 0.05 and 4\\/4.4 vs. 8.1\\/9, P < 0.05. respectively). The chemoattractant effect of IL-8 was also attenuated. These results identify for the first time that dopamine attenuates the initial interaction between PMN and the endothelium

  17. The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex.

    Science.gov (United States)

    Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Bini, Valentina; Gessa, Gian Luigi

    2014-07-01

    The dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking. Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats. Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2 -adrenoceptor agonist clonidine. It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2 -adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine- and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex.

  18. Selective detection of dopamine combining multilayers of conducting polymers with gold nanoparticles.

    Science.gov (United States)

    Fabregat, Georgina; Armelin, Elaine; Alemán, Carlos

    2014-05-01

    Electrodes based on the combination of three-layered films formed by two different conducting polymers and gold nanoparticles have been developed for the selective voltammetric determination of dopamine in mixtures with ascorbic acid and uric acid and human urine samples with real interferents. Voltammetric studies of solution mixtures indicate that electrodes formed by alternated layers of poly(3,4-ethylenedioxithiophene) (internal and external layer) and poly(N-methylpyrrole) (intermediate layer) show the best performance in terms of sensitivity and resolution. Furthermore, the sensitivity of such three-layered electrodes increases only slightly after coating its surface with gold nanoparticles (AuNPs), indicating that the catalytic effect typically played by AuNPs in the oxidation of dopamine is less effective in this case. Electrochemical pretreatments based on the application of consecutive oxidation-reduction cycles to electrodes before the detection process have been found to improve the selectivity without altering the sensitivity. On the other hand, the flux of dopamine to the three-layered surface increases linearly with the scan rate. The detection limit for these electrodes is around 10 μM DA in mixtures with uric acid, ascorbic acid, and cetaminophen, decreasing to 2-3 μM in the absence of such interferents. The utility of three-layered electrodes as sensors has also been demonstrated by determining DA in human samples with real interferents.

  19. New copper(II) complexes with dopamine hydrochloride and vanillymandelic acid: Spectroscopic and thermal characterization

    Science.gov (United States)

    Mohamed, Gehad G.; Nour El-Dien, F. A.; El-Nahas, R. G.

    2011-10-01

    The dopamine derivatives participate in the regulation of wide variety of physiological functions in the human body and in medication life. Increase and/or decrease in the concentration of dopamine in human body reflect an indication for diseases such as Schizophrenia and/or Parkinson diseases. The Cu(II) chelates with coupled products of dopamine hydrochloride (DO.HCl) and vanillymandelic acid (VMA) with 4-aminoantipyrine (4-AAP) are prepared and characterized. Different physico-chemical techniques namely IR, magnetic and UV-vis spectra are used to investigate the structure of these chelates. Cu(II) forms 1:1 (Cu:DO) and 1:2 (Cu:VMA) chelates. DO behave as a uninegative tridentate ligand in binding to the Cu(II) ion while VMA behaves as a uninegative bidentate ligand. IR spectra show that the DO is coordinated to the Cu(II) ion in a tridentate manner with ONO donor sites of the phenolic- OH, -NH and carbonyl- O, while VMA is coordinated with OO donor sites of the phenolic- OH and -NH. Magnetic moment measurements reveal the presence of Cu(II) chelates in octahedral and square planar geometries with DO and VMA, respectively. The thermal decomposition of Cu(II) complexes is studied using thermogravimetric (TG) and differential thermal analysis (DTA) techniques. The activation thermodynamic parameters, such as, energy of activation, enthalpy, entropy and free energy change of the complexes are evaluated and the relative thermal stability of the complexes are discussed.

  20. NOvelty-related motivation of anticipation and exploration by dopamine (NOMAD): implications for healthy aging.

    Science.gov (United States)

    Düzel, Emrah; Bunzeck, Nico; Guitart-Masip, Marc; Düzel, Sandra

    2010-04-01

    Studies in humans and animals show that dopaminergic neuromodulation originating from the substantia nigra/ventral tegmental area (SN/VTA) of the midbrain enhances hippocampal synaptic plasticity for novel events and has a motivationally energizing effect on actions through striatal mechanisms. In this review, we discuss how these mechanisms of dopaminergic neuromodulation connect to the behavioural and functional consequences that age-related structural degeneration of the SN/VTA exerts on declarative memory. We propose a framework called 'NOvelty-related Motivation of Anticipation and exploration by Dopamine' (NOMAD) which captures existing links between novelty, dopamine, long-term memory, plasticity, energization and their relation to aging. We propose that maximizing the use of this mechanism by maintaining mobility and exploration of novel environments could be a potential mechanism to slow age-related decline of memory. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. Expression and purification of the metal-containing monooxygenases tryptophan hydroxylase and dopamine β-hydroxylase

    DEFF Research Database (Denmark)

    Karlsen, Pernille Efferbach

    to abnormal levels of the neurotransmitters serotonin, dopamine and norepinephrine and the regulation of tryptophan hydroxylase and dopamine β-hydroxylase. These include depression, anxiety disorders, obsessive compulsive disorder (OCD), schizophrenia, Parkinson's disease and attention deficit......-containing enzyme which belongs to the aromatic amino acid hydroxylase (AAAH) family. It exist in two isoforms, TPH1 and TPH2, which are expressed in different tissues and have different properties. TPH is known as a very diffcult protein to work with especially due to instability and only truncated forms of TPH1...... to the family of ascorbate dependent type II Cu monooxygenases. Very little knowledge exist on DβH and most of it comes from investigations of related proteins. Attempts to express human DβH in bacterial systems have been done in the Metalloprotein Chemistry and Engineering Group, but at present no system...

  2. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning.

    Science.gov (United States)

    Frank, Michael J; Moustafa, Ahmed A; Haughey, Heather M; Curran, Tim; Hutchison, Kent E

    2007-10-09

    What are the genetic and neural components that support adaptive learning from positive and negative outcomes? Here, we show with genetic analyses that three independent dopaminergic mechanisms contribute to reward and avoidance learning in humans. A polymorphism in the DARPP-32 gene, associated with striatal dopamine function, predicted relatively better probabilistic reward learning. Conversely, the C957T polymorphism of the DRD2 gene, associated with striatal D2 receptor function, predicted the degree to which participants learned to avoid choices that had been probabilistically associated with negative outcomes. The Val/Met polymorphism of the COMT gene, associated with prefrontal cortical dopamine function, predicted participants' ability to rapidly adapt behavior on a trial-to-trial basis. These findings support a neurocomputational dissociation between striatal and prefrontal dopaminergic mechanisms in reinforcement learning. Computational maximum likelihood analyses reveal independent gene effects on three reinforcement learning parameters that can explain the observed dissociations.

  3. Phytic acid/graphene oxide nanocomposites modified electrode for electrochemical sensing of dopamine.

    Science.gov (United States)

    Wang, Donglei; Xu, Fei; Hu, Jiajie; Lin, Meng

    2017-02-01

    An electrochemical sensor for determining dopamine was developed by modifying phytic acid/graphene oxide (PA/GO) nanocomposites onto a glassy carbon electrode (GCE). PA functionalized GO was prepared by an ultra-sonication method. Subsequently, the PA/GO nanocomposites were drop-casted on a glassy carbon substrate. The structural feature of the PA/GO modified GCE was confirmed by attenuated total reflection infrared (ATR-IR) spectroscopy. The proposed electrochemical sensor was applied to detect various concentrations of DA by differential pulse voltammetry (DPV). The PA/GO/GCE was considered to be highly sensitive to DA in the range of 0.05-10μM. In addition, the PA/GO/GCE demonstrated high electrochemical selectivity toward DA in the presence of ascorbic acid (AA) and uric acid (UA). The prepared electrochemical DA sensor was applied for detection of DA in dopamine hydrochloride injection and spiked samples of human urine with satisfactory results.

  4. Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

    Directory of Open Access Journals (Sweden)

    Tatyana D Sotnikova

    2005-08-01

    Full Text Available Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

  5. Hub and switches: endocannabinoid signalling in midbrain dopamine neurons.

    Science.gov (United States)

    Melis, Miriam; Pistis, Marco

    2012-12-05

    The last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Because dysfunctions of the dopamine system underlie diverse neuropsychiatric disorders, including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, because dopamine neurons are critical in controlling incentive-motivated behaviours, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light on the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse.

  6. Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

    NARCIS (Netherlands)

    Mele, A.; Avena, M.; Roullet, P.; Leonibus, E. de; Mandillo, S.; Sargolini, F.; Coccurello, R.; Oliverio, A.

    2004-01-01

    Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular event

  7. Opening the black box: dopamine, predictions, and learning.

    Science.gov (United States)

    Eshel, Neir; Tian, Ju; Uchida, Naoshige

    2013-09-01

    Dopamine neurons are thought to promote learning by signaling prediction errors, that is, the difference between actual and expected outcomes. Whether these signals are sufficient for associative learning, however, remains untested. A recent study used optogenetics in a classic behavioral paradigm to confirm the role of dopamine prediction errors in learning.

  8. Dopamine receptor and Gα(olf expression in DYT1 dystonia mouse models during postnatal development.

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    Full Text Available DYT1 dystonia is a heritable, early-onset generalized movement disorder caused by a GAG deletion (ΔGAG in the DYT1 gene. Neuroimaging studies and studies using mouse models suggest that DYT1 dystonia is associated with dopamine imbalance. However, whether dopamine imbalance is key to DYT1 or other forms of dystonia continues to be debated.We used Dyt1 knock out (Dyt1 KO, Dyt1 ΔGAG knock-in (Dyt1 KI, and transgenic mice carrying one copy of the human DYT1 wild type allele (DYT1 hWT or human ΔGAG mutant allele (DYT1 hMT. D1R, D2R, and Gα(olf protein expression was analyzed by western blot in the frontal cortex, caudate-putamen and ventral midbrain in young adult (postnatal day 60; P60 male mice from all four lines; and in the frontal cortex and caudate putamen in juvenile (postnatal day 14; P14 male mice from the Dyt1 KI and KO lines. Dopamine receptor and Gα(olf protein expression were significantly decreased in multiple brain regions of Dyt1 KI and Dyt1 KO mice and not significantly altered in the DYT1 hMT or DYT1 hWT mice at P60. The only significant change at P14 was a decrease in D1R expression in the caudate-putamen of the Dyt1 KO mice.We found significant decreases in key proteins in the dopaminergic system in multiple brain regions of Dyt1 KO and Dyt1 KI mouse lines at P60. Deletion of one copy of the Dyt1 gene (KO mice produced the most pronounced effects. These data offer evidence that impaired dopamine receptor signaling may be an early and significant contributor to DYT1 dystonia pathophysiology.

  9. Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation.

    Science.gov (United States)

    Dehnes, Yvette; Shan, Jufang; Beuming, Thijs; Shi, Lei; Weinstein, Harel; Javitch, Jonathan A

    2014-07-01

    The dopamine transporter (DAT), a member of the neurotransmitter:sodium symporter family, mediates the reuptake of dopamine at the synaptic cleft. DAT is the primary target for psychostimulants such as cocaine and amphetamine. We previously demonstrated that cocaine binding and dopamine transport alter the accessibility of Cys342 in the third intracellular loop (IL3). To study the conformational changes associated with the functional mechanism of the transporter, we made cysteine substitution mutants, one at a time, from Phe332 to Ser351 in IL3 of the background DAT construct, X7C, in which 7 endogenous cysteines were mutated. The accessibility of the 20 engineered cysteines to polar charged sulfhydryl reagents was studied in the absence and presence of cocaine or dopamine. Of the 11 positions that reacted with methanethiosulfonate ethyl ammonium, as evidenced by inhibition of ligand binding, 5 were protected against this inhibition by cocaine and dopamine (S333C, S334C, N336C, M342C and T349C), indicating that reagent accessibility is affected by conformational changes associated with inhibitor and substrate binding. In some of the cysteine mutants, transport activity is disrupted, but can be rescued by the presence of zinc, most likely because the distribution between inward- and outward-facing conformations is restored by zinc binding. The experimental data were interpreted in the context of molecular models of DAT in both the inward- and outward-facing conformations. Differences in the solvent accessible surface area for individual IL3 residues calculated for these states correlate well with the experimental accessibility data, and suggest that protection by ligand binding results from the stabilization of the outward-facing configuration. Changes in the residue interaction networks observed from the molecular dynamics simulations also revealed the critical roles of several positions during the conformational transitions. We conclude that the IL3 region of DAT

  10. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  11. Novos agonistas dopaminérgicos

    Directory of Open Access Journals (Sweden)

    MATTOS JAMES PITÁGORAS DE

    1999-01-01

    Full Text Available Apresentamos breve revisão da literatura sobre os agonistas dopaminérgicos. Referimos os cinco receptores conhecidos e onde estão localizados, as vantagens e as desvantagens de sua utilização nos pacientes com a doença de Parkinson.Introduzidos com o objetivo principal de controlar as limitações da levodopa, aumentando a janela terapêutica, analisamos a farmacocinética, a eficácia e os efeitos colaterais da cabergolina, do ropinirole e do pramipexole.

  12. Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training.

    Science.gov (United States)

    Clark, Jeremy J; Collins, Anne L; Sanford, Christina Akers; Phillips, Paul E M

    2013-02-20

    Dopamine is highly implicated both as a teaching signal in reinforcement learning and in motivating actions to obtain rewards. However, theoretical disconnects remain between the temporal encoding properties of dopamine neurons and the behavioral consequences of its release. Here, we demonstrate in rats that dopamine evoked by Pavlovian cues increases during acquisition, but dissociates from stable conditioned appetitive behavior as this signal returns to preconditioning levels with extended training. Experimental manipulation of the statistical parameters of the behavioral paradigm revealed that this attenuation of cue-evoked dopamine release during the postasymptotic period was attributable to acquired knowledge of the temporal structure of the task. In parallel, conditioned behavior became less dopamine dependent after extended training. Thus, the current work demonstrates that as the presentation of reward-predictive stimuli becomes anticipated through the acquisition of task information, there is a shift in the neurobiological substrates that mediate the motivational properties of these incentive stimuli.

  13. Label-free dopamine imaging in live rat brain slices.

    Science.gov (United States)

    Sarkar, Bidyut; Banerjee, Arkarup; Das, Anand Kant; Nag, Suman; Kaushalya, Sanjeev Kumar; Tripathy, Umakanta; Shameem, Mohammad; Shukla, Shubha; Maiti, Sudipta

    2014-05-21

    Dopaminergic neurotransmission has been investigated extensively, yet direct optical probing of dopamine has not been possible in live cells. Here we image intracellular dopamine with sub-micrometer three-dimensional resolution by harnessing its intrinsic mid-ultraviolet (UV) autofluorescence. Two-photon excitation with visible light (540 nm) in conjunction with a non-epifluorescent detection scheme is used to circumvent the UV toxicity and the UV transmission problems. The method is established by imaging dopamine in a dopaminergic cell line and in control cells (glia), and is validated by mass spectrometry. We further show that individual dopamine vesicles/vesicular clusters can be imaged in cultured rat brain slices, thereby providing a direct visualization of the intracellular events preceding dopamine release induced by depolarization or amphetamine exposure. Our technique opens up a previously inaccessible mid-ultraviolet spectral regime (excitation ~270 nm, emission free imaging of native molecules in live tissue.

  14. ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

    Science.gov (United States)

    Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

    2014-01-01

    Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. PMID:24656971

  15. Surface functionalization of polyamide fiber via dopamine polymerization

    Science.gov (United States)

    Kuang, Xiao-Hui; Guan, Jin-Ping; Tang, Ren-Cheng; Chen, Guo-Qiang

    2017-09-01

    The oxidative polymerization of dopamine for the functional surface modification of textile fibers has drawn great attention. In this work, the functionalization of polyamide fiber via dopamine polymerization was studied with the aim of the fabrication of hydrophilic and antistatic surface. The conditions of dopamine application were first discussed in the absence of specific oxidants in terms of the apparent color depth of polyamide fiber. Dopamine concentration, pH and time were found to exert great impact on color depth. The highest color depth was achieved at pH 8.5. In the process of modification, polydopamine was deposited onto the surface of polyamide fiber. The modified polyamide fiber displayed a yellowish brown color with excellent wash and light color fastness, and exhibited good hydrophilic, UV protection and antistatic effects. A disadvantage of the present approach was the slow rate of dopamine polymerization and functionalization.

  16. Dopamine release in ventral striatum of pathological gamblers losing money

    DEFF Research Database (Denmark)

    Linnet, J; Peterson, E; Doudet, D J;

    2010-01-01

    Linnet J, Peterson E, Doudet DJ, Gjedde A, Møller A. Dopamine release in ventral striatum of pathological gamblers losing money. Objective: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue...... gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). Method: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure...... dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). Results: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. Conclusion: Our findings...

  17. Reactive oxygen species and dopamine receptor function in essential hypertension.

    Science.gov (United States)

    Zeng, Chunyu; Villar, Van Anthony M; Yu, Peiying; Zhou, Lin; Jose, Pedro A

    2009-04-01

    Essential hypertension is a major risk factor for stroke, myocardial infarction, and heart and kidney failure. Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones and humoral factors. However, the mechanisms leading to impaired dopamine receptor function in hypertension states are not clear. Compelling experimental evidence indicates a role of reactive oxygen species (ROS) in hypertension, and there are increasing pieces of evidence showing that in conditions associated with oxidative stress, which is present in hypertensive states, dopamine receptor effects, such as natriuresis, diuresis, and vasodilation, are impaired. The goal of this review is to present experimental evidence that has led to the conclusion that decreased dopamine receptor function increases ROS activity and vice versa. Decreased dopamine receptor function and increased ROS production, working in concert or independent of each other, contribute to the pathogenesis of essential hypertension.

  18. [Multiple Dopamine Signals and Their Contributions to Reinforcement Learning].

    Science.gov (United States)

    Matsumoto, Masayuki

    2016-10-01

    Midbrain dopamine neurons are activated by reward and sensory cue that predicts reward. Their responses resemble reward prediction error that indicates the discrepancy between obtained and expected reward values, which has been thought to play an important role as a teaching signal in reinforcement learning. Indeed, pharmacological blockade of dopamine transmission interferes with reinforcement learning. Recent studies reported, however, that not all dopamine neurons transmit the reward-related signal. They found that a subset of dopamine neurons transmits signals related to non-rewarding, salient experiences such as aversive stimulations and cognitively demanding events. How these signals contribute to animal behavior is not yet well understood. This article reviews recent findings on dopamine signals related to rewarding and non-rewarding experiences, and discusses their contributions to reinforcement learning.

  19. Carbon Dot Based Sensing of Dopamine and Ascorbic Acid

    Directory of Open Access Journals (Sweden)

    Upama Baruah

    2014-01-01

    Full Text Available We demonstrate carbon dot based sensor of catecholamine, namely, dopamine and ascorbic acid. Carbon dots (CDs were prepared from a green source: commercially available Assam tea. The carbon dots prepared from tea had particle sizes of ∼0.8 nm and are fluorescent. Fluorescence of the carbon dots was found to be quenched in the presence of dopamine and ascorbic acid with greater sensitivity for dopamine. The minimum detectable limits were determined to be 33 μM and 98 μM for dopamine and ascorbic acid, respectively. The quenching constants determined from Stern-Volmer plot were determined to be 5 × 10−4 and 1 × 10−4 for dopamine and ascorbic acid, respectively. A probable mechanism of quenching has been discussed in the paper.

  20. Characterization of pre- and postsynaptic dopamine receptors in Lymnaea.

    Science.gov (United States)

    Audesirk, T E

    1989-01-01

    1. The effects of dopamine and several synthetic agonists and antagonists were studied using two identified neurons of the snail Lymnaea stagnalis. 2. In both the buccal-2 (B-2) neurons and the pedal giant (RPeD1) neuron dopamine elicited a hyperpolarizing response at least partly due to potassium efflux. RPeD1 is itself dopaminergic, implicating autoreceptors in its response to dopamine. 3. The following agents were tested: agonists--LY171555, pergolide, SKF38393, (-)-3-PPP, R(-)NPA and dopamine; antagonists--SCH23390, sulpiride, and metaclopramide. Dibutyryl cAMP was applied to determine whether the response is cAMP-mediated. 4. Results indicate that the pharmacological profiles of dopamine receptors on these neurons are inconsistent with those of either D-1, D-2 or autoreceptors in mammals.

  1. Arithmetic and local circuitry underlying dopamine prediction errors.

    Science.gov (United States)

    Eshel, Neir; Bukwich, Michael; Rao, Vinod; Hemmelder, Vivian; Tian, Ju; Uchida, Naoshige

    2015-09-10

    Dopamine neurons are thought to facilitate learning by comparing actual and expected reward. Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area while mice engaged in classical conditioning. Here we demonstrate, by manipulating the temporal expectation of reward, that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA (γ-aminobutyric acid) neurons in the ventral tegmental area reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction-error calculations. Finally, bilaterally stimulating ventral tegmental area GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors.

  2. A causal link between prediction errors, dopamine neurons and learning.

    Science.gov (United States)

    Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2013-07-01

    Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.

  3. Investigation on the co-luminescence effect of europium (III)-lanthanum(III)-dopamine-sodium dodecylbenzene sulfonate system and its application.

    Science.gov (United States)

    Si, Hailin; Zhao, Fang; Cai, Huan

    2013-01-01

    A novel luminescence, enhancement phenomenon in the europium(III)-dopamine-sodium dodecylbenzene sulfonate system was observed when lanthanum(III) was added. Based on this, a sensitive co-luminescence method was established for the determination of dopamine. The luminescence signal for the europium (III)-lanthanum(III)-dopamine-sodium dodecylbenzene sulfonate system was monitored at λ(ex) = 300 nm, λ(em) = 618 nm and pH 8.3. Under optimized conditions, the enhanced luminescence signal responded linearly to the concentration of dopamine in the range 1.0 × 10(-10)-5.0 × 10(-7) mol/L with a correlation coefficient of 0.9993 (n = 11). The detection limit (3σ) was 2.7 × 10(-11) mol/L and the relative standard deviation for 11 parallel measurements of 3.0 × 10(-8) mol/L dopamine was 1.9%. The presented method was successfully applied for the estimation of dopamine in samples of pharmaceutical preparations, human serum and urine. The possible luminescence enhancement mechanism of the system is discussed briefly.

  4. Voltammetric behavior of dopamine at a glassy carbon electrode modified with NiFe(2)O(4) magnetic nanoparticles decorated with multiwall carbon nanotubes.

    Science.gov (United States)

    Ensafi, Ali A; Arashpour, B; Rezaei, B; Allafchian, Ali R

    2014-06-01

    Voltammetric behavior of dopamine was studied on a glassy carbon electrode (GCE) modified-NiFe(2)O(4) magnetic nanoparticles decorated with multiwall carbon nanotubes. Impedance spectroscopy and cyclic voltammetry were used to characterize the behavior of dopamine at the surface of modified-GCE. The modified electrode showed a synergic effect toward the oxidation of dopamine. The oxidation peak current is increased linearly with the dopamine concentration (at pH7.0) in wide dynamic ranges of 0.05-6.0 and 6.0-100μmolL(-1) with a detection limit of 0.02μmolL(-1), using differential pulse voltammetry. The selectivity of the method was studied and the results showed that the modified electrode is free from interference of organic compounds especially ascorbic acid, uric acid, cysteine and urea. Its applicability in the determination of dopamine in pharmaceutical, urine samples and human blood serum was also evaluated. The proposed electrochemical sensor has appropriate properties such as high selectivity, low detection limit and wide linear dynamic range when compared with that of the previous reported papers for dopamine detection.

  5. A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

    Science.gov (United States)

    Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

    2015-07-01

    There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

  6. Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Chen, Honglei [Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yue, Jiang [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Li, Ying, E-mail: lyying0@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China)

    2015-07-15

    Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor

  7. Preparation of copper (I) oxide nanohexagon decorated reduced graphene oxide nanocomposite and its application in electrochemical sensing of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Sivasubramanian, R., E-mail: rss@psgias.ac.in; Biji, P.

    2016-08-15

    Highlights: • Cu{sub 2}O nanohexagon–reduced graphene oxide (rGO) nanocomposite has been prepared by in-situ reduction method. • The rGO-Cu{sub 2}O/GCE exhibited excellent catalytic properties for dopamine due to the synergistic action of the nanocomposite. • The proposed sensor is highly selective toward dopamine in the presence of ascorbic acid and uric acid. - Graphical Abstract: - Abstract: An electrochemical sensor using copper (I) oxide nanostructure decorated reduced graphene oxide (rGO) nanocomposite has been proposed for selective detection of dopamine. The rGO–Cu{sub 2}O nanocomposite was synthesized by in-situ chemical reduction method and was characterized using Transmission Electron Microscope (TEM), Energy Dispersive X-ray (EDX) analysis, X-ray Diffraction (XRD) patterns, Fourier Transform Infrared (FTIR), UV–vis and Raman Spectroscopy, respectively. From Cyclic Voltammetric (CV) studies, it was inferred that rGO–Cu{sub 2}O/GCE exhibits excellent electrocatalytic activity toward dopamine, which is attributed to the enhanced conductivity as well as the synergistic effect of the nanocomposite. The sensing was carried out using Differential Pulse Voltammetry (DPV) wherefrom a Limit of Detection (LOD) of 50 nM with a linear range from 10 µM to 900 µM was estimated. The effect of potential interfering agents such as Uric Acid (UA), Ascorbic Acid (AA), glucose, K{sup +}, Na{sup +}, Cl{sup −}, and SO{sub 4}{sup −} ions toward sensing were investigated. The performance of the sensor toward the estimation of dopamine in human blood and urine samples were analyzed. The facile method for the preparation of a nanocomposite in conjunction with the low detection limit and the wide linear range for dopamine sensing is the advantage of this present study.

  8. The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium: a meta-analysis.

    NARCIS (Netherlands)

    Munster, B.C. van; Rooij, S.E.J.A. de; Yazdanpanah, M.; Tienari, P.J.; Pitkala, K.H.; Osse, R.J.; Adamis, D.; Smit, O.; Steen, M.S. van der; Houten, M. van; Rahkonen, T.; Sulkava, R.; Laurila, J.V.; Strandberg, T.E.; Tulen, J.H.M.; Zwang, L.; Macdonald, A.J.D.; Treloar, A.; Sijbrands, E.J.G.; Zwinderman, A.H.; Korevaar, J.C.

    2010-01-01

    Delirium is the most common neuropsychiatric syndrome in elderly ill patients. Previously, associations between delirium and the dopamine transporter gene (solute carrier family 6, member 3 (SLC6A3)) and dopamine receptor 2 gene (DRD2) were found. The aim of this study was to validate whether marker

  9. Palmitoylation mechanisms in dopamine transporter regulation.

    Science.gov (United States)

    Rastedt, Danielle E; Vaughan, Roxanne A; Foster, James D

    2017-10-01

    The neurotransmitter dopamine (DA) plays a key role in several biological processes including reward, mood, motor activity and attention. Synaptic DA homeostasis is controlled by the dopamine transporter (DAT) which transports extracellular DA into the presynaptic neuron after release and regulates its availability to receptors. Many neurological disorders such as schizophrenia, bipolar disorder, Parkinson disease and attention-deficit hyperactivity disorder are associated with imbalances in DA homeostasis that may be related to DAT dysfunction. DAT is also a target of psychostimulant and therapeutic drugs that inhibit DA reuptake and lead to elevated dopaminergic neurotransmission. We have recently demonstrated the acute and chronic modulation of DA reuptake activity and DAT stability through S-palmitoylation, the linkage of a 16-carbon palmitate group to cysteine via a thioester bond. This review summarizes the properties and regulation of DAT palmitoylation and describes how it serves to affect various transporter functions. Better understanding of the role of palmitoylation in regulation of DAT function may lead to identification of therapeutic targets for modulation of DA homeostasis in the treatment of dopaminergic disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Dopamine in Socioecological and Evolutionary Perspectives: Implications for Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Yoshie eYamaguchi

    2015-06-01

    Full Text Available Dopamine (DA transmission in brain areas such as the prefrontal cortex (PFC and nucleus accumbens (NAcc plays important roles in cognitive and affective function. As such, DA deficits have been implicated in a number of psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (ADHD. Accumulating evidence suggests that DA is also involved in social behavior of animals and humans. Although most animals organize and live in social groups, how the DA system functions in such social groups of animals, and its dysfunction causes compromises in the groups has remained less understood. Here we propose that alterations of DA signaling and associated genetic variants and behavioral phenotypes, which have been normally considered as deficits in investigation at an individual level, may not necessarily yield disadvantages, and even work advantageously, depending on social contexts in subjects with such DA alterations living in social groups. This hypothesis could provide a novel insight into our understanding of the biological mechanisms of psychiatric disorders, and a potential explanation that disadvantageous phenotypes associated with DA deficits in psychiatric disorders have remained in humans through evolution.

  11. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    Science.gov (United States)

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.

  12. Kinetic Diversity of Striatal Dopamine: Evidence from a Novel Protocol for Voltammetry.

    Science.gov (United States)

    Walters, Seth H; Robbins, Elaine M; Michael, Adrian C

    2016-05-18

    In vivo voltammetry reveals substantial diversity of dopamine kinetics in the rat striatum. To substantiate this kinetic diversity, we evaluate the temporal distortion of dopamine measurements arising from the diffusion-limited adsorption of dopamine to voltammetric microelectrodes. We validate two mathematical procedures for correcting adsorptive distortion, both of which substantiate that dopamine's apparent kinetic diversity is not an adsorption artifact.

  13. Novel impedimetric dopamine biosensor based on boronic acid functional polythiophene modified electrodes.

    Science.gov (United States)

    Dervisevic, Muamer; Senel, Mehmet; Cevik, Emre

    2017-03-01

    In this study we report a new, simple and first impedimetric biosensor based on 3-Thienyl boronic acid for dopamine detection. Biosensor electrode preparation is 1min long by simple electro-polymerization of 3-Thienyl boronic acid and copolymer Thiophene P(TBA0.50Th0.50). Strong interaction between dopamine and thin layer of boronic acid has provided bio-sensing electrode high selectivity and stability, linear range of 7.8 to 125μM, and detection limit of 0.3μM. Characterization and optimization studies were conducted using electrochemical impedance spectroscopy (EIS) and cyclic voltammogram (CV). In order to test reliability of proposed biosensor real sample application study has been conducted using non-diluted human urine and it has been found that biosensor selectivity and recovery is excellent. As well P(TBA0.50Th0.50) based electrode and dopamine interaction has been proven by single frequency impedance measurements. Biosensors acquired good reproducibility, stability, selectivity and very low interference. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Graphene-loaded nanofiber-modified electrodes for the ultrasensitive determination of dopamine

    Energy Technology Data Exchange (ETDEWEB)

    Rodthongkum, Nadnudda, E-mail: Nadnudda.R@chula.ac.th [Metallurgy and Materials Science Research Institute, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Ruecha, Nipapan [Program in Macromolecular Science, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Rangkupan, Ratthapol [Metallurgy and Materials Science Research Institute, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Center of Innovative Nanotechnology, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand); Vachet, Richard W. [Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01002 (United States); Chailapakul, Orawon, E-mail: corawon@chula.ac.th [Electrochemistry and Optical Spectroscopy Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330 (Thailand)

    2013-12-04

    Graphical abstract: -- Highlights: •A novel electrode based on electrospun graphene/polyaniline/polystyrene nanofibers has been developed. •The proposed system provides ultrahigh sensitivity, good selectivity and wide linearity for the determination of dopamine. •This system was successfully applied to determine dopamine in complex biological environment with excellent reproducibility. -- Abstract: A novel and highly sensitive electrochemical system based on electrospun graphene/polyaniline/polystyrene (G/PANI/PS) nanofiber-modified screen-printed carbon electrodes has been developed for dopamine (DA) determination. A dramatic increase (9 times) in the current signal for the redox reaction of a standard, ferri/ferrocyanide [Fe(CN){sub 6}]{sup 3−/4−} couple was found when compared to an unmodified electrode. This modified electrode also exhibited favorable electron transfer kinetics and excellent electrocatalytic activity toward the oxidation of DA. When used together with square wave voltammetry (SWV), DA can be selectively determined in the presence of the common interferents (i.e. ascorbic acid and uric acid). Under optimal conditions, a very low limit of detection (0.05 nM) and limit of quantification (0.30 nM) were achieved for DA. In addition, a wide dynamic range of 0.1 nM to 100 μM was found for this electrode system. Finally, the system can be successfully applied to determine DA in complex biological environment (e.g. human serum, urine) with excellent reproducibility.

  15. A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia.

    Science.gov (United States)

    Boley, Angela M; Perez, Stephanie M; Lodge, Daniel J

    2014-08-01

    Postmortem studies in schizophrenia patients have demonstrated robust alterations in GABAergic markers throughout the neuraxis. It has been suggested that these alterations are restricted to subpopulations of interneurons, such as those containing the calcium binding protein parvalbumin. Indeed, a reduction in parvalbumin expression is a consistent observation in human postmortem studies, as well as, in a wide and diverse variety of animal models. However, it still remains to be determined whether this decrease in parvalbumin expression contributes to, or is a consequence of the disease. Here we utilize lentiviral delivered shRNA and demonstrate that a selective reduction in parvalbumin mRNA expression induces hyperactivity within the ventral hippocampus. In addition, we observe downstream increases in dopamine neuron population activity without changes in average firing rate or percent burst firing. These changes in dopamine neuron activity were associated with an enhanced locomotor response to amphetamine administration. These data therefore demonstrate that a reduction in ventral hippocampal parvalbumin expression is sufficient, in and of itself, to induce an augmented dopamine system function and behavioral hyper-responsivity to amphetamine, implicating a potential key role for parvalbumin in the pathophysiology of schizophrenia.

  16. Dissociable Effects of Serotonin and Dopamine on the Valuation of Harm in Moral Decision Making.

    Science.gov (United States)

    Crockett, Molly J; Siegel, Jenifer Z; Kurth-Nelson, Zeb; Ousdal, Olga T; Story, Giles; Frieband, Carolyn; Grosse-Rueskamp, Johanna M; Dayan, Peter; Dolan, Raymond J

    2015-07-20

    An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy. Past work has highlighted monoaminergic influences on aggression, but a mechanistic account of how monoamines regulate antisocial motives remains elusive. We previously observed that most people show a greater aversion to inflicting pain on others than themselves. Here, we investigated whether this hyperaltruistic disposition is susceptible to monoaminergic control. We observed dissociable effects of the serotonin reuptake inhibitor citalopram and the dopamine precursor levodopa on decisions to inflict pain on oneself and others for financial gain. Computational models of choice behavior showed that citalopram increased harm aversion for both self and others, while levodopa reduced hyperaltruism. The effects of citalopram were stronger than those of levodopa. Crucially, neither drug influenced the physical perception of pain or other components of choice such as motor impulsivity or loss aversion, suggesting a direct and specific influence of serotonin and dopamine on the valuation of harm. We also found evidence for dose dependency of these effects. Finally, the drugs had dissociable effects on response times, with citalopram enhancing behavioral inhibition and levodopa reducing slowing related to being responsible for another's fate. These distinct roles of serotonin and dopamine in modulating moral behavior have implications for potential treatments of social dysfunction that is a common feature as well as a risk factor for many psychiatric disorders.

  17. Role of dopamine agonists in Parkinson's disease: an update.

    Science.gov (United States)

    Bonuccelli, Ubaldo; Pavese, Nicola

    2007-10-01

    At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

  18. Dopamine modulates metabolic rate and temperature sensitivity in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Taro Ueno

    Full Text Available Homeothermal animals, such as mammals, maintain their body temperature by heat generation and heat dissipation, while poikilothermal animals, such as insects, accomplish it by relocating to an environment of their favored temperature. Catecholamines are known to regulate thermogenesis and metabolic rate in mammals, but their roles in other animals are poorly understood. The fruit fly, Drosophila melanogaster, has been used as a model system for the genetic studies of temperature preference behavior. Here, we demonstrate that metabolic rate and temperature sensitivity of some temperature sensitive behaviors are regulated by dopamine in Drosophila. Temperature-sensitive molecules like dTrpA1 and shi(ts induce temperature-dependent behavioral changes, and the temperature at which the changes are induced were lowered in the dopamine transporter-defective mutant, fumin. The mutant also displays a preference for lower temperatures. This thermophobic phenotype was rescued by the genetic recovery of the dopamine transporter in dopamine neurons. Flies fed with a dopamine biosynthesis inhibitor (3-iodo-L-tyrosine, which diminishes dopamine signaling, exhibited preference for a higher temperature. Furthermore, we found that the metabolic rate is up-regulated in the fumin mutant. Taken together, dopamine has functions in the temperature sensitivity of behavioral changes and metabolic rate regulation in Drosophila, as well as its previously reported functions in arousal/sleep regulation.

  19. Noncovalent Interactions between Dopamine and Regular and Defective Graphene.

    Science.gov (United States)

    Fernández, Ana C Rossi; Castellani, Norberto J

    2017-08-05

    The role of noncovalent interactions in the adsorption of biological molecules on graphene is a subject of fundamental interest regarding the use of graphene as a material for sensing and drug delivery. The adsorption of dopamine on regular graphene and graphene with monovacancies (GV) is theoretically studied within the framework of density functional theory. Several adsorption modes are considered, and notably those in which the dopamine molecule is oriented parallel or quasi-parallel to the surface are the more stable. The adsorption of dopamine on graphene implies an attractive interaction of a dispersive nature that competes with Pauli repulsion between the occupied π orbitals of the dopamine ring and the π orbitals of graphene. If dopamine adsorbs at the monovacancy in the A-B stacking mode, a hydrogen bond is produced between one of the dopamine hydroxy groups and one carbon atom around the vacancy. The electronic charge redistribution due to adsorption is consistent with an electronic drift from the graphene or GV surface to the dopamine molecule. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Striatal dopamine release codes uncertainty in pathological gambling.

    Science.gov (United States)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka; Møller, Arne; Doudet, Doris Jeanne; Gjedde, Albert

    2012-10-30

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors.

  1. Good riddance to dopamine: roles for the dopamine transporter in synaptic function and dopamine-associated brain disorders.

    Science.gov (United States)

    Gowrishankar, Raajaram; Hahn, Maureen K; Blakely, Randy D

    2014-07-01

    The neurotransmitter dopamine (DA) plays a critical role in CNS circuits that provide for attention, executive function, reward responses, motivation and movement. DA is inactivated by the cocaine- and amphetamine-sensitive DA transporter (DAT), a protein that also provides a pathway for non-vesicular DA release. After a brief review of DAT function and psychostimulant actions, we consider the importance DAT in relation to the distinct firing patterns of DA neurons that permit awareness of novelty and reward. Finally, we review recent efforts to gather direct support for DAT-linked disorders, with a specific focus on DAT mutations recently identified in subjects with ADHD. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Thinking and doing: the effects of dopamine and oxytocin genes and executive function on mothering behaviours.

    Science.gov (United States)

    Tombeau Cost, K; Unternaehrer, E; Plamondon, A; Steiner, M; Meaney, M; Atkinson, L; Kennedy, J L; Fleming, A S

    2017-02-01

    Animal and human studies suggest that initial expression of maternal behaviour depends on oxytocin and dopamine systems. However, the mechanism by which these systems affect parenting behaviours and the timing of these effects are not well understood. This article explores the role of mothers' executive function in mediating the relation between oxytocin and dopamine gene variants and maternal responsiveness at 48 months post-partum. Participants (n = 157) were mothers recruited in the Maternal Adversity, Vulnerability and Neurodevelopment Study, which assesses longitudinally two cohorts of mothers and children in Canada. We examined single nucleotide polymorphisms (SNPs) related to the dopamine and oxytocin systems (DRD1 rs686, DRD1 rs265976, OXTR rs237885 and OXTR rs2254298), assessed mothers' decision-making at 48 months using the Cambridge Neurological Automated Testing Battery (CANTAB) and evaluated maternal responsiveness from videotaped interactions during the Etch-A-Sketch co-operation task. Mediation analyses showed that OXTR rs2254298 A-carriers had an indirect effect on positive parenting which was mediated by mothers' performance on decision-making task (estimate = 0.115, P Dopamine SNPs were not associated with any measure of executive function or parenting (all P > 0.05). While oxytocin has previously been associated with only the early onset of maternal behaviour, we show that an OXTR polymorphism is involved in maternal behaviour at 48 months post-partum through mothers' executive function. This research highlights the importance of the oxytocin system to maternal parenting beyond infancy. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  3. Impact of five SNPs in dopamine-related genes on executive function.

    Science.gov (United States)

    Mitaki, S; Isomura, M; Maniwa, K; Yamasaki, M; Nagai, A; Nabika, T; Yamaguchi, S

    2013-01-01

    Dopamine neurotransmission is a critical factor for executive function, which is controlled by the prefrontal cortex in humans. Although the contribution of genetic factors to the regulation of brain dopaminergic activity is widely acknowledged, identification of a genotype-phenotype association has not yet been clearly established. In this study, we therefore evaluated the effects of five functional single-nucleotide polymorphisms (SNPs) in specific genes related to dopamine neurotransmission on executive function in a general population. Participants of the health examination at the Shimane Institute of Health Science were recruited for this study (n = 964). To evaluate executive function, the Frontal Assessment Battery (FAB) was administered. SNPs were genotyped using the TaqMan method. A significant association was found between an SNP in the catechol-O-methyltransferase (COMT) gene (rs4680) encoding the low-activity Met allele and FAB score (P = 0.003). Of note, the flexibility subset of the FAB was associated with the SNP in COMT (P = 0.003) after adjustment for confounding factors. The generalized multifactor dimensionality reduction method identified that the combination of two SNPs in the COMT gene (rs4680) and the dopamine D4 receptor gene (rs1800955) had a significant effect on FAB score. Our study indicates a contribution of rs4680 in the COMT gene to the variability in executive function, as assessed by the FAB. In addition, we have indicated that a complex gene-gene interaction between SNPs in the genes related to dopamine neurotransmission may influence executive function in a general population. © 2012 John Wiley & Sons A/S.

  4. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease.

    Science.gov (United States)

    Göttle, Martin; Prudente, Cecilia N; Fu, Rong; Sutcliffe, Diane; Pang, Hong; Cooper, Deborah; Veledar, Emir; Glass, Jonathan D; Gearing, Marla; Visser, Jasper E; Jinnah, H A

    2014-07-01

    Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy. Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS). Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line. These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype. © 2014 American Neurological Association.

  5. Loss of Dopamine Phenotype Among Midbrain Neurons in Lesch–Nyhan Disease

    Science.gov (United States)

    Göttle, Martin; Prudente, Cecilia N.; Fu, Rong; Sutcliffe, Diane; Pang, Hong; Cooper, Deborah; Veledar, Emir; Glass, Jonathan D.; Gearing, Marla; Visser, Jasper E.; Jinnah, H. A.

    2016-01-01

    Objective Lesch–Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy. Methods Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS). Results Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line. Interpretation These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype. PMID:24891139

  6. Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Carreno, Flavia R; Frazer, Alan; Lodge, Daniel J

    2014-07-01

    Vagal nerve stimulation (VNS) is an alternative therapy for epilepsy and treatment refractory depression. Here we examine VNS as a potential therapy for the treatment of schizophrenia in the methylozoxymethanol acetate (MAM) rodent model of the disease. We have previously demonstrated that hyperactivity within ventral regions of the hippocampus (vHipp) drives the dopamine system dysregulation in this model. Moreover, by targeting the vHipp directly, we can reverse aberrant dopamine system function and associated behaviors in the MAM model. Although the central effects of VNS have not been completely delineated, positron emission topographic measurements of cerebral blood flow in humans have consistently reported that VNS stimulation induces bilateral decreases in hippocampal activity. Based on our previous observations, we performed in vivo extracellular electrophysiological recordings in MAM- and saline-treated rats to evaluate the effect of chronic (2 week) VNS treatment on the activity of putative vHipp pyramidal neurons, as well as downstream dopamine neuron activity in the ventral tegmental area. Here we demonstrate that chronic VNS was able to reverse both vHipp hyperactivity and aberrant mesolimbic dopamine neuron function in the MAM model of schizophrenia. Additionally, VNS reversed a behavioral correlate of the positive symptoms of schizophrenia. Because current therapies for schizophrenia are far from adequate, with a large number of patients discontinuing treatment due to low efficacy or intolerable side effects, it is important to explore alternative nonpharmacological treatments. These data provide the first preclinical evidence that VNS may be a possible alternative therapeutic approach for the treatment of schizophrenia.

  7. Methamphetamine Regulation of Firing Activity of Dopamine Neurons.

    Science.gov (United States)

    Lin, Min; Sambo, Danielle; Khoshbouei, Habibeh

    2016-10-05

    Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca(2+) homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca(2+)-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane.

  8. Dopamine does not limit fetal cerebrovascular responses to hypoxia.

    Science.gov (United States)

    Mayock, Dennis E; Bennett, Rachel; Robinson, Roderick D; Gleason, Christine A

    2007-01-01

    Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.

  9. Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia

    Science.gov (United States)

    Nevalainen, Nina; af Bjerkén, Sara; Lundblad, Martin; Gerhardt, Greg A.; Strömberg, Ingrid

    2011-01-01

    L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned L-DOPA naïve, and dopamine-denervated chronically L-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local L-DOPA administration into normal and intact hemisphere of dopamine-lesioned L-DOPA naïve animals significantly increased the potassium-evoked dopamine release. L-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted L-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, while no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local L-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared to those measured in L-DOPA naïve dopamine-denervated striatum. To conclude, L-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, L-DOPA loading does not increase the dopamine release in dyskinetic animals as found in L-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior. PMID:21534956

  10. Impact of disruption of secondary binding site S2 on dopamine transporter function.

    Science.gov (United States)

    Zhen, Juan; Reith, Maarten E A

    2016-09-01

    The structures of the leucine transporter, drosophila dopamine transporter, and human serotonin transporter show a secondary binding site (designated S2 ) for drugs and substrate in the extracellular vestibule toward the membrane exterior in relation to the primary substrate recognition site (S1 ). The present experiments are aimed at disrupting S2 by mutating Asp476 and Ile159 to Ala. Both mutants displayed a profound decrease in [(3) H]DA uptake compared with wild-type associated with a reduced turnover rate kcat . This was not caused by a conformational bias as the mutants responded to Zn(2+) (10 μM) similarly as WT. The dopamine transporters with either the D476A or I159A mutation both displayed a higher Ki for dopamine for the inhibition of [3H](-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane binding than did the WT transporter, in accordance with an allosteric interaction between the S1 and S2 sites. The results provide evidence in favor of a general applicability of the two-site allosteric model of the Javitch/Weinstein group from LeuT to dopamine transporter and possibly other monoamine transporters. X-ray structures of transporters closely related to the dopamine (DA) transporter show a secondary binding site S2 in the extracellular vestibule proximal to the primary binding site S1 which is closely linked to one of the Na(+) binding sites. This work examines the relationship between S2 and S1 sites. We found that S2 site impairment severely reduced DA transport and allosterically reduced S1 site affinity for the cocaine analog [(3) H]CFT. Our results are the first to lend direct support for the application of the two-site allosteric model, advanced for bacterial LeuT, to the human DA transporter. The model states that, after binding of the first DA molecule (DA1 ) to the primary S1 site (along with Na(+) ), binding of a second DA (DA2 ) to the S2 site triggers, through an allosteric interaction, the release of DA1 and Na(+) into the cytoplasm. © 2016

  11. Acrylamide increases dopamine levels by affecting dopamine transport and metabolism related genes in the striatal dopaminergic system.

    Science.gov (United States)

    Pan, Xiaoqi; Guo, Xiongxiong; Xiong, Fei; Cheng, Guihong; Lu, Qing; Yan, Hong

    2015-07-01

    Dopaminergic system dysfunction is proved to be a possible mechanism in acrylamide (ACR) -induced neurotoxicity. The neurotransmitter dopamine (DA) has an increasingly important role in the dopaminergic system. Thus, the goal of this study is to evaluate effects of ACR on dopamine and its metabolite levels, dopamine transport and metabolic gene expression in dopaminergic neurons. Male Sprague-Dawley (SD) rats were dosed orally with ACR at 0 (saline), 20, 30, and 40 mg/kg/day for 20 days. Splayed hind limbs, reduced tail flick time and abnormal gait which preceded other neurologic parameters were observed in the above rats. ACR significantly increased dopamine levels, decreased 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) contents in an area dependent manner in rat striatum. Immunohistochemical staining of the striatum revealed that the number of tyrosine hydroxylase (TH) positive cells significantly increased, while monoamine oxidase (MAO) positive cells were drastically reduced, which was consistent with changes in their mRNA and protein expressions. In addition, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression levels were both down-regulated in the striatum. These results suggest that dopamine levels increase significantly in response to ACR, presumably due to changes in the dopamine transport and metabolism related genes expression in the striatal dopaminergic neurons.

  12. Poly(N-isopropylacrylamide)/poly(dopamine) capsules.

    Science.gov (United States)

    Zhang, Yan; Teo, Boon M; Goldie, Kenneth N; Städler, Brigitte

    2014-05-20

    Polymer capsules are an interesting concept considered in nanobiotechnology. Approaches that facilitate their assembly remain sought after. Poly(dopamine) (PDA) has been considered and successfully applied in this context. We recently demonstrated that PDA could be copolymerized with different types of poly(N-isopropylacrylamide) (pNiPAAm) to assemble mixed films on planar substrates. Herein, we transferred this approach onto colloidal substrates and characterized the film thickness depending on the film composition and template particles size. While the membrane of capsules assembled using 5 μm template particles exhibited strong dependency on the film composition, smaller templates led to capsules with similar membrane thickness. We then compared the permeability of different capsules using fluorescently labeled dextran and fluorescein. We found that the permeability of capsules was heavily dependent on the polymer composition and the template particle size. These fundamental findings contribute to the potential of these capsules, assembled in one-step, for biomedical applications.

  13. Role of Dopamine Signaling in Drug Addiction.

    Science.gov (United States)

    Chen, Wan; Nong, Zhihuan; Li, Yaoxuan; Huang, Jianping; Chen, Chunxia; Huang, Luying

    2017-01-01

    Addiction is a chronic, relapsing disease of the brain that includes drug-induced compulsive seeking behavior and consumption of drugs. Dopamine (DA) is considered to be critical in drug addiction due to reward mechanisms in the midbrain. In this article, we review the major animal models in addictive drug experiments in vivo and in vitro. We discuss the relevance of the structure and pharmacological function of DA receptors. To improve the understanding of the role of DA receptors in reward pathways, specific brain regions, including the Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, and Habenula, are highlighted. These factors contribute to the development of novel therapeutic targets that act at DA receptors. In addiction, the development of neuroimaging method will increase our understanding of the mechanisms underlying drug addiction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Whole organic electronic synapses for dopamine detection

    Science.gov (United States)

    Giordani, Martina; Di Lauro, Michele; Berto, Marcello; Bortolotti, Carlo A.; Vuillaume, Dominique; Gomes, Henrique L.; Zoli, Michele; Biscarini, Fabio

    2016-09-01

    A whole organic artificial synapse has been fabricated by patterning PEDOT:PSS electrodes on PDMS that are biased in frequency to yield a STP response. The timescale of the STP response is shown to be sensitive to the concentration of dopamine, DA, a neurotransmitter relevant for monitoring the development of Parkinson's disease and potential locoregional therapies. The sensitivity of the sensor towards DA has been validated comparing signal variation in the presence of DA and its principal interfering agent, ascorbic acid, AA. The whole organic synapse is biocompatible, soft and flexible, and is attractive for implantable devices aimed to real-time monitoring of DA concentration in bodily fluids. This may open applications in chronic neurodegenerative diseases such as Parkinson's disease.

  15. Dopamine function in Lesch-Nyhan disease.

    Science.gov (United States)

    Nyhan, W L

    2000-01-01

    Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter. PMID:10852837

  16. Dopamine Signaling in reward-related behaviors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun eBaik

    2013-10-01

    Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  17. Prefrontal cortex, dopamine, and jealousy endophenotype.

    Science.gov (United States)

    Marazziti, Donatella; Poletti, Michele; Dell'Osso, Liliana; Baroni, Stefano; Bonuccelli, Ubaldo

    2013-02-01

    Jealousy is a complex emotion characterized by the perception of a threat of loss of something that the person values,particularly in reference to a relationship with a loved one, which includes affective, cognitive, and behavioral components. Neural systems and cognitive processes underlying jealousy are relatively unclear, and only a few neuroimaging studies have investigated them. The current article discusses recent empirical findings on delusional jealousy, which is the most severe form of this feeling, in neurodegenerative diseases. After reviewing empirical findings on neurological and psychiatric disorders with delusional jealousy, and after considering its high prevalence in patients with Parkinson's disease under dopamine agonist treatment, we propose a core neural network and core cognitive processes at the basis of (delusional) jealousy, characterizing this symptom as possible endophenotype. In any case,empirical investigation of the neural bases of jealousy is just beginning, and further studies are strongly needed to elucidate the biological roots of this complex emotion.

  18. Dopamine signaling in reward-related behaviors.

    Science.gov (United States)

    Baik, Ja-Hyun

    2013-01-01

    Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  19. Size-controlled gold nanoparticles obtained from electrodeposited amidoferrocenylpoly(propyleneimine) dendrimer-templates for the electrochemical sensing of dopamine

    Science.gov (United States)

    Villena, Carlos; Bravo, Marta; Alonso, Beatriz; Casado, Carmen M.; Losada, José; García Armada, M. Pilar

    2017-10-01

    Nanometer-scale gold particles exhibit size-dependent electronic properties with important sensing and biosensing applications. In the same way, a lot of analytes show some type of surface-sensitive reaction and the electrode material has a strong influence on the catalytic activity. In this work we study the kinetics and electrochemistry of electrodes with size controlled gold nanoparticles, obtained by electrodeposited amidoferrocenylpoly(propyleneimine) dendrimers of two generations as templates, and the kinetics and the analytical response to the oxidation of dopamine. We demonstrate that the four-types of modified electrodes show good catalytic responses toward the oxidation of dopamine via different processes in relation with the absence or presence of gold nanoparticles and their size. The best response was obtained with the largest nanoparticles, obtained with the first generation dendrimer-template at 0.3 V vs. SCE, with three linear ranges (0-70, 70-600 and 600-1000 μM), with sensitivities 585.7; 466.0 and 314.3 μA/mM cm2, and limit of detection of 0.01 μM. The effect of interfering substances has been studied by differential pulse voltammetry and the developed sensor has been successfully used for the determination of dopamine in a commercial dopamine hydrochloride injection and in spiked Human urine.

  20. Dopamine-mediated reinforcement learning signals in the striatum and ventromedial prefrontal cortex underlie value-based choices.

    Science.gov (United States)

    Jocham, Gerhard; Klein, Tilmann A; Ullsperger, Markus

    2011-02-02

    A large body of evidence exists on the role of dopamine in reinforcement learning. Less is known about how dopamine shapes the relative impact of positive and negative outcomes to guide value-based choices. We combined administration of the dopamine D(2) receptor antagonist amisulpride with functional magnetic resonance imaging in healthy human volunteers. Amisulpride did not affect initial reinforcement learning. However, in a later transfer phase that involved novel choice situations requiring decisions between two symbols based on their previously learned values, amisulpride improved participants' ability to select the better of two highly rewarding options, while it had no effect on choices between two very poor options. During the learning phase, activity in the striatum encoded a reward prediction error. In the transfer phase, in the absence of any outcome, ventromedial prefrontal cortex (vmPFC) continually tracked the learned value of the available options on each trial. Both striatal prediction error coding and tracking of learned value in the vmPFC were predictive of subjects' choice performance in the transfer phase, and both were enhanced under amisulpride. These findings show that dopamine-dependent mechanisms enhance reinforcement learning signals in the striatum and sharpen representations of associative values in prefrontal cortex that are used to guide reinforcement-based decisions.

  1. Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease.

    Science.gov (United States)

    Richardson, Jason R; Caudle, W Michael; Wang, Minzheng; Dean, E Danielle; Pennell, Kurt D; Miller, Gary W

    2006-08-01

    Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.

  2. Preparation and characterization of the dopamine film electrochemically deposited on a gold template and its applications for dopamine sensing in aqueous solution

    Energy Technology Data Exchange (ETDEWEB)

    Luczak, Teresa [Department of Physical Chemistry, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, PL-60-780 Poznan (Poland)

    2008-08-01

    A dopamine polymer film was electrogenerated on the bare gold template from a 5 x 10{sup -3} M dopamine solution in phosphate buffer at pH 7 and next subjected to overoxidation in 0.1 M sodium hydroxide solution. The overoxidized dopamine polymer film obtained shows good permeability to cationic species and was used for quantitative determination of dopamine. A linear relationship between dopamine concentration and current response was obtained in the range of 1 x 10{sup -6} M to 6 x 10{sup -4} M with the detection limit 2 x 10{sup -7} M. The results have shown that using the overoxidized dopamine film it is possible to perform electrochemical analysis of dopamine without interference of ascorbic and uric acids, which is the major limitation in dopamine determination. The modified electrode shows good selectivity, sensitivity, reproducibility and high stability. (author)

  3. Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD

    Directory of Open Access Journals (Sweden)

    Jason C Lee

    2016-09-01

    Full Text Available It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD. What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a stuck accelerator. Interestingly, increasing evidence demonstrates that dopamine (DA – traditionally known for its role in motivation, reward prediction, and addiction– is also crucial in regulating fear learning and anxiety. Yet how DA neurons control stress resilience is unclear, especially given that DA neurons have multiple subtypes with distinct temporal dynamics. Here, we propose the Rebound-Excitation Theory, which posits that DA neurons’ rebound-excitation at the termination of fearful experiences serves as an important brake by providing intrinsic safety-signals to fear-processing neural circuits in a spatially and temporally controlled manner. We discuss how DA neuron rebound-excitation may be regulated by genetics and experiences, and how such physiological properties may be used as a brain-activity biomarker to predict and confer individual resilience to stress and anxiety.

  4. Molecular profiling of midbrain dopamine regions in cocaine overdose victims

    National Research Council Canada - National Science Library

    Tang, Wen‐Xue; Fasulo, Wendy H; Mash, Deborah C; Hemby, Scott E

    2003-01-01

    .... To evaluate whether the alterations in gene expression in cocaine overdose victims are associated with specific dopamine populations in the midbrain, cDNA arrays and western blotting were used...

  5. Interaction of size-selected gold nanoclusters with dopamine

    Science.gov (United States)

    Montone, Georgia R.; Hermann, Eric; Kandalam, Anil K.

    2016-12-01

    We present density functional theory based results on the interaction of size-selected gold nanoclusters, Au10 and Au20, with dopamine molecule. The gold clusters interact strongly with the nitrogen site of dopamine, thereby forming stable gold-dopamine complexes. Our calculations further show that there is no site specificity on the planar Au10 cluster with all the edge gold atoms equally preferred. On the other hand, in the pyramidal Au20 cluster, the vertex metal atom is the most active site. As the size increased from Au10 to Au20, the interaction strength has shown a declining trend. The effect of aqueous environment on the interaction strengths were also studied by solvation model. It is found that the presence of solvent water stabilizes the interaction between the metal cluster and dopamine molecule, even though for Au10 cluster the energy ordering of the isomers changed from that of the gas-phase.

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

    DEFF Research Database (Denmark)

    Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa

    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......-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...

  7. Queen Pheromone Modulates Brain Dopamine Function in Worker Honey Bees

    National Research Council Canada - National Science Library

    Kyle T. Beggs; Kelly A. Glendining; Nicola M. Marechal; Vanina Vergoz; Ikumi Nakamura; Keith N. Slessor; Alison R. Mercer

    2007-01-01

    .... But how does this pheromone operate at the cellular level? This study reveals that QMP has profound effects on dopamine pathways in the brain, pathways that play a central role in behavioral regulation and motor control...

  8. Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement.

    Science.gov (United States)

    Cumper, Samantha K; Ahle, Gabriella M; Liebman, Lauren S; Kellner, Charles H

    2014-06-01

    In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD.

  9. The dopamine hypothesis of drug addiction and its potential therapeutic value.

    Directory of Open Access Journals (Sweden)

    Marco eDiana

    2011-11-01

    Full Text Available Dopamine (DA transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid and other drug-dependent rats. Further, DA release in the Nacc is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the Medium Spiny Neuron (MSN of the Nucleus accumbens (Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin and alcohol-dependent subjects, thereby offering visual proof of the ‘dopamine-impoverished’ addicted human brain.The reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse and drug-seeking/taking. In theory, it may be achieved pharmacologically and/or with novel interventions such as Transcranial Magnetic Stimulation (TMS. Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

  10. Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-i