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Sample records for downregulates dopamine synthesis

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

    SciTech Connect

    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.

  2. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model

    PubMed Central

    Best, Janet A; Nijhout, H Frederik; Reed, Michael C

    2009-01-01

    Background Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine [1]. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake. Methods We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings. Results We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed half-lives of extracellular

  3. Relationship of striatal dopamine synthesis capacity to age and cognition.

    PubMed

    Braskie, Meredith N; Wilcox, Claire E; Landau, Susan M; O'Neil, James P; Baker, Suzanne L; Madison, Cindee M; Kluth, Jennifer T; Jagust, William J

    2008-12-24

    Past research has demonstrated that performance on frontal lobe-dependent tasks is associated with dopamine system integrity and that various dopamine system deficits occur with aging. The positron emission tomography (PET) radiotracer 6-[(18)F]fluoro-l-m-tyrosine (FMT) is a substrate of the dopamine-synthesizing enzyme, aromatic amino acid decarboxylase (AADC). Studies using 6-[(18)F]fluorodopa (FDOPA) (another AADC substrate) to measure how striatal PET signal and age relate have had inconsistent outcomes. The varying results occur in part from tracer processing that renders FDOPA signal subject to aspects of postrelease metabolism, which may themselves change with aging. In contrast, FMT remains a purer measure of AADC function. We used partial volume-corrected FMT PET scans to measure age-related striatal dopamine synthesis capacity in 21 older (mean, 66.9) and 16 younger (mean, 22.8) healthy adults. We also investigated how striatal FMT signal related to a cognitive measure of frontal lobe function. Older adults showed significantly greater striatal FMT signal than younger adults. Within the older group, FMT signal in dorsal caudate (DCA) and dorsal putamen was greater with age, suggesting compensation for deficits elsewhere in the dopamine system. In younger adults, FMT signal in DCA was lower with age, likely related to ongoing developmental processes. Younger adults who performed worse on tests of frontal lobe function showed greater FMT signal in right DCA, independent of age effects. Our data suggest that higher striatal FMT signal represents nonoptimal dopamine processing. They further support a relationship between striatal dopamine processing and frontal lobe cognitive function.

  4. Synthesis and in vitro studies on a potential dopamine prodrug.

    PubMed

    Giannola, L I; De Caro, V; Giandalia, G; Siragusa, M G; Lamartina, L

    2008-10-01

    Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is described. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log Papp (0.76) indicated that the physico-chemical characteristics of compound 7 are adequate to cross biological membranes. Compound 7 was enzymatically cleaved to free dopamine in rat brain homogenate (t1/2 = 460 min). In human plasma, the t1/2 of 7 was estimated comparable to that reported for L-DOPA. In view of a possible oral administration of 7, studies of its chemical behavior under conditions simulating those of the gastrointestinal tract showed that no dopamine production occurred; furthermore, 7 is able to permeate through a simulated intestinal mucosal membrane. The collected data suggest that compound 7 could beconsidered a very valuable candidate for subsequent in vivo evaluation.

  5. Autoregulation of dopamine synthesis in subregions of the rat nucleus accumbens.

    PubMed

    Heidbreder, C A; Baumann, M H

    2001-01-05

    The discovery of a core-shell dichotomy within the nucleus accumbens has opened new lines of investigation into the neuronal basis of psychiatric disorders and drug dependence. In the present study, the autoregulation of dopamine synthesis in subdivisions of the rat nucleus accumbens was examined. We measured the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) after the inhibition of aromatic L-amino acid decarboxylase with 3-hydroxylbenzylhydrazine (NSD-1015, 100 mg kg(-1)) as an in vivo index of dopamine synthesis. The effect of the dopamine D(1)/D(2) receptor agonist apomorphine (0, 20, 100, 500 microgram kg(-1)) and the dopamine D(2)/D(3) receptor agonist quinpirole (0, 20, 100, 500 microgram kg(-1)) on dopamine synthesis was determined in the dorsolateral core, ventromedial shell, and rostral pole of the nucleus accumbens. DOPA accumulation was also measured in the frontal cortex, olfactory tubercle, and caudate nucleus of the same rats for comparative purposes. The results show that the three sectors of the nucleus accumbens had similar basal levels of DOPA. Both apomorphine and quinpirole produced a decrease in the dopamine synthesis rate in all brain regions examined. In general, the dopamine D(2)/D(3) receptor agonist quinpirole produced a significantly greater decrease in DOPA accumulation than the dopamine D(1)/D(2) receptor agonist apomorphine. Within the nucleus accumbens, we found no core-shell differences in the agonist-induced suppression of dopamine synthesis, but the rostral pole was less sensitive to the highest dose of both dopamine agonists. These results suggest that differences in dopamine function between the core and shell might not involve region-specific differences in the receptor-mediated autoregulation of dopamine neurotransmission. Moreover, the blunted effect of dopamine agonists in the rostral pole illustrates that this region of the accumbens is functionally distinct, possibly due to a lower dopamine receptor reserve when

  6. Azepino- and diazepinoindoles: synthesis and dopamine receptor binding profiles.

    PubMed

    Kraxner, J; Hübner, H; Gmeiner, P

    2000-09-01

    Starting from the readily available building blocks 7, 10, 11, and 15, the synthesis of the fused indoles 1, 2, 5, and 6, respectively, is reported. The syntheses involved Pictet-Spengler cyclizations, Michael addition reactions, lactamization, directed metallation, and reductive amination as the key reaction steps. Radioligand displacement studies comprising the dopamine receptor subtypes D1, D2long D2short, D3, and D4.4 were performed when the diazepinoindole 6 revealed D1 and D4 affinities (Ki = 0.11 microM and 1.7 microM, respectively) which are comparable to the partial D1 agonist SKF 38393 (3b). In contrast to the benzazepine 3b, the indole based test compounds turned out less selective over the D2 and D3 receptor subtype.

  7. Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits.

    PubMed

    Hitora-Imamura, Natsuko; Miura, Yuki; Teshirogi, Chie; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

    2015-07-30

    Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders.

  8. Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits

    PubMed Central

    Hitora-Imamura, Natsuko; Miura, Yuki; Teshirogi, Chie; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

    2015-01-01

    Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders. DOI: http://dx.doi.org/10.7554/eLife.08274.001 PMID:26226637

  9. In vivo downregulation of protein synthesis in the snail Helix apersa during estivation.

    PubMed

    Pakay, Julian L; Withers, Philip C; Hobbs, Andrew A; Guppy, Michael

    2002-07-01

    Protein synthesis is downregulated during metabolic depression in a number of systems where the metabolic depression is effected by obvious extrinsic cues. The metabolic depression of the estivating land snail Helix apersa occurs in the absence of any obvious physiological stress and has an intrinsic component independent of temperature, pH, O(2) status, or osmolality. We show that this metabolic depression is accompanied by a downregulation of protein synthesis in vivo. The rate of protein synthesis decreases in two major tissues during estivation: to 23% and 53% of the awake rate in hepatopancreas and foot muscle, respectively. We show from calculations of the theoretical contribution of protein synthesis to total O(2) consumption that the depression of protein synthesis must be a significant, obligate, in vivo component of metabolic depression in H. aspersa.

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

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

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

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

    SciTech Connect

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

    2010-09-15

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

  12. Ventral striatal prediction error signaling is associated with dopamine synthesis capacity and fluid intelligence.

    PubMed

    Schlagenhauf, Florian; Rapp, Michael A; Huys, Quentin J M; Beck, Anne; Wüstenberg, Torsten; Deserno, Lorenz; Buchholz, Hans-Georg; Kalbitzer, Jan; Buchert, Ralph; Bauer, Michael; Kienast, Thorsten; Cumming, Paul; Plotkin, Michail; Kumakura, Yoshitaka; Grace, Anthony A; Dolan, Raymond J; Heinz, Andreas

    2013-06-01

    Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a sample of 28 healthy male adults using multimodal imaging and biological parametric mapping with (1) functional magnetic resonance imaging during a reversal learning task and (2) in a subsample of 17 subjects also with positron emission tomography using 6-[(18) F]fluoro-L-DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA K inapp). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that individual differences in the capacity for flexible problem solving relate to ventral striatal activation during reward-related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity.

  13. Sonochemical synthesis of Ag nanoclusters: electrogenerated chemiluminescence determination of dopamine.

    PubMed

    Liu, Tao; Zhang, Lichun; Song, Hongjie; Wang, Zhonghui; Lv, Yi

    2013-01-01

    We report a facile one-pot sonochemical approach to preparing highly water-soluble Ag nanoclusters (NCs) using bovine serum albumin as a stabilizing agent and reducing agent in aqueous solution. Intensive electrogenerated chemiluminescence (ECL) was observed from the as-prepared Ag (NCs) and successfully applied for the ECL detection of dopamine with high sensitivity and a wide detection range. A possible ECL mechanism is proposed for the preparation of Ag NCs. With this method, the dopamine concentration was determined in the range of 8.3 × 10(-9) to 8.3 × 10(-7) mol/L without the obvious interference of uric acid, ascorbic acid and some other neurotransmitters, such as serotonin, epinephrine and norepinephrine, and the detection limit was 9.2 × 10(-10) mol/L at a signal/noise ratio of 3.

  14. A potential benefit of albinism in Astyanax cavefish: downregulation of the oca2 gene increases tyrosine and catecholamine levels as an alternative to melanin synthesis.

    PubMed

    Bilandžija, Helena; Ma, Li; Parkhurst, Amy; Jeffery, William R

    2013-01-01

    Albinism, the loss of melanin pigmentation, has evolved in a diverse variety of cave animals but the responsible evolutionary mechanisms are unknown. In Astyanax mexicanus, which has a pigmented surface dwelling form (surface fish) and several albino cave-dwelling forms (cavefish), albinism is caused by loss of function mutations in the oca2 gene, which operates during the first step of the melanin synthesis pathway. In addition to albinism, cavefish have evolved differences in behavior, including feeding and sleep, which are under the control of the catecholamine system. The catecholamine and melanin synthesis pathways diverge after beginning with the same substrate, L-tyrosine. Here we describe a novel relationship between the catecholamine and melanin synthesis pathways in Astyanax. Our results show significant increases in L-tyrosine, dopamine, and norepinephrine in pre-feeding larvae and adult brains of Pachón cavefish relative to surface fish. In addition, norepinephrine is elevated in cavefish adult kidneys, which contain the teleost homologs of catecholamine synthesizing adrenal cells. We further show that the oca2 gene is expressed during surface fish development but is downregulated in cavefish embryos. A key finding is that knockdown of oca2 expression in surface fish embryos delays the development of pigmented melanophores and simultaneously increases L-tyrosine and dopamine. We conclude that a potential evolutionary benefit of albinism in Astyanax cavefish may be to provide surplus L-tyrosine as a precursor for the elevated catecholamine synthesis pathway, which could be important for adaptation to the challenging cave environment.

  15. Dipeptides Inhibit Melanin Synthesis in Mel-Ab Cells through Down-Regulation of Tyrosinase

    PubMed Central

    Lee, Hyun-e; Kim, Eun-Hyun; Choi, Hye-Ryung; Sohn, Uy Dong; Yun, Hye-Young; Baek, Kwang Jin; Kwon, Nyoun Soo; Park, Kyoung-Chan

    2012-01-01

    This study investigated the effects of proline-serine (PS) and valine-serine (VS) dipeptides on melanogenesis in Mel-Ab cells. Proline-serine and VS significantly inhibited melanin synthesis in a concentration-dependent manner, though neither dipeptide directly inhibited tyrosinase activity in a cell-free system. Both PS and VS down-regulated the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. In a follow-up study also described here, the effects of these dipeptides on melanogenesis-related signal transduction were quantified. Specifically, PS and VS induced ERK phosphorylation, though they had no effect on phosphorylation of the cAMP response element binding protein (CREB). These data suggest that PS and VS inhibit melanogenesis through ERK phosphorylation and subsequent down-regulation of MITF and tyrosinase. Properties of these dipeptides are compatible with application as skin-whitening agents. PMID:22915995

  16. Triiodothyronine (T3) inhibits hyaluronate synthesis in a human dermal equivalent by downregulation of HAS2.

    PubMed

    Pouyani, Tara; Sadaka, Basma H; Papp, Suzanne; Schaffer, Lana

    2013-03-01

    Triiodothyronine (T3) is a thyroid hormone that can have varying effects on skin. In order to assess the effects of T3 on the human dermis, we prepared dermal equivalents using neonatal dermal cells via the process of self-assembly in the presence of differing concentrations of T3. These dermal equivalents were prepared in the absence of serum and a three dimensional matrix allowing for the direct assessment of different concentrations of T3 on dermal extracellular matrix formation. Three different concentrations of T3 were chosen, 20 pM, which is part of the base medium, 0.2 nM T3 and 2 nM T3. We find that self-assembled dermal equivalents formed under these conditions show a progressive "thinning" with increasing T3 concentrations. While we observed no change in total collagen content, inhibition of hyaluronate (HA) synthesis was observed in the 0.2- and 2-nM T3 constructs as compared to the 20-pM construct. Other glycosaminoglycan synthesis was not affected by increasing T3 concentrations. In order to identify the gene(s) responsible for inhibition of HA synthesis in the 2-nM T3 dermal equivalent, we conducted a differential gene array analysis. The results of these experiments demonstrate the differential expression of 40 genes, of these, 34 were upregulated and 6 genes were downregulated. The results from these experiments suggest that downregulation of HAS2 may be responsible for inhibition of hyaluronate synthesis in the self-assembled 2-nM T3 human dermal matrix.

  17. Zeolitic imidazolate framework-8 (ZIF-8) as a sacrificial template: one-pot synthesis of hollow poly(dopamine) nanocapsules and yolk-structured poly(dopamine) nanocomposites

    NASA Astrophysics Data System (ADS)

    Ran, Jingyu; Xiao, Lihua; Wu, Weidang; Liu, Yike; Qiu, Wei; Wu, Jianming

    2017-02-01

    Hollow poly(dopamine) (PDA) nanocapsules and yolk-structured PDA nanocomposites were prepared by an aqueous one-pot synthesis method utilizing zeolitic imidazolate framework-8 (ZIF-8) nanocrystals as a sacrificial template without any special etchant. The resulting PDA nanocapsules show negligible cytotoxicity in HeLa cells after incubation for 48 h at various doses, which implies their potential as candidates for practical applications in drug transport and targeting.

  18. Zeolitic imidazolate framework-8 (ZIF-8) as a sacrificial template: one-pot synthesis of hollow poly(dopamine) nanocapsules and yolk-structured poly(dopamine) nanocomposites.

    PubMed

    Ran, Jingyu; Xiao, Lihua; Wu, Weidang; Liu, Yike; Qiu, Wei; Wu, Jianming

    2017-02-03

    Hollow poly(dopamine) (PDA) nanocapsules and yolk-structured PDA nanocomposites were prepared by an aqueous one-pot synthesis method utilizing zeolitic imidazolate framework-8 (ZIF-8) nanocrystals as a sacrificial template without any special etchant. The resulting PDA nanocapsules show negligible cytotoxicity in HeLa cells after incubation for 48 h at various doses, which implies their potential as candidates for practical applications in drug transport and targeting.

  19. Downregulation of de Novo Fatty Acid Synthesis in Subcutaneous Adipose Tissue of Moderately Obese Women.

    PubMed

    Guiu-Jurado, Esther; Auguet, Teresa; Berlanga, Alba; Aragonès, Gemma; Aguilar, Carmen; Sabench, Fàtima; Armengol, Sandra; Porras, José Antonio; Martí, Andreu; Jorba, Rosa; Hernández, Mercè; del Castillo, Daniel; Richart, Cristóbal

    2015-12-16

    The purpose of this work was to evaluate the expression of fatty acid metabolism-related genes in human adipose tissue from moderately obese women. We used qRT-PCR and Western Blot to analyze visceral (VAT) and subcutaneous (SAT) adipose tissue mRNA expression involved in de novo fatty acid synthesis (ACC1, FAS), fatty acid oxidation (PPARα, PPARδ) and inflammation (IL6, TNFα), in normal weight control women (BMI < 25 kg/m², n = 35) and moderately obese women (BMI 30-38 kg/m², n = 55). In SAT, ACC1, FAS and PPARα mRNA expression were significantly decreased in moderately obese women compared to controls. The downregulation reported in SAT was more pronounced when BMI increased. In VAT, lipogenic-related genes and PPARα were similar in both groups. Only PPARδ gene expression was significantly increased in moderately obese women. As far as inflammation is concerned, TNFα and IL6 were significantly increased in moderate obesity in both tissues. Our results indicate that there is a progressive downregulation in lipogenesis in SAT as BMI increases, which suggests that SAT decreases the synthesis of fatty acid de novo during the development of obesity, whereas in VAT lipogenesis remains active regardless of the degree of obesity.

  20. Regulation of dopamine synthesis and release in striatal and prefrontal cortical brain slices

    SciTech Connect

    Wolf, M.E.

    1986-01-01

    Brain slices were used to investigate the role of nerve terminal autoreceptors in modulating dopamine (DA) synthesis and release in striatum and prefrontal cortex. Accumulation of dihydroxyphenylalanine (DOPA) was used as an index of tyrosine hydroxylation in vitro. Nomifensine, a DA uptake blocker, inhibited DOPA synthesis in striatal but not prefrontal slices. This effect was reversed by the DA antagonist sulpiride, suggesting it involved activation of DA receptors by elevated synaptic levels of DA. The autoreceptor-selective agonist EMD-23-448 also inhibited striatal but not prefrontal DOPA synthesis. DOPA synthesis was stimulated in both brain regions by elevated K/sup +/, however only striatal synthesis could be further enhanced by sulpiride. DA release was measured by following the efflux of radioactivity from brain slices prelabeled with (/sup 3/H)-DA. EMD-23-448 and apomorphine inhibited, while sulpiride enhanced, the K/sup +/-evoked overflow of radioactivity from both striatal and prefrontal cortical slices. These findings suggest that striatal DA nerve terminals possess autoreceptors which modulate tyrosine hydroxylation as well as autoreceptors which modulate release. Alternatively, one site may be coupled to both functions through distinct transduction mechanisms. In contrast, autoreceptors on prefrontal cortical terminals appear to regulate DA release but not DA synthesis.

  1. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

    PubMed Central

    Harkitis, P.; Lang, M. A.; Marselos, M.; Fotopoulos, A.; Albucharali, G.; Konstandi, M.

    2015-01-01

    Dopaminergic systems regulate the release of several hormones including growth hormone (GH), thyroid hormones, insulin, glucocorticoids and prolactin (PRL) that play significant roles in the regulation of various Cytochrome P450 (CYP) enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR) and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90) and AhR nuclear translocator (ARNT) was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens. PMID:26466350

  2. Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

    PubMed Central

    Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L

    2014-01-01

    Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors. DOI: http://dx.doi.org/10.7554/eLife.01936.001 PMID:24843012

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

    PubMed

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

    2016-07-01

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

  4. Royal jelly reduces melanin synthesis through down-regulation of tyrosinase expression.

    PubMed

    Han, Sang Mi; Yeo, Joo Hong; Cho, Yoon Hee; Pak, Sok Cheon

    2011-01-01

    For cosmetic reasons, the demand for effective and safe skin-whitening agents is high. Since the key enzyme in the melanin synthetic pathway is tyrosinase, many depigmenting agents in the treatment of hyperpigmentation act as tyrosinase inhibitors. In this study, we have investigated the hypo-pigmentary mechanism of royal jelly in a mouse melanocyte cell line, B16F1. Treatment of B16F1 cells with royal jelly markedly inhibited melanin biosynthesis in a dose-dependent manner. Decreased melanin content occurred through the decrease of tyrosinase activity. The mRNA levels of tyrosinase were also reduced by royal jelly. These results suggest that royal jelly reduces melanin synthesis by down-regulation of tyrosinase mRNA transcription and serves as a new candidate in the design of new skin-whitening or therapeutic agents.

  5. Additional nitrogen fertilization at heading time of rice down-regulates cellulose synthesis in seed endosperm.

    PubMed

    Midorikawa, Keiko; Kuroda, Masaharu; Terauchi, Kaede; Hoshi, Masako; Ikenaga, Sachiko; Ishimaru, Yoshiro; Abe, Keiko; Asakura, Tomiko

    2014-01-01

    The balance between carbon and nitrogen is a key determinant of seed storage components, and thus, is of great importance to rice and other seed-based food crops. To clarify the influence of the rhizosphere carbon/nitrogen balance during the maturation stage of several seed components, transcriptome analysis was performed on the seeds from rice plants that were provided additional nitrogen fertilization at heading time. As a result, it was assessed that genes associated with molecular processes such as photosynthesis, trehalose metabolism, carbon fixation, amino acid metabolism, and cell wall metabolism were differentially expressed. Moreover, cellulose and sucrose synthases, which are involved in cellulose synthesis, were down-regulated. Therefore, we compared cellulose content of mature seeds that were treated with additional nitrogen fertilization with those from control plants using calcofluor staining. In these experiments, cellulose content in endosperm from plants receiving additional nitrogen fertilization was less than that in control endosperm. Other starch synthesis-related genes such as starch synthase 1, starch phosphorylase 2, and branching enzyme 3 were also down-regulated, whereas some α-amylase and β-amylase genes were up-regulated. On the other hand, mRNA expression of amino acid biosynthesis-related molecules was up-regulated. Moreover, additional nitrogen fertilization caused accumulation of storage proteins and up-regulated Cys-poor prolamin mRNA expression. These data suggest that additional nitrogen fertilization at heading time changes the expression of some storage substance-related genes and reduces cellulose levels in endosperm.

  6. Effects of dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on GDNF, NGF, and BDNF synthesis in cultured mouse astrocytes.

    PubMed

    Ohta, Kiyoe; Kuno, Sadako; Mizuta, Ikuko; Fujinami, Aya; Matsui, Hidehito; Ohta, Mitsuhiro

    2003-06-20

    We examined the stimulatory effects of the dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on the synthesis and secretion of neurotrophic factors (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; and glial cell line-derived neurotrophic factor, GDNF) in cultured mouse astrocytes, and clarified the role of dopamine D1 and D2 receptors in these effects. Bromocriptine, a D2 agonist, elevated NGF levels in the culture medium 6.8-fold vs. control, and significantly decreased GDNF and BDNF levels, at 24 h. Both pergolide, a D1/D2 agonist, and cabergoline, a D2/weak D1 agonist, rapidly elevated NGF and GDNF levels at 4-6 h, respectively to 21- and 1.5-fold, respectively, and 84- and 9-fold, respectively, of control levels at 24 h. SKF-38393, a D1 agonist, elevated NGF and GDNF levels to 20- and 2.8-fold of controls, respectively, at 24 h. Relative levels of NGF and GDNF mRNA detected by Northern blot analysis or semiquantitative reverse transcriptase-polymerase chain reaction confirmed that increases in levels of the 2 proteins in culture medium were due to overexpression as opposed to leakage from cells. Cabergoline rapidly increased GDNF mRNA expression at 4 h, producing a potent and long-lasting increase in GDNF levels. Bromocriptine significantly suppressed GDNF synthesis. These findings suggest that stimulation of dopamine D1 receptors may be required for GDNF synthesis and secretion, and that concurrent stimulation of dopamine D1 and D2 receptors may augment synthesis and secretion of NGF and GDNF. These dopamine agonists may play a role in neuronal survival by stimulating NGF and GDNF synthesis in the brain, and as drugs are good candidates as NGF and GDNF inducers.

  7. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.

    PubMed

    González, Sergio; Moreno-Delgado, David; Moreno, Estefanía; Pérez-Capote, Kamil; Franco, Rafael; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ortiz, Jordi; Ferré, Sergi; Canela, Enric; McCormick, Peter J

    2012-01-01

    The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D₄ receptors. Through α(₁B)-D₄ and β₁-D₄ receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D₄ was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D₄ receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs.

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

    PubMed

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

    2015-07-15

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

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

    NASA Astrophysics Data System (ADS)

    Chen, Zhengming; Yang, Ji; Skolnick, Phil

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

  10. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

    PubMed Central

    Witt, Jonathan O.; McCollum, Andrea L.; Hurtado, Miguel A.; Huseman, Eric D.; Jeffries, Daniel E.; Temple, Kayla J.; Plumley, Hyekyung C.; Blobaum, Anna L.; Lindsley, Craig W.; Hopkins, Corey R.

    2017-01-01

    Herein, we report the synthesis and structure–activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl) oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1 µM against D1, D2L, D2S, D3, and D5). PMID:27080176

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

    PubMed Central

    Lawrence, Andrew D.; Brooks, David J.

    2014-01-01

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

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

    SciTech Connect

    Ares, J.J.

    1986-01-01

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

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

    PubMed Central

    Hanna, Marley E.; Bednár̂ová, Andrea; Rakshit, Kuntol; Chaudhuri, Anathbandhu; O’Donnell, Janis M.; Krishnan, Natraj

    2015-01-01

    The impact of mutations in four essential genes involved in dopamine (DA) synthesis and transport on longevity, motor behavior, and resistance to oxidative stress was monitored in Drosophila melanogaster. The fly lines used for this study were: (i) a loss of function mutation in Catecholamines up (Catsup26), which is a negative regulator of the rate limiting enzyme for DA synthesis, (ii) a mutant for the gene pale (ple2) that encodes for the rate limiting enzyme tyrosine hydroxylase (TH), (iii) a mutant for the gene Punch (PuZ22) that encodes guanosine triphosphate cyclohydrolase, required for TH activity, and (iv) a mutant in the vesicular monoamine transporter (VMATΔ14), which is required for packaging of DA as vesicles inside DA neurons. Median lifespans of ple2, PuZ22 and VMATΔ14 mutants were significantly decreased compared to Catsup26 and wild type controls that did not significantly differ between each other. Catsup26 flies survived longer when exposed to hydrogen peroxide (80 μM) or paraquat (10 mM) compared to ple2, PuZ22 or VMATΔ14 and controls. These flies also exhibited significantly higher negative geotaxis activity compared to ple2, PuZ22, VMATΔ14 and controls. All mutant flies demonstrated rhythmic circadian locomotor activity in general, albeit Catsup26 and VMATΔ14 flies had slightly weaker rhythms. Expression analysis of some key antioxidant genes revealed that glutathione S-transferase Omega-1 (GSTO1) expression was significantly up-regulated in all DA synthesis pathway mutants and especially in Catsup26 and VMATΔ14 flies at both mRNA and protein levels. Taken together, we hypothesize that DA could directly influence GSTO1 transcription and thus play a significant role in the regulation of response to oxidative stress. Additionally, perturbations in DA synthesis do not appear to have a significant impact on circadian locomotor activity rhythms per se, but do have an influence on general locomotor activity levels. PMID:25585352

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

    SciTech Connect

    Onali, P.; Olianas, M.C.

    1987-03-23

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

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

    PubMed Central

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

    2012-01-01

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

  16. Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle.

    PubMed Central

    Commissiong, J. W.; Slimovitch, C.; Toffano, G.

    1990-01-01

    1. After physical (knife-cut) or chemically-mediated (tetrodotoxin 300 nM, 1.5 microliters; 1.0 microliters min-1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post-transection, at which time 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 +/- 13 vs 80 +/- 17 nmol g-1; HVA: 6.66 +/- 3.57 vs 54 +/- 18 nmol g-1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side. 2. In both experimental situations, haloperidol (1.0 mg kg-1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract. 3. Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to less than 5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected L-DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA-treated rats, haloperidol (1.0 mg kg-1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2361171

  17. One-step synthesis of boronic acid functionalized gold nanoclusters for photoluminescence sensing of dopamine

    NASA Astrophysics Data System (ADS)

    Chen, Huide; Liu, Chunxiu; Xia, Yunsheng

    2017-03-01

    This study is the first to report one-step synthesis of boronic acid functionalized gold nanoclusters (AuNCs) using mixed ligands of 4-mercaptophenylboronic acid (MPBA) and glutathione. Furthermore, the emission color of the products can be fancily tuned from green to near-infrared by simply changing the proportion of the two stabilizers. In basic media, dopamine (DA) molecules themselves polymerize each other and form polydopamine with large amounts of cis-diol groups, which then react with boronic acid groups on the AuNC’s surface based on the formation of boronate esters. As a result, the photoluminescence of the AuNCs is well quenched by the electron transfer effect. Accordingly, DA molecules are assayed from 0.5 to 9 μM, and the detection limit is as low as 0.1 μM. The as-prepared AuNCs exhibit high selectivity; the existing biomolecules including various amino acids, ascorbic acid, uric acid, glucose, etc, do not interfere with the assay. The proposed method is successfully applied to the assay of DA in human serum, indicating its practical potential.

  18. 2beta-Substituted analogues of 4'-iodococaine: synthesis and dopamine transporter binding potencies.

    PubMed

    Avor, K S; Singh, S; Seale, T W; Pouw, B; Basmadjian, G P

    1998-06-18

    A series of 2beta-substituted analogues of 4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2beta-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenylphosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The binding affinity of 4'-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4'-iodococaine (3). Hydroxylation of 8 at the 2'-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.

  19. The human testis determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism

    PubMed Central

    Czech, Daniel P.; Lee, Joohyung; Sim, Helena; Parish, Clare L.; Vilain, Eric; Harley, Vincent R.

    2012-01-01

    The male sex is determined by the sex determining region on the Y chromosome (SRY) transcription factor. The unexpected action of SRY in the control of voluntary movement in male rodents suggests a role in regulation of dopamine transmission and dopamine-related disorders with sex bias such as Parkinson’s disease. We investigated SRY expression in the human brain and function in vitro. SRY immunoreactivity was detected in the human male, but not female, substantia nigra pars compacta (SNc) within a sub-population of tyrosine hydroxylase (TH) positive neurons. SRY protein also co-localised with TH positive neurons in the ventral tegmental area and GAD-positive neurons in the substantia nigra pars reticulate (SNr). Retinoic acid-induced differentiation of precursor NT2 cells into dopaminergic cells (NT2N) increased expression of TH, NURR1, D2R and SRY. In the human neuroblastoma cell line, M17, SRY knockdown resulted in a reduction in TH, DDC, DBH and MAO-A expression; enzymes which control dopamine synthesis and metabolism. Conversely, SRY overexpression increased TH, DDC, DBH, D2R and MAO-A levels, which was accompanied by increased extracellular dopamine levels. A luciferase assay demonstrated that SRY activated a 4.6 kb 5′ upstream regulatory region of the human TH promoter/nigral enhancer. Combined, these results suggest that SRY may play a role as a positive regulator of catecholamine synthesis and metabolism in the human male midbrain. Given the limitations of human tissue analysis, further studies are required to provide a definitive answer on SRY expression in human brain regions. PMID:22568433

  20. The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow.

    PubMed

    Goker-Alpan, Ozlem; Masdeu, Joseph C; Kohn, Philip D; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C; Cropp, Brett; Eisenberg, Daniel P; Maniwang, Emerson D; Davis, Joie; Wiggs, Edythe; Sidransky, Ellen; Berman, Karen F

    2012-08-01

    Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion

  1. Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D3 receptor

    PubMed Central

    Joyce, Jeffrey N; Woolsey, Cheryl; Ryoo, Han; Borwege, Sabine; Hagner, Diane

    2004-01-01

    Background Our aim was to determine if pramipexole, a D3 preferring agonist, effectively reduced dopamine neuron and fiber loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model when given at intraperitoneal doses corresponding to clinical doses. We also determined whether subchronic treatment with pramipexole regulates dopamine transporter function, thereby reducing intracellular transport of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+). Methods Ten 12-month old C57BL/6 mice were treated with MPTP (or saline) twice per day at 20 mg/kg s.c. (4 injections over 48 h). Mice were pretreated for 3 days and during the 2-day MPTP regimen with pramipexole (0.1 mg/kg/day) or saline. Stereological quantification of dopamine neuron number and optical density measurement of dopamine fiber loss were carried out at 1 week after treatment, using immunostaining for dopamine transporter (DAT) and tyrosine hydroxylase (TH). Additional wild-type (WT) and D3 receptor knockout (KO) mice were treated for 5 days with pramipexole (0.1 mg/kg/day) or vehicle. The kinetics of [3H]MPP+ and [3H]DA uptake (Vmax and Km) were determined 24 h later; and at 24 h and 14 days dopamine transporter density was measured by quantitative autoradiography. Results Pramipexole treatment completely antagonized the neurotoxic effects of MPTP, as measured by substantia nigra and ventral tegmental area TH-immunoreactive cell counts. MPTP- induced loss of striatal innervation, as measured by DAT-immunoreactivity, was partially prevented by pramipexole, but not with regard to TH-IR. Pramipexole also reduced DAT- immunoreactivity in non-MPTP treated mice. Subchronic treatment with pramipexole lowered the Vmax for [3H]DA and [3H]MPP+ uptake into striatal synaptosomes of WT mice. Pramipexole treatment lowered Vmax in WT but not D3 KO mice; however, D3 KO mice had lower Vmax for [3H]DA uptake. There was no change in DAT number in WT with pramipexole treatment or D3 KO mice at

  2. Synthesis of palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel for electrochemical detection of dopamine.

    PubMed

    Li, Ruiyi; Yang, Tingting; Li, Zaijun; Gu, Zhiguo; Wang, Guangli; Liu, Junkang

    2017-02-15

    Integration of noble metal nanomaterials on graphene nanosheets potentially paves one way to improve their electronic, chemical and electrochemical properties. The study reported synthesis of palladium@gold nanoalloys/nitrogen and sulphur-functionalized multiple graphene aerogel composite (Pd@Au/N,S-MGA). The as-prepared composite offers a well-defined three-dimensional architecture with rich of mesopores. The Pd@Au nanoalloys were dispersed on the graphene framework networks and their active sites were fully exposed. The unique structure achieves to ultra high electron/ion conductivity, electrocatalytic activity and structural stability. The sensor based on the Pd@Au/N,S-MGA creates ultrasensitive electrochemical response towards dopamine due to significantly electrochemical synergy between Pd, Au and N,S-MGA. Its differential pulse voltammetric signal linearly increases with the increase of dopamine concentration in the range from 1.0 × 10(-9) M to 4.0 × 10(-5) M with the detection limit of 3.6 × 10(-10) M (S/N = 3). The analytical method provides the advantage of sensitivity, reproducibility, rapidity and long-term stability. It has been successfully applied in the detection of trace dopamine in biological samples. The study also opens a window on the electronic properties of graphene aerogel and metal nanomaterials as well their nanohybrids to meet needs of further applications as nanoelectronics in diagnosis, bioanalysis and catalysis.

  3. D1-like dopamine receptors downregulate Na+-K+-ATPase activity and increase cAMP production in the posterior gills of the blue crab Callinectes sapidus

    PubMed Central

    Arnaldo, Francis B.; Villar, Van Anthony M.; Konkalmatt, Prasad R.; Owens, Shaun A.; Asico, Laureano D.; Jones, John E.; Yang, Jian; Lovett, Donald L.; Armando, Ines; Concepcion, Gisela P.

    2014-01-01

    Dopamine-mediated regulation of Na+-K+-ATPase activity in the posterior gills of some crustaceans has been reported to be involved in osmoregulation. The dopamine receptors of invertebrates are classified into three groups based on their structure and pharmacology: D1- and D2-like receptors and a distinct invertebrate receptor subtype (INDR). We tested the hypothesis that a D1-like receptor is expressed in the blue crab Callinectes sapidus and regulates Na+-K+-ATPase activity. RT-PCR, using degenerate primers, showed the presence of D1βR mRNA in the posterior gill. The blue crab posterior gills showed positive immunostaining for a dopamine D5 receptor (D5R or D1βR) antibody in the basolateral membrane and cytoplasm. Confocal microscopy showed colocalization of Na+-K+-ATPase and D1βR in the basolateral membrane. To determine the effect of D1-like receptor stimulation on Na+-K+-ATPase activity, intact crabs acclimated to low salinity for 6 days were given an intracardiac infusion of the D1-like receptor agonist fenoldopam, with or without the D1-like receptor antagonist SCH23390. Fenoldopam increased cAMP production twofold and decreased Na+-K+-ATPase activity by 50% in the posterior gills. This effect was blocked by coinfusion with SCH23390, which had no effect on Na+-K+-ATPase activity by itself. Fenoldopam minimally decreased D1βR protein expression (10%) but did not affect Na+-K+-ATPase α-subunit protein expression. This study shows the presence of functional D1βR in the posterior gills of euryhaline crabs chronically exposed to low salinity and highlights the evolutionarily conserved function of the dopamine receptors on sodium homeostasis. PMID:25080496

  4. D1-like dopamine receptors downregulate Na+-K+-ATPase activity and increase cAMP production in the posterior gills of the blue crab Callinectes sapidus.

    PubMed

    Arnaldo, Francis B; Villar, Van Anthony M; Konkalmatt, Prasad R; Owens, Shaun A; Asico, Laureano D; Jones, John E; Yang, Jian; Lovett, Donald L; Armando, Ines; Jose, Pedro A; Concepcion, Gisela P

    2014-09-15

    Dopamine-mediated regulation of Na(+)-K(+)-ATPase activity in the posterior gills of some crustaceans has been reported to be involved in osmoregulation. The dopamine receptors of invertebrates are classified into three groups based on their structure and pharmacology: D1- and D2-like receptors and a distinct invertebrate receptor subtype (INDR). We tested the hypothesis that a D1-like receptor is expressed in the blue crab Callinectes sapidus and regulates Na(+)-K(+)-ATPase activity. RT-PCR, using degenerate primers, showed the presence of D1βR mRNA in the posterior gill. The blue crab posterior gills showed positive immunostaining for a dopamine D5 receptor (D5R or D1βR) antibody in the basolateral membrane and cytoplasm. Confocal microscopy showed colocalization of Na(+)-K(+)-ATPase and D1βR in the basolateral membrane. To determine the effect of D1-like receptor stimulation on Na(+)-K(+)-ATPase activity, intact crabs acclimated to low salinity for 6 days were given an intracardiac infusion of the D1-like receptor agonist fenoldopam, with or without the D1-like receptor antagonist SCH23390. Fenoldopam increased cAMP production twofold and decreased Na(+)-K(+)-ATPase activity by 50% in the posterior gills. This effect was blocked by coinfusion with SCH23390, which had no effect on Na(+)-K(+)-ATPase activity by itself. Fenoldopam minimally decreased D1βR protein expression (10%) but did not affect Na(+)-K(+)-ATPase α-subunit protein expression. This study shows the presence of functional D1βR in the posterior gills of euryhaline crabs chronically exposed to low salinity and highlights the evolutionarily conserved function of the dopamine receptors on sodium homeostasis.

  5. The monoamine stabilizer (−)‐OSU6162 counteracts downregulated dopamine output in the nucleus accumbens of long‐term drinking Wistar rats

    PubMed Central

    Feltmann, Kristin; Fredriksson, Ida; Wirf, Malin; Schilström, Björn

    2015-01-01

    Abstract We recently established that the monoamine stabilizer (−)‐OSU6162 (OSU6162) decreased voluntary alcohol‐mediated behaviors, including alcohol intake and cue/priming‐induced reinstatement, in long‐term drinking rats, while blunting alcohol‐induced dopamine output in the nucleus accumbens (NAc) of alcohol‐naïve rats. Therefore, we hypothesized that OSU6162 attenuates alcohol‐mediated behaviors by blunting alcohol's rewarding effects. Here, we evaluated the effects of long‐term drinking and OSU6162 treatment (30 mg/kg, sc) on basal and alcohol‐induced (2.5 g/kg, ip) NAc dopamine outputs in Wistar rats after 10 months of intermittent access to 20% alcohol. The results showed that basal and alcohol‐induced NAc dopamine outputs were significantly lower in long‐term drinking rats, compared with alcohol‐naïve rats. In the long‐term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4 hours. Furthermore, OSU6162 pre‐treatment did not blunt the alcohol‐induced output in the long‐term drinking rats, a finding that contrasted with our previous results in alcohol‐naïve rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long‐term drinking or alcohol‐naïve rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol‐mediated behaviors by counteracting NAc dopamine deficits in long‐term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162's beneficial side‐effect profile, the present study merits evaluation of OSU6162's clinical efficacy to attenuate alcohol use in alcohol‐dependent patients. PMID:26464265

  6. The inhibition of dopamine synthesis in fetuses changes the pattern of T-lymphocyte maturation in the thymus of adult rats.

    PubMed

    Lifantseva, N V; Koneeva, Ts O; Voronova, S N; Zakharova, L A; Melnikova, V I

    2016-09-01

    The mRNA for dopamine receptors of type D1, D3, D5, but not type D2, was detected in the thymus of rats starting from day 16 of embryonic development (E16). Dopamine at concentrations of 10(-8)-10(‒6) M inhibited fetus thymocyte response to mitogen, confirming the functionality of the receptors and the possibility of a direct effect of dopamine on the developing thymus. Pharmacological inhibition of catecholamine synthesis in the crucial period of thymus development leads to long-term changes in the T-system immunity due to increased production of natural regulatory T-lymphocytes. The presence and functional activity of dopamine receptors in the fetal thymus indicates its ability to influence the development of the immune system of rats during ontogeny.

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

    PubMed

    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.

  8. Relation between Dopamine Synthesis Capacity and Cell-Level Structure in Human Striatum: A Multi-Modal Study with Positron Emission Tomography and Diffusion Tensor Imaging

    PubMed Central

    Kawaguchi, Hiroshi; Obata, Takayuki; Takano, Harumasa; Nogami, Tsuyoshi; Suhara, Tetsuya; Ito, Hiroshi

    2014-01-01

    Positron emission tomography (PET) study has shown that dopamine synthesis capacity varied among healthy individuals. This interindividual difference might be due to a difference in the cell-level structure of presynaptic dopaminergic neurons, i.e., cellular density and/or number. In this study, the relations between the dopamine synthesis capacity measured by PET and the parameter estimates in diffusion tensor imaging (DTI) in striatal subregions were investigated in healthy human subjects. DTI and PET studies with carbon-11 labeled L-DOPA were performed in ten healthy subjects. Age-related changes in the above parameters were also considered. Fractional anisotropy showed a significant positive correlation with age in the posterior caudate. There was significant negative correlation between dopamine synthesis capacity and mean diffusivity in the posterior caudate and putamen. Assuming that mean diffusivity reflects the density of wide-spreading axonal terminals in the striatum, the result suggests that dopamine synthesis may be related to the density of dopaminergic neuronal fibers. It is evident that PET/DTI combined measurements can contribute to investigations of the pathophysiology of neuropsychiatric diseases involving malfunction of dopaminergic neurons. PMID:24498218

  9. Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators.

    PubMed

    Shoda, Takuji; Kato, Masashi; Harada, Rintaro; Fujisato, Takuma; Okuhira, Keiichiro; Demizu, Yosuke; Inoue, Hideshi; Naito, Mikihiko; Kurihara, Masaaki

    2015-07-01

    Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-{4-[2-(dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERα via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs.

  10. Colorimetric detection of copper ions in tap water during the synthesis of silver/dopamine nanoparticles.

    PubMed

    Ma, Yu-rong; Niu, Hong-yun; Zhang, Xiao-le; Cai, Ya-qi

    2011-12-21

    A facile, economic and eco-friendly colorimetric sensor for Cu(2+) using dopamine/silver nanoparticles was developed. The sensor shows excellent sensitivity and selectivity toward Cu(2+) in the range of 3.2-512 ppb and can be applied for Cu(2+) detection in tap water.

  11. Altered pattern of brain dopamine synthesis in male adolescents with attention deficit hyperactivity disorder

    PubMed Central

    Forssberg, Hans; Fernell, Elisabeth; Waters, Susanna; Waters, Nicholas; Tedroff, Joakim

    2006-01-01

    Background Limited data from positron emission tomography (PET) studies of subjects with attention-deficit/hyperactivity disorder (ADHD) indicate alterations in brain dopamine neurotransmission. However, these studies have used conventional univariate approaches that are less sensitive to detect complex interactions that may exist between different brain dopamine pathways and individual symptoms of ADHD. We aimed to investigate these potential interactions in adolescents with ADHD. Methods We used a 3D PET scan to measure utilization of native L-[11C]-DOPA to map dopamine presynaptic function in various cortical, striatal and midbrain regions in a group of 8 male adolescents with ADHD and 6 age matched controls. To evaluate the interactions between the studied brain regions, multivariate statistical methods were used. Results Abnormal dopaminergic function was found in multiple brain regions of patients with ADHD. A main finding was lower L-[11C]-DOPA utilization in adolescent with ADHD as compared to control subjects, especially in subcortical regions. This pattern of dopaminergic activity was correlated specifically with symptoms of inattention. Conclusion Dopamine signalling in the brain plays an important modulatory role in a variety of motor and cognitive functions. We have identified region-specific functional abnormalities in dopaminergic function, which may help better account for the symptoms of ADHD. PMID:17144907

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

    SciTech Connect

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

    1990-01-01

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

  13. Iron chelation down-regulates dopamine transporter expression by decreasing mRNA stability and increasing endocytosis in N2a cells.

    PubMed

    Hegde, Narasimha V; Jensen, Gordon L; Unger, Erica L

    2011-02-15

    Cell surface expression of the dopamine transporter (DAT) is determined by the relative rates of its internalization and recycling. Changes in the cellular labile iron pool (LIP) affect many cellular mechanisms including those that regulate DAT trafficking. In this study, we analyzed DAT expression and posttranslational modifications in response to changes in cellular iron in transfected neuroblastoma cells (N2a). Iron chelation by desferrioxamine (DFO) altered DAT protein levels by decreasing the stability of DAT mRNA. Increased phosphorylation and ubiquitination of this transporter protein following DFO treatment were also observed. Cellular iron depletion elevated protein levels of the early endosomal marker Rab5. Moreover, confocal microscopy studies showed increased localization of DAT into the endosomal compartment in DFO-treated cells compared to control. Together, these findings suggest that cellular iron depletion regulates DAT expression through reducing mRNA stability as well as an increasing in endocytosis.

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

    NASA Astrophysics Data System (ADS)

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

    2005-07-01

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

  15. A one-step automated synthesis of the dopamine transporter ligand [(18)F]FECNT from the chlorinated precursor.

    PubMed

    Pijarowska-Kruszyna, Justyna; Jaron, Antoni; Kachniarz, Artur; Malkowski, Bogdan; Garnuszek, Piotr; Mikolajczak, Renata

    2016-03-01

    The use of [(18)F]labelled nortropane derivative 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) as a dopamine transporter ligand for PET imaging is dependent on efficient radiosynthesis method. Herein, the automated synthesis of [(18)F]FECNT from its chlorinated precursor in commercially available SynChrom [(18)F] R&D module has been developed. The synthesis unit was readily configured for the one-step synthesis from corresponding chlorinated precursor. The radiolabeling process involved a classical [(18)F]fluoride nucleophilic substitution performed at 110 °C for 12 min and finally HPLC and SPE purification. Crude [(18)F]FECNT was obtained with a radiolabeling yield of 59 ± 12% (n = 5). The average uncorrected amount of [(18)F]FECNT in the final formulated dose was 2.0 ± 0.5 GBq (32 ± 7% overall decay-corrected yields) obtained with radiochemical purity over 99% and specific activity of 55 GBq/µmol. The total duration of the procedure was 80-90 min. An automated radiosynthesis of [(18)F]FECNT with high radiochemical purity may provide a simple and robust method of radiopharmaceutical preparation for routine clinical applications.

  16. Down-Regulation by Resveratrol of Basic Fibroblast Growth Factor-Stimulated Osteoprotegerin Synthesis through Suppression of Akt in Osteoblasts

    PubMed Central

    Kuroyanagi, Gen; Otsuka, Takanobu; Yamamoto, Naohiro; Matsushima-Nishiwaki, Rie; Nakakami, Akira; Mizutani, Jun; Kozawa, Osamu; Tokuda, Haruhiko

    2014-01-01

    It is firmly established that resveratrol, a natural food compound abundantly found in grape skins and red wine, has beneficial properties for human health. In the present study, we investigated the effect of basic fibroblast growth factor (FGF-2) on osteoprotegerin (OPG) synthesis in osteoblast-like MC3T3-E1 cells and whether resveratrol affects the OPG synthesis. FGF-2 stimulated both the OPG release and the expression of OPG mRNA. Resveratrol significantly suppressed the FGF-2-stimulated OPG release and the mRNA levels of OPG. SRT1720, an activator of SIRT1, reduced the FGF-2-induced OPG release and the OPG mRNA expression. PD98059, an inhibitor of upstream kinase activating p44/p42 mitogen-activated protein (MAP) kinase, had little effect on the FGF-2-stimulated OPG release. On the other hand, SB203580, an inhibitor of p38 MAP kinase, SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Akt inhibitor suppressed the OPG release induced by FGF-2. Resveratrol failed to affect the FGF-2-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase or SAPK/JNK. The phosphorylation of Akt induced by FGF-2 was significantly suppressed by resveratrol or SRT1720. These findings strongly suggest that resveratrol down-regulates FGF-2-stimulated OPG synthesis through the suppression of the Akt pathway in osteoblasts and that the inhibitory effect of resveratrol is mediated at least in part by SIRT1 activation. PMID:25290095

  17. Incorporation of 5-hydroxyindazole into the self-polymerization of dopamine for novel polymer synthesis.

    PubMed

    Peterson, Matthew B; Le-Masurier, Solomon P; Lim, Khoon; Hook, James M; Martens, Penny; Granville, Anthony M

    2014-02-01

    Investigation into the mussel-inspired polymerization of dopamine has led to the realization that other compounds possessing potential quinone structures could undergo similar self-polymerizations in mild buffered aqueous conditions. To this end, 5-hydroxyindazole was added to a dopamine polymerization matrix in varying amounts, to study its incorporation into a polydopamine coating of silica particles. Solid-state (13) C NMR spectroscopy confirmed the presence of the indazole in the polymer shell when coated onto silica gel. SEM and DLS analysis also confirmed that the presence of the indazole in the reaction matrix yielded monodisperse polymer-coated particles, which retained their polymer shell upon HF etching, except when high levels of the indazole were used. Characterization data and examination of incorporation mechanism suggests that the 5-hydroxyindazole performs the function of a chain-terminating agent. Cytotoxicity studies of the polymer particles containing 5-hydroxyindazole showed dramatically lower toxicity levels compared to polydopamine alone.

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

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

  20. Chinese Medicine Formula “Jian-Pi-Zhi-Dong Decoction” Attenuates Tourette Syndrome via Downregulating the Expression of Dopamine Transporter in Mice

    PubMed Central

    Wang, Dao-han; Li, Wei; Liu, Xiao-fang; Zhang, Jin-ming; Wang, Su-mei

    2013-01-01

    Jian-Pi-Zhi-Dong Decoction (JPZDD) is dedicated to the treatment for Tourette syndrome (TS) with the guidance of the theories of Traditional Chinese Medicine (TCM). This study aims to investigate the expression of dopamine transporter (DAT) in the striatum and stereotyped behavior of TS mice model by intervention of JPZDD. Mice were induced by 3,3′-iminodipropionitrile (IDPN, 350 mg kg−1 day−1, i.p.) for 7 days and divided into 4 groups (n = 20, each): control and IDPN groups were gavaged with saline and the remaining 2 groups with Tiapride (Tia, 50 mg kg−1 day−1) and JPZDD (20 g kg−1 day−1), respectively. The results showed that the scores of stereotyped behavior in IDPN+JPZDD group were significantly reduced. A noticeably increased 11C-β-CFT binding at bilateral striatum was observed after administration of JPZDD versus that of IDPN or Tia. Immunohistochemistry and in situ hybridization studies manifested higher levels of DAT protein and mRNA in IDPN+JPZDD group. These findings not only demonstrated that JPZDD could effectively inhibit the abnormal behaviors of TS mice model, but also increase the level of DAT in striatum. Therefore, JPZDD could be one of potential treatments of patients with TS. PMID:23431337

  1. Extremely low-frequency electromagnetic field exposure during chronic morphine treatment strengthens downregulation of dopamine D2 receptors in rat dorsal hippocampus after morphine withdrawal.

    PubMed

    Wang, Xiusong; Liu, Yadong; Lei, Yanlin; Zhou, Dongming; Fu, Yu; Che, Yi; Xu, Ruchang; Yu, Hualin; Hu, Xintian; Ma, Yuanye

    2008-03-15

    The aim of this study was to investigate the effect of extremely low-frequency electromagnetic field (ELF-EMF) exposure during morphine treatment on dopamine D2 receptor (D2R) density in the rat dorsal hippocampus following withdrawal. Rats were exposed to ELF-EMF (20 Hz, 14 mT) or sham exposed for 1h per day before injection of morphine (10mg/kg, i.p.) once daily for 12 days. The saline control group was sham exposed for the same period. Immunohistochemistry was used to detect the density of D2Rs on the 1st, 3rd and 5th morphine withdrawal days. The results showed that the density of D2Rs in sham-exposed morphine-treated rats on the 1st and 3rd days of morphine withdrawal was significantly lower than that of the saline control group. The ELF-EMF-exposed morphine group also exhibited a significantly lower density of D2Rs on the 1st and 3rd withdrawal days relative to the sham-exposed morphine group. However, the D2R density in both groups tended to recover as morphine withdrawal days increased. The results suggest that dorsal hippocampal D2Rs are sensitive to morphine withdrawal and that this is potentiated by ELF-EMF pre-exposure during morphine treatment.

  2. Cooperation of taurine uptake and dopamine D1 receptor activation facilitates the induction of protein synthesis-dependent late LTP.

    PubMed

    Suárez, Luz M; Bustamante, Julián; Orensanz, Luís M; Martín del Río, Rafael; Solís, José M

    2014-04-01

    Co-activation of NMDA and dopamine receptors is required for the induction of the late phase of LTP (L-LTP) that is dependent on new protein synthesis. Other neuromodulatory substances may also contribute to this process. Here, we examined whether taurine is one of the neuromodulators contributing to L-LTP induction, since it is known that taurine uptake induces a long-lasting synaptic potentiation dependent on protein synthesis, and taurine uptake inhibition blocks L-LTP induced by tetanization. Experiments were conducted using rat hippocampal slices where field synaptic potentials were evoked and recorded in CA3-CA1 synapses. Taurine (1 mM) applied 10 min before a high frequency stimulation (HFS) train converted a transitory early-LTP (E-LTP) into an L-LTP dependent on protein synthesis. This taurine effect was blocked by a taurine uptake inhibitor. A facilitation of L-LTP induction was also obtained by pre-application of SKF38393, a D1/D5 dopamine receptor (D1R) agonist. In this case, LTP facilitation was not affected by the taurine uptake inhibitor. Nevertheless, when taurine and SKF38393 were simultaneously pre-applied at a concentration that individually did not modify E-LTP, they produced a synergistic mechanism that facilitated the induction of L-LTP with a sole HFS train. This facilitation of L-LTP was blocked by inhibiting either taurine uptake or D1R activation. Taurine and SKF38393 activated different signaling pathways to transform E-LTP into L-LTP. Taurine-induced L-LTP facilitation required MAPK activation, while D1R-agonist-induced facilitation depended mainly on PKA activation and partially on MAPK activation. On the other hand, the synergistic mechanisms induced by the cooperative action of taurine and SKF38393 were impaired by inhibitors against MAPK, PKA and PI3-K. This pharmacological profile resembles that displayed by L-LTP induced by three HFS trains at 10-min intervals. These results indicate that taurine uptake is necessary and

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

    PubMed

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

    2013-06-01

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

  4. A thyroid hormone analogue, triiodothyroacetic acid, corrects corticosteroid-downregulated collagen synthesis.

    PubMed

    Yazdanparast, Parviz; Carlsson, Bo; Oikarinen, Aarne; Risteli, Juha; Faergemann, Jan

    2004-05-01

    The aim of this study was to compare the change in collagen synthesis between topical treatments with two doses of triiodothyroacetic acid (TRIAC), a thyroid hormone analogue, and placebo, after pretreatment with topical betamethasone 17-valerate (BM). Eighteen healthy volunteers were pretreated with BM on abdominal skin for 3 days, and were then treated for 14 days with a cream containing TRIAC (0.03% or 0.1%) or a placebo cream. Collagen production was assessed by quantifying the amino terminal propeptides of human type I and type III procollagen (PINP and PIIINP) in fluids from suction-induced blisters on the treated skin. Three days of treatment with BM led to an average reduction of PINP of 70% and of PIIINP of 50%. Seven days after treatment, the median increase in PINP was 230% (p = 0.03) in the Triac 0.03% group, 148% (p = 0.2) in the TRIAC 0.1% and 5% in the placebo group. The median increase in PINP in the skin area from the start of treatment to the end of treatment was 521% (p = 0.06) in the TRIAC 0.03% group, 339% (p = 0.2) in the TRIAC 0.1% group, and 55% in the placebo group (the p values are related to baseline). Seven days after treatment, the median increase in PIIINP was 24% (p = 0.6) in the Triac 0.03% group, 23% (p = 0.6) in the TRIAC 0.1% group, and -12% in the placebo group. The median increase in PIIINP in the skin area from the start of treatment to the end of treatment was 137% (p = 0.7) in the TRIAC 0.03% group, 230% (p = 0.9) in the TRIAC 0.1% group and 58% in the placebo group (the p values are related to baseline). Histologic examinations of sections from punch biopsies taken at the end of the treatment showed more thickened collagen fibers and increased density of PINP-producing dermal fibroblasts in the TRIAC groups compared to the placebo group. The result suggests a potential role for TRIAC-containing cream concomitant with anti-inflammatory topical treatment with potent glucocorticoids to prevent their suppressive activity on

  5. The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism.

    PubMed

    Czech, Daniel P; Lee, Joohyung; Sim, Helena; Parish, Clare L; Vilain, Eric; Harley, Vincent R

    2012-07-01

    The male gender is determined by the sex-determining region on the Y chromosome (SRY) transcription factor. The unexpected action of SRY in the control of voluntary movement in male rodents suggests a role in the regulation of dopamine transmission and dopamine-related disorders with gender bias, such as Parkinson's disease. We investigated SRY expression in the human brain and function in vitro. SRY immunoreactivity was detected in the human male, but not female substantia nigra pars compacta, within a sub-population of tyrosine hydroxylase (TH) positive neurons. SRY protein also co-localized with TH positive neurons in the ventral tegmental area, and with GAD-positive neurons in the substantia nigra pars reticulata. Retinoic acid-induced differentiation of human precursor NT2 cells into dopaminergic cells increased expression of TH, NURR1, D2 R and SRY. In the human neuroblastoma cell line, M17, SRY knockdown resulted in a reduction in TH, DDC, DBH and MAO-A expression; enzymes which control dopamine synthesis and metabolism. Conversely, SRY over-expression increased TH, DDC, DBH, D2 R and MAO-A levels, accompanied by increased extracellular dopamine levels. A luciferase assay demonstrated that SRY activated a 4.6 kb 5' upstream regulatory region of the human TH promoter/nigral enhancer. Combined, these results suggest that SRY plays a role as a positive regulator of catecholamine synthesis and metabolism in the human male midbrain. This ancillary genetic mechanism might contribute to gender bias in fight-flight behaviours in men or their increased susceptibility to dopamine disorders, such as Parkinson's disease and schizophrenia.

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

    PubMed

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

    2011-08-01

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

  7. The ligand binding ability of dopamine D1 receptors synthesized using a wheat germ cell-free protein synthesis system with liposomes.

    PubMed

    Arimitsu, Eiji; Ogasawara, Tomio; Takeda, Hiroyuki; Sawasaki, Tatsuya; Ikeda, Yoshio; Hiasa, Yoichi; Maeyama, Kazutaka

    2014-12-15

    G-protein coupled receptors (GPCRs) share a common seven-transmembrane topology and mediate cellular responses to a variety of extracellular signals. However, structural and functional approaches to GPCRs have often been limited by the difficulty of producing a sufficient amount of receptor protein using conventional expression systems. We synthesized human dopamine D1 receptors using a wheat cell-free protein synthesis system with liposomes and then analyzed their receptor binding ability. We determined the specific binding of [(3)H]SCH23390 to the synthesized receptors generated from a cell-free protein synthesis system or rat striatal membranes. From Scatchard plot analysis, the dissociation constant (Kd) and the maximum density (Bmax) of the synthesized receptors were 6.61±0.06 nM and 1.85±0.05 pmol/mg protein, respectively. The same analysis for rat striatal membrane gave a Kd of 2.67±0.05 nM and Bmax of 0.70±0.10 pmol/mg protein. Using a competition binding assay, Ki values of antagonists, SCH23390, LE300 and SKF83566, for the synthetic receptors were the same as those for rat striatal membranes, but Ki values of agonists, A68930, SKF38393 and dopamine, were 5-17 fold higher than those for rat striatal membranes. These results suggest that the dopamine D1 receptors synthesized in liposomes have a functional binding capacity. The different patterns of binding of antagonists and agonists to the synthetic receptors and rat striatal membranes indicate that G proteins are involved in agonist binding to dopamine D1 receptors. The cell-free protein synthesis method with liposomes will be invaluable for the functional analysis of GPCRs.

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

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2015-02-15

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

  12. Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1*

    PubMed Central

    Ishikawa, Shizuma; Taira, Takahiro; Niki, Takeshi; Takahashi-Niki, Kazuko; Maita, Chinatsu; Maita, Hiroshi; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M. M.

    2009-01-01

    Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-l-phenylalanine decarboxylase (DDC). DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H2O2, 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO2H and SO3H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. PMID:19703902

  13. Oxidative status of DJ-1-dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-dihydroxy-L-phenylalanine (L-DOPA) decarboxylase with DJ-1.

    PubMed

    Ishikawa, Shizuma; Taira, Takahiro; Niki, Takeshi; Takahashi-Niki, Kazuko; Maita, Chinatsu; Maita, Hiroshi; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M M

    2009-10-16

    Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-L-phenylalanine decarboxylase (DDC). DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H(2)O(2), 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO(2)H and SO(3)H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD.

  14. 2'-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies.

    PubMed

    el-Moselhy, T F; Avor, K S; Basmadjian, G P

    2001-09-01

    A series of 2'-substituted cocaine analogs (4-8) was prepared and evaluated in an in vitro dopamine transporter (DAT) binding assay. Compounds 4-7 were prepared by esterifying the 3 beta-hydroxyl group of ecgonine methyl ester (3) using the appropriate acid chloride in the presence of Et3N and benzene. Compound 3 was obtained from cocaine (1) by hydrolysis using 1N HCl to afford ecgonine.HCl which was subjected to acid catalyzed esterification using methanol saturated with HCl gas. Compound 8 was obtained by hydrogenation of 7 using H2/Pd-C. The IC50 values were calculated from displacement experiment of the radioligand [3H]WIN-35,428 (2). 2'-Aminococaine (8) showed high binding affinity to the DAT (14- and 1.3-fold more active than cocaine and the radioligand 2, respectively). These results, along with previous results, emphasize the importance of a hydrogen-bond donor group at the 2'-position of cocaine to enhance binding affinity to the DAT.

  15. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    SciTech Connect

    Deng, Yu; Cao, Hong; Cu, Fenglong; Xu, Dan; Lei, Youying; Tan, Yang; Magdalou, Jacques; Wang, Hui; Chen, Liaobin

    2013-05-15

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes.

  16. Human cytomegalovirus miR-US33-5p inhibits viral DNA synthesis and viral replication by down-regulating expression of the host Syntaxin3.

    PubMed

    Guo, Xin; Qi, Ying; Huang, Yujing; Liu, Zhongyang; Ma, Yanping; Shao, Yaozhong; Jiang, Shujuan; Sun, Zhengrong; Ruan, Qiang

    2015-02-13

    During infection with human cytomegalovirus (HCMV), overexpression of hcmv-miR-US33 can inhibit the lytic viral replication and down-regulate US29 mRNA. However, it remains unknown whether inhibition of viral replication by miR-US33 is mediated by down-regulation of expression of US29 or another host gene. Here, we identified the host gene Syntaxin3 (STX3) to be a direct target of hcmv-miR-US33-5p using Hybrid-PCR and luciferase-reporter assays. It was further demonstrated that the levels of STX3 protein were down-regulated in hcmv-miR-US33-5p-overexpressing cells. Experiments with STX3-specific siRNA, or with an inhibitor of hcmv-miR-US33-5p confirmed that hcmv-miR-US33-5p-mediated inhibition of HCMV DNA synthesis and of viral replication are specifically mediated by down-regulation of STX3 expression.

  17. Synthesis and dopamine transporter binding of 2beta-isopropyl ester analogs of cocaine.

    PubMed

    El-Moselhy, Tarek F; Avor, Kwasi S; Basmadjian, Garo P

    2002-02-01

    A series of 2beta-isopropyl ester analogs of cocaine (7-11) was synthesised and evaluated in an in vitro dopamine transporter (DAT) binding assays. Ecgonine HCl (5) was obtained from (-)-cocaine (1) by hydrolysis using 1 N HCl. Acid catalysed esterification of 5 using 2-propanol and HCl gas afforded 2beta-isopropyl ecgonine (6). Compounds 7-9 were obtained via esterification of the 3beta-hydroxyl group of 6 using the appropriate acid chloride. Compound 10 was obtained via selective hydrolysis and re-esterification of 7 using 2-propanol and HCl gas. Compound 11 was obtained by reduction of 9 using H(2)/Pd-C. Compounds 7, 10 and 11 showed high binding affinity to the DAT (as indicated from the inhibition of the binding of [(3)H]WIN 35,428 (3)) with IC(50) values (mean +/- S.E.M.) 208.5 +/- 9.5, 47.43 +/- 1.79 and 11.25 +/- 3.37 nM, respectively). Compound 7 is comparatively as active as cocaine, 10 is ca. fivefold more active than cocaine and 11 is ca. 20-fold more active than cocaine and even twice more active than the radioligand 3. Compound 11, like its methyl ester analog (2' aminococaine), exhibited the highest affinity to the DAT. These results, along with previous results, emphasise the importance of a hydrogen-bond donor group at the 2'-position of cocaine and its isopropyl ester analogs to enhance binding affinity to the DAT.

  18. Stimulus-Dependent Dopamine Release in Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Sikstrom, Sverker; Soderlund, Goran

    2007-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is related to an attenuated and dysfunctional dopamine system. Normally, a high extracellular dopamine level yields a tonic dopaminergic input that down-regulates stimuli-evoked phasic dopamine responses through autoreceptors. Abnormally low tonic extracellular dopamine in ADHD up-regulates the…

  19. 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3

    SciTech Connect

    Kultti, Anne; Pasonen-Seppaenen, Sanna; Jauhiainen, Marjo; Rilla, Kirsi J.; Kaernae, Riikka; Pyoeriae, Emma; Tammi, Raija H.; Tammi, Markku I.

    2009-07-01

    Hyaluronan accumulation on cancer cells and their surrounding stroma predicts an unfavourable disease outcome, suggesting that hyaluronan enhances tumor growth and spreading. 4-Methylumbelliferone (4-MU) inhibits hyaluronan synthesis and retards cancer spreading in experimental animals through mechanisms not fully understood. These mechanisms were studied in A2058 melanoma cells, MCF-7 and MDA-MB-361 breast, SKOV-3 ovarian and UT-SCC118 squamous carcinoma cells by analysing hyaluronan synthesis, UDP-glucuronic acid (UDP-GlcUA) content, and hyaluronan synthase (HAS) mRNA levels. The maximal inhibition in hyaluronan synthesis ranged 22-80% in the cell lines tested. Active glucuronidation of 4-MU produced large quantities of 4-MU-glucuronide, depleting the cellular UDP-GlcUA pool. The maximal reduction varied between 38 and 95%. 4-MU also downregulated HAS mRNA levels: HAS3 was 84-60% lower in MDA-MB-361, A2058 and SKOV-3 cells. HAS2 was the major isoenzyme in MCF-7 cells and lowered by 81%, similar to 88% in A2058 cells. These data indicate that both HAS substrate and HAS2 and/or HAS3 mRNA are targeted by 4-MU. Despite different target point sensitivities, the reduction of hyaluronan caused by 4-MU was associated with a significant inhibition of cell migration, proliferation and invasion, supporting the importance of hyaluronan synthesis in cancer, and the therapeutic potential of hyaluronan synthesis inhibition.

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  1. Down-regulation of the mitochondrial aspartate-glutamate carrier isoform 1 AGC1 inhibits proliferation and N-acetylaspartate synthesis in Neuro2A cells.

    PubMed

    Profilo, Emanuela; Peña-Altamira, Luis Emiliano; Corricelli, Mariangela; Castegna, Alessandra; Danese, Alberto; Agrimi, Gennaro; Petralla, Sabrina; Giannuzzi, Giulia; Porcelli, Vito; Sbano, Luigi; Viscomi, Carlo; Massenzio, Francesca; Palmieri, Erika Mariana; Giorgi, Carlotta; Fiermonte, Giuseppe; Virgili, Marco; Palmieri, Luigi; Zeviani, Massimo; Pinton, Paolo; Monti, Barbara; Palmieri, Ferdinando; Lasorsa, Francesco Massimo

    2017-02-21

    The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca(2+)-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGC1 display a significant proliferation deficit associated with reduced mitochondrial respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGC1 restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGC1 impairment is associated with inappropriate aspartate levels to support neuronal proliferation when glutamine is not used as metabolic substrate, and we propose that delayed myelination in AGC1 deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NAA synthesis occurring during the nervous system development.

  2. 3-Chlorotyramine Acting as Ligand of the D2 Dopamine Receptor. Molecular Modeling, Synthesis and D2 Receptor Affinity.

    PubMed

    Angelina, Emilio; Andujar, Sebastian; Moreno, Laura; Garibotto, Francisco; Párraga, Javier; Peruchena, Nelida; Cabedo, Nuria; Villecco, Margarita; Cortes, Diego; Enriz, Ricardo D

    2015-01-01

    We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2 -DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2 -DR to that reported for DA.

  3. Down-regulation of sorbitol dehydrogenase and up-regulation of sucrose synthase in shoot tips of the transgenic apple trees with decreased sorbitol synthesis.

    PubMed

    Zhou, Rui; Cheng, Lailiang; Dandekar, Abhaya M

    2006-01-01

    Both sorbitol and sucrose are translocated to, and utilized in, sink tissues of apple (Malus domestica). Considering that antisense suppression of aldose 6-phosphate reductase resulted in lower concentrations of sorbitol and higher concentrations of sucrose in source leaves without altering the vegetative growth of apple trees, it was hypothesized that sorbitol metabolism is down-regulated and sucrose metabolism is up-regulated in shoot tips of the transgenic plants. Carbohydrate measurements indicated that sorbitol concentration was lower whereas sucrose concentration was higher in the shoot tips of transgenic apple plants with decreased sorbitol synthesis compared with the untransformed control. However, the shoot relative growth rate was not altered in the transgenic plants. Sorbitol dehydrogenase (SDH) activity was decreased; acid invertase activity and neutral invertase activity remained the same, whereas sucrose synthase (SUSY) activity was increased in shoot tips of the transgenic plants. The SDH transcript level was lower whereas the SUSY transcript level was higher in shoot tips of the transgenic plants. SDH activity and SDH transcript level were specifically stimulated by exogenous sorbitol fed to the shoot tips via the transpiration stream but were specifically inhibited by sucrose. SUSY activity and SUSY transcript level were dramatically enhanced by sucrose, but decreased by glucose and fructose. Neither acid invertase nor neutral invertase activity responded to sucrose, glucose, fructose, or any other sugars tested. It is concluded that sorbitol dehydrogenase is down-regulated, whereas sucrose synthase is up-regulated in shoot tips of the transgenic apple trees with decreased sorbitol synthesis, leading to homeostasis of vegetative growth. Sorbitol and sucrose act as signal molecules to modulate the expression and activities of sorbitol dehydrogenase and sucrose synthase, both of which play an important role in determining the sink strength of apple

  4. Facile in Situ Synthesis of Silver Nanoparticles on the Surface of Metal-Organic Framework for Ultrasensitive Surface-Enhanced Raman Scattering Detection of Dopamine.

    PubMed

    Jiang, Zhongwei; Gao, Pengfei; Yang, Lin; Huang, Chengzhi; Li, Yuanfang

    2015-12-15

    Surface-enhanced Raman scattering (SERS) signals are intensively dominated by the Raman hot spots and distance between analyte molecules and metallic nanostructures. Herein, an efficient SERS substrate was developed by in situ synthesis of silver nanoparticles (AgNPs) on the surface of MIL-101 (Fe), a typical metal-organic framework (MOF). The as-prepared SERS substrate combines the numerous Raman hot spots between the high-density Ag NPs and the excellent adsorption performance of MOFs, making it an excellent SERS substrate for highly sensitive SERS detection by effectively concentrating analytes in close proximity to the Raman hot spots domains between the adjacent AgNPs. The resulting hybrid material was used for ultrasensitive SERS detection of dopamine based on the peroxidase-like activity of MIL-101 (Fe) by utilizing the enzyme-linked immunosorbent assay (ELISA) colorimetric substrate, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) as a SERS marker. This new developed method showed good linearity in the range from 1.054 pM to 210.8 nM for dopamine with the correlation coefficient of 0.992, detection limit of approximately 0.32 pM [signal-to-noise ratio (S/N) = 3], and acceptable recoveries ranging from 99.8% to 108.0% in human urine. These results predict that the proposed SERS system may open up a new opportunity for chemical and biological assay applications.

  5. New series of morpholine and 1,4-oxazepane derivatives as dopamine D4 receptor ligands: synthesis and 3D-QSAR model.

    PubMed

    Audouze, Karine; Nielsen, Elsebet Østergaard; Peters, Dan

    2004-06-03

    Since the identification of the dopamine D(4) receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D(4) ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D(4) receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.

  6. LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions.

    PubMed

    Liu, Fakeng; Jin, Rui; Liu, Xiuju; Huang, Henry; Wilkinson, Scott C; Zhong, Diansheng; Khuri, Fadlo R; Fu, Haian; Marcus, Adam; He, Yulong; Zhou, Wei

    2016-01-19

    We analyzed the mechanism underlying 5-aminoimidazole-4-carboxamide riboside (AICAR) mediated apoptosis in LKB1-null non-small cell lung cancer (NSCLC) cells. Metabolic profile analysis revealed depletion of the intracellular pyrimidine pool after AICAR treatment, but uridine was the only nucleotide precursor capable of rescuing this apoptosis, suggesting the involvement of RNA metabolism. Because half of RNA transcription in cancer is for pre-ribosomal RNA (rRNA) synthesis, which is suppressed by over 90% after AICAR treatment, we evaluated the role of TIF-IA-mediated rRNA synthesis. While the depletion of TIF-IA by RNAi alone promoted apoptosis in LKB1-null cells, the overexpression of a wild-type or a S636A TIF-IA mutant, but not a S636D mutant, attenuated AICAR-induced apoptosis. In LKB1-null H157 cells, pre-rRNA synthesis was not suppressed by AICAR when wild-type LKB1 was present, and cellular fractionation analysis indicated that TIF-IA quickly accumulated in the nucleus in the presence of a wild-type LKB1 but not a kinase-dead mutant. Furthermore, ectopic expression of LKB1 was capable of attenuating AICAR-induced death in AMPK-null cells. Because LKB1 promotes cell survival by modulating TIF-IA-mediated pre-rRNA synthesis, this discovery suggested that targeted depletion of uridine related metabolites may be exploited in the clinic to eliminate LKB1-null cancer cells.

  7. Extra virgin olive oil phenols down-regulate lipid synthesis in primary-cultured rat-hepatocytes.

    PubMed

    Priore, Paola; Siculella, Luisa; Gnoni, Gabriele Vincenzo

    2014-07-01

    Hydroxytyrosol, tyrosol, and oleuropein, the main phenols present in extra virgin olive oil, have been reported to exert several biochemical and pharmacological effects. Here, we investigated the short-term effects of these compounds on lipid synthesis in primary-cultured rat-liver cells. Hydroxytyrosol, tyrosol and oleuropein inhibited both de novo fatty acid and cholesterol syntheses without an effect on cell viability. The inhibitory effect of individual compounds was already evident within 2 h of 25 μM phenol addition to the hepatocytes. The degree of cholesterogenesis reduction was similar for all phenol treatments (-25/30%), while fatty acid synthesis showed the following order of inhibition: hydroxytyrosol (-49%) = oleuropein (-48%) > tyrosol (-30%). A phenol-induced reduction of triglyceride synthesis was also detected. To clarify the lipid-lowering mechanism of these compounds, their influence on the activity of key enzymes of fatty acid biosynthesis (acetyl-CoA carboxylase and fatty acid synthase), triglyceride synthesis (diacylglycerol acyltransferase) and cholesterogenesis (3-hydroxy-3-methyl-glutaryl-CoA reductase) was investigated in situ by using digitonin-permeabilized hepatocytes. Acetyl-CoA carboxylase, diacylglycerol acyltransferase and 3-hydroxy-3-methyl-glutaryl-CoA reductase activities were reduced after 2 h of 25 μM phenol treatment. No change in fatty acid synthase activity was observed. Acetyl-CoA carboxylase inhibition (hydroxytyrosol, -41%, = oleuropein, -38%, > tyrosol, -17%) appears to be mediated by phosphorylation of AMP-activated protein kinase. These findings suggest that a decrease in hepatic lipid synthesis may represent a potential mechanism underlying the reported hypolipidemic effect of phenols of extra virgin olive oil.

  8. The natural yeast extract isolated by ethanol precipitation inhibits melanin synthesis by modulating tyrosinase activity and downregulating melanosome transfer.

    PubMed

    Lee, Woo Jin; Rhee, Do Young; Bang, Seung Hyun; Kim, Su Yeon; Won, Chong Hyun; Lee, Mi Woo; Choi, Jee Ho; Chang, Sung Eun

    2015-01-01

    This study was conducted to examine the effects of EP-2, a natural yeast extract isolated by ethanol precipitation from Saccharomyces cerevisiae, on melanogenesis and to determine its underlying mechanism of action. Our results show that although EP-2 is not a direct tyrosinase inhibitor, when EP-2 was added to the culture media of B16F10 melanoma cells, intracellular tyrosinase activity was decreased. However, EP-2 had no effect on the expression of microphthalmia-associated transcription factor or tyrosinase. EP-2 was found to inhibit melanogenesis and melanosome transfer when it was added to melanocytes and keratinocytes in coculture. In addition, protease-activated receptor 2, a key protein associated with melanosome transfer from melanocytes to keratinocytes, was downregulated in the presence of EP-2. In conclusion, EP-2 is a potent inhibitor of melanogenesis and its hypomelanogenic effect is related to the inhibition of tyrosinase activity and transfer of melanosomes.

  9. Synthesis and characterization of 4-(2-aminoethyl)aniline imprinted polymer as a highly effective sorbent of dopamine.

    PubMed

    Luliński, Piotr; Dana, Mariusz; Maciejewska, Dorota

    2014-02-01

    The aim of the study was to develop an efficient sorbent for the separation of dopamine. 4-(2-Aminoethyl)aniline was chosen as a pseudo-template to produce the imprinted polymers from seven different functional monomers in the presence of ethylene glycol dimethacrylate as a cross-linker. The binding capacity showed that the highest binding specificity towards dopamine was achieved when methacrylic acid was used as the monomer in methanol solution to form a polymer matrix. The imprinting factor value was equal to 22.96. Other biogenic amines were bound much more weakly. A simple theoretical model was used to give an insight into the imprinting process and the selectivity of polymer matrix. Two artificial urine samples were used as the complex matrices to show the usefulness of the new sorbent for bioanalysis.

  10. LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions

    PubMed Central

    Liu, Xiuju; Huang, Henry; Wilkinson, Scott C.; Zhong, Diansheng; Khuri, Fadlo R.; Fu, Haian; Marcus, Adam; He, Yulong; Zhou, Wei

    2016-01-01

    We analyzed the mechanism underlying 5-aminoimidazole-4-carboxamide riboside (AICAR) mediated apoptosis in LKB1-null non-small cell lung cancer (NSCLC) cells. Metabolic profile analysis revealed depletion of the intracellular pyrimidine pool after AICAR treatment, but uridine was the only nucleotide precursor capable of rescuing this apoptosis, suggesting the involvement of RNA metabolism. Because half of RNA transcription in cancer is for pre-ribosomal RNA (rRNA) synthesis, which is suppressed by over 90% after AICAR treatment, we evaluated the role of TIF-IA-mediated rRNA synthesis. While the depletion of TIF-IA by RNAi alone promoted apoptosis in LKB1-null cells, the overexpression of a wild-type or a S636A TIF-IA mutant, but not a S636D mutant, attenuated AICAR-induced apoptosis. In LKB1-null H157 cells, pre-rRNA synthesis was not suppressed by AICAR when wild-type LKB1 was present, and cellular fractionation analysis indicated that TIF-IA quickly accumulated in the nucleus in the presence of a wild-type LKB1 but not a kinase-dead mutant. Furthermore, ectopic expression of LKB1 was capable of attenuating AICAR-induced death in AMPK-null cells. Because LKB1 promotes cell survival by modulating TIF-IA-mediated pre-rRNA synthesis, this discovery suggested that targeted depletion of uridine related metabolites may be exploited in the clinic to eliminate LKB1-null cancer cells. PMID:26506235

  11. Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter.

    PubMed

    Singh, S; Basmadjian, G P; Avor, K S; Pouw, B; Seale, T W

    1997-08-01

    Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19, 21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtained from 2'-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4'-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2'-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2'-Hydroxylation also enhanced the bidning potency of 4'-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.

  12. Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators.

    PubMed

    Tutone, Marco; Chinnici, Aurora; Almerico, Anna Maria; Perricone, Ugo; Sutera, Flavia Maria; De Caro, Viviana

    2016-11-29

    The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D1 dopamine receptors (D1DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two new conjugates (DA-Trp 2C, and DA-Leu 3C) have been identified as the most promising candidates, and consequently synthesized. Preliminary evaluation in terms of distribution coefficient (D(pH7.4)), stability in rat brain homogenate, and in human plasma confirmed that DA-Trp (2C), and DA-Leu (3C) could be considered as very valuable candidates for further in vivo studies as new dopaminergic drugs.

  13. 1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase.

    PubMed

    Wilmanski, Tomasz; Buhman, Kimberly; Donkin, Shawn S; Burgess, John R; Teegarden, Dorothy

    2017-02-01

    Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)₂D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)₂D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)₂D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)₂D-mediated regulation and hypothesized that 1,25(OH)₂D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)₂D treatment at 2 (73%±6 relative to vehicle) and 5 (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)₂D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)₂D regulates lipid metabolism in malignant breast epithelial cells.

  14. Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

    PubMed

    Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Barak, Larry S; Wetsel, William C; Caron, Marc G; Gainetdinov, Raul R

    2005-08-01

    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.

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

    PubMed

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

    2013-10-01

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

  16. Cooperative synthesis of dopamine by non-dopaminergic neurons as a compensatory mechanism in the striatum of mice with MPTP-induced Parkinsonism.

    PubMed

    Kozina, Elena A; Kim, Aleksandr R; Kurina, Anna Y; Ugrumov, Michael V

    2017-02-01

    Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l-DOPA, produced in monoenzymatic TH-containing neurons, to neurons containing AADC by means of l-leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l-DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might

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

    PubMed

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

    2016-04-12

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

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

    PubMed

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

    2016-07-15

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

  19. Long-term daily access to alcohol alters dopamine-related synthesis and signaling proteins in the rat striatum.

    PubMed

    Kashem, Mohammed Abul; Ahmed, Selina; Sarker, Ranjana; Ahmed, Eakhlas U; Hargreaves, Garth A; McGregor, Iain S

    2012-12-01

    Chronic alcohol exposure can adversely affect neuronal morphology, synaptic architecture and associated neuroplasticity. However, the effects of moderate levels of long-term alcohol intake on the brain are a matter of debate. The current study used 2-DE (two-dimensional gel electrophoresis) proteomics to examine proteomic changes in the striatum of male Wistar rats after 8 months of continuous access to a standard off-the-shelf beer in their home cages. Alcohol intake under group-housed conditions during this time was around 3-4 g/kg/day, a level below that known to induce physical dependence in rats. After 8 months of access rats were euthanased and 2-DE proteomic analysis of the striatum was conducted. A total of 28 striatal proteins were significantly altered in the beer drinking rats relative to controls. Strikingly, many of these were dopamine (DA)-related proteins, including tyrosine hydroxylase (an enzyme of DA biosynthesis), pyridoxal phosphate phosphatase (a co-enzyme in DA biosynthesis), DA and cAMP regulating phosphoprotein (a regulator of DA receptors and transporters), protein phosphatase 1 (a signaling protein) and nitric oxide synthase (which modulates DA uptake). Selected protein expression changes were verified using Western blotting. We conclude that long-term moderate alcohol consumption is associated with substantial alterations in the rat striatal proteome, particularly with regard to dopaminergic signaling pathways. This provides potentially important evidence of major neuroadaptations in dopamine systems with daily alcohol consumption at relatively modest levels.

  20. Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells

    SciTech Connect

    Wang, Tsung-Pao; Pan, Yun-Ru; Fu, Chien-Yu; Chang, Hwan-You

    2010-10-15

    UDP-glucose dehydrogenase (UGDH) catalyzes oxidation of UDP-glucose to yield UDP-glucuronic acid, a precursor of hyaluronic acid (HA) and other glycosaminoglycans (GAGs) in extracellular matrix. Although association of extracellular matrix with cell proliferation and migration has been well documented, the importance of UGDH in these behaviors is not clear. Using UGDH-specific small interference RNA to treat HCT-8 colorectal carcinoma cells, a decrease in both mRNA and protein levels of UGDH, as well as the cellular UDP-glucuronic acid and GAG production was observed. Treatment of HCT-8 cells with either UGDH-specific siRNA or HA synthesis inhibitor 4-methylumbelliferone effectively delayed cell aggregation into multicellular spheroids and impaired cell motility in both three-dimensional collagen gel and transwell migration assays. The reduction in cell aggregation and migration rates could be restored by addition of exogenous HA. These results indicate that UGDH can regulate cell motility through the production of GAG. The enzyme may be a potential target for therapeutic intervention of colorectal cancers.

  1. Facile Synthesis of Molecularly Imprinted Graphene Quantum Dots for the Determination of Dopamine with Affinity-Adjustable.

    PubMed

    Zhou, Xi; Wang, Anqi; Yu, Chenfei; Wu, Shishan; Shen, Jian

    2015-06-10

    A facilely prepared fluorescence sensor was developed for dopamine (DA) determination based on polyindole/graphene quantum dots molecularly imprinted polymers (PIn/GQDs@MIPs). The proposed sensor exhibits a high sensitivity with a linear range of 5 × 10(-10) to 1.2 × 10(-6) M and the limit of detection as low as 1 × 10(-10) M in the determination of DA, which is probably due to the tailor-made imprinted cavities for binding DA thought hydrogen bonds between amine groups of DA and oxygen-containing groups of the novel composite. Furthermore, the prepared sensor can rebind DA in dual-type: a low affinity type (noncovalent interaction is off) and a high affinity type (noncovalent interaction is on), and the rebinding interaction can be adjusted by tuning the pH, which shows a unique potential for adjusting the binding interaction while keeping the specificity, allowing for wider applications.

  2. Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands†

    PubMed Central

    Tu, Zhude; Li, Shihong; Li, Aixiao; Taylor, Michelle; Ho, David; Malik, Maninder; Luedtke, Robert R.

    2013-01-01

    A series of substituted 1H-indolyl carboxylic acid amides that contain a N-(2-methoxyphenyl)piperazine or N-(2-fluoroethoxy)piperazine group were synthesized and their affinities for human dopamine D2, D3, and D4 receptors were determined. Two of these compounds, 14a and 14b, displayed high binding affinity at D3 (Ki = 0.18 and 0.4 nM, respectively), and selectivity for D3 vs. D2 receptors (87-fold and 60-fold, respectively). These two compounds had low binding affinity at D4 receptors and σ receptor sites. The intrinsic activity of these compounds at D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay; both 14a and 14b were found to be partial agonists. Furthermore, for compound 14a, the log D value of 2.85 suggested it has suitable lipophilicity for crossing the blood–brain-barrier. PMID:24156012

  3. One-Pot Green Synthesis of Graphene Nanosheets Encapsulated Gold Nanoparticles for Sensitive and Selective Detection of Dopamine

    NASA Astrophysics Data System (ADS)

    Thirumalraj, Balamurugan; Rajkumar, Chellakannu; Chen, Shen-Ming; Palanisamy, Selvakumar

    2017-01-01

    We report a simple new approach for green preparation of gallic acid supported reduced graphene oxide encapsulated gold nanoparticles (GA-RGO/AuNPs) via one-pot hydrothermal method. The as-prepared composites were successfully characterized by using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray powder diffraction techniques (XRD), scanning electron microscope (SEM), high resolution transmission electron microscopy (HRTEM) and elemental analysis. The GA-RGO/AuNPs modified electrode behaves as a hybrid electrode material for sensitive and selective detection of dopamine (DA) in presence of ascorbic acid (AA) and uric acid (UA). The GA-RGO/AuNPs modified electrode displays an excellent electrocatalytic activity towards the oxidation of DA and exhibits a wide linear response range over the DA concentrations from 0.01–100.3 μM with a detection limit (LOD) of 2.6 nM based on S/N = 3. In addition, the proposed sensor could be applied for the determination of DA in human serum and urine samples for practical analysis.

  4. Facile synthesis of NiAl-layered double hydroxide/graphene hybrid with enhanced electrochemical properties for detection of dopamine.

    PubMed

    Li, Meixia; Zhu, Jun E; Zhang, Lili; Chen, Xu; Zhang, Huimin; Zhang, Fazhi; Xu, Sailong; Evans, David G

    2011-10-05

    Layered double hydroxides (LDHs), also known as hydrotalcite-like anionic clays, have been investigated widely as promising electrochemical active materials. Due to the inherently weak conductivity, the electrochemical properties of LDHs were improved typically by utilization of either functional molecules intercalated between LDH interlayer galleries, or proteins confined between exfoliated LDH nanosheets. Here, we report a facile protocol to prepare NiAl-LDH/graphene (NiAl-LDH/G) nanocomposites using a conventional coprecipitation process under low-temperature conditions and subsequent reduction of the supporting graphene oxide. Electrochemical tests showed that the NiAl-LDH/G modified electrode exhibited highly enhanced electrochemical performance of dopamine electrooxidation in comparison with the pristine NiAl-LDH modified electrode. Results of high-resolution transmission electron microscopy and Raman spectra provide convincing information on the nanostructure and composition underlying the enhancement. Our results of the NiAl-LDH/G modified electrodes with the enhanced electrochemical performance may allow designing a variety of promising hybrid sensors via a simple and feasible approach.

  5. One-Pot Green Synthesis of Graphene Nanosheets Encapsulated Gold Nanoparticles for Sensitive and Selective Detection of Dopamine

    PubMed Central

    Thirumalraj, Balamurugan; Rajkumar, Chellakannu; Chen, Shen-Ming; Palanisamy, Selvakumar

    2017-01-01

    We report a simple new approach for green preparation of gallic acid supported reduced graphene oxide encapsulated gold nanoparticles (GA-RGO/AuNPs) via one-pot hydrothermal method. The as-prepared composites were successfully characterized by using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray powder diffraction techniques (XRD), scanning electron microscope (SEM), high resolution transmission electron microscopy (HRTEM) and elemental analysis. The GA-RGO/AuNPs modified electrode behaves as a hybrid electrode material for sensitive and selective detection of dopamine (DA) in presence of ascorbic acid (AA) and uric acid (UA). The GA-RGO/AuNPs modified electrode displays an excellent electrocatalytic activity towards the oxidation of DA and exhibits a wide linear response range over the DA concentrations from 0.01–100.3 μM with a detection limit (LOD) of 2.6 nM based on S/N = 3. In addition, the proposed sensor could be applied for the determination of DA in human serum and urine samples for practical analysis. PMID:28128225

  6. Dopamine D1 agonist R-[11C]SKF 82957: synthesis and in vivo characterization in rats.

    PubMed

    DaSilva, J N; Schwartz, R A; Greenwald, E R; Lourenco, C M; Wilson, A A; Houle, S

    1999-07-01

    The active enantiomer R-SKF 82957 was labeled with 11C by N-[11C]methylation of the full dopamine (D1) agonist R-SKF 81297, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine, in high specific activity, radiochemical purity and yields. Compared with the D1 agonist R/S-[11C]SKF 82957, R-[11C]SKF 82957 showed higher binding in the D1 rich regions, such as striatum and olfactory tubercles (approximately 1.7 times), thereby improving the tissue contrast. R-[11C]SKF 82957 exhibited high in vivo binding selectivity for D1 receptors in rats, because only high doses of D1 competitors, but not D2 or serotonin (5-HT2) blockers, significantly reduced the radioactivity levels in all brain areas. No labeled metabolites were detected in rat brain. These results indicate that R-[11C]SKF 82957 will provide more sensitive measurements of D1 receptors in in vivo studies than the racemic mixture.

  7. Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: reduced synthesis or increased catabolism?

    PubMed

    Sancesario, Giuseppe; Morrone, Luigi Antonio; D'Angelo, Vincenza; Castelli, Valentina; Ferrazzoli, Davide; Sica, Francesco; Martorana, Alessandro; Sorge, Roberto; Cavaliere, Federica; Bernardi, Giorgio; Giorgi, Mauro

    2014-12-01

    Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP-phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment.

  8. Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats.

    PubMed

    Iñiguez, S D; Cortez, A M; Crawford, C A; McDougall, S A

    2008-01-01

    The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increasingly prescribed to children, alters DA synthesis via actions at autoreceptors in the dorsal striatum and medial prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic agents to alter DOPA accumulation in the striatum and mPFC was measured after NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipulated by administering reserpine, gamma-butyrolactone (GBL), or through amphetamine withdrawal. Results showed that the partial agonists aripiprazole and terguride increased striatal DOPA accumulation under normosensitive conditions, but decreased DOPA accumulation in states of low dopaminergic tone. A different pattern of results was observed in the mPFC, because terguride and haloperidol, but not aripiprazole, increased DOPA accumulation under normosensitive conditions. In conclusion, the present data show that aripiprazole affects striatal synthesis modulating autoreceptors in an adult-typical manner during the late preweanling period. Unlike in adult rats, however, the mPFC of preweanling rats appears to contain transitory synthesis modulating autoreceptors that are sensitive to drug manipulation.

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

    PubMed

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

    2014-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  11. Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra

    PubMed Central

    2012-01-01

    Background Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5α-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels. Results We find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERβ mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. Conclusions We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and

  12. A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.

    PubMed

    Liu, Danyang; Dijkstra, Durk; de Vries, Jan B; Wikström, Håkan V

    2008-03-15

    Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.

  13. Divergence in enzyme regulation between Caenorhabditis elegans and human tyrosine hydroxylase, the key enzyme in the synthesis of dopamine.

    PubMed

    Calvo, Ana C; Pey, Angel L; Miranda-Vizuete, Antonio; Døskeland, Anne P; Martinez, Aurora

    2011-02-15

    TH (tyrosine hydroxylase) is the rate-limiting enzyme in the synthesis of catecholamines. The cat-2 gene of the nematode Caenorhabditis elegans is expressed in mechanosensory dopaminergic neurons and has been proposed to encode a putative TH. In the present paper, we report the cloning of C. elegans full-length cat-2 cDNA and a detailed biochemical characterization of the encoded CAT-2 protein. Similar to other THs, C. elegans CAT-2 is composed of an N-terminal regulatory domain followed by a catalytic domain and a C-terminal oligomerization domain and shows high substrate specificity for L-tyrosine. Like hTH (human TH), CAT-2 is tetrameric and is phosphorylated at Ser35 (equivalent to Ser40 in hTH) by PKA (cAMP-dependent protein kinase). However, CAT-2 is devoid of characteristic regulatory mechanisms present in hTH, such as negative co-operativity for the cofactor, substrate inhibition or feedback inhibition exerted by catecholamines, end-products of the pathway. Thus TH activity in C. elegans displays a weaker regulation in comparison with the human orthologue, resembling a constitutively active enzyme. Overall, our data suggest that the intricate regulation characteristic of mammalian TH might have evolved from more simple models to adjust to the increasing complexity of the higher eukaryotes neuroendocrine systems.

  14. Dopamine-Secreting Paraganglioma in the Retroperitoneum.

    PubMed

    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.

  15. Continuous illumination through larval development suppresses dopamine synthesis in the suprachiasmatic nucleus, causing activation of α-MSH synthesis in the pituitary and abnormal metamorphic skin pigmentation in flounder.

    PubMed

    Itoh, Kae; Washio, Youhei; Fujinami, Yuichiro; Shimizu, Daisuke; Uji, Susumu; Yokoi, Hayato; Suzuki, Tohru

    2012-04-01

    In order to better understand the endocrine aberrations related to abnormal metamorphic pigmentation that appear in flounder larvae reared in tanks, this study examined the effects of continuous 24-h illumination (LL) through larval development on the expression of tyrosine hydroxylase-1 (th1), proopiomelanocortin (pomc), α-melanophore-stimulating hormone (α-MSH) and melanin concentrating hormone (MCH), which are known to participate in the control of background adaptation of body color. We observed two conspicuous deviations in the endocrine system under LL when compared with natural light conditions (LD). First, LL severely suppressed th1 expression in the dopaminergic neurons in the anterior diencephalon, including the suprachiasmatic nucleus (SCN). Second, pomc and α-MSH expression in the pars intermedia melanotrophs was enhanced by LL. Skin color was paler under LL than LD before metamorphic pigmentation, and abnormal metamorphic pigmentation occurred at a higher ratio in LL. We therefore hypothesize that continuous LL inhibited dopamine synthesis in the SCN, which resulted in up-regulation of pomc mRNA expression in the melanotrophs. In spite of the up-regulation of pomc in the melanotrophs, larval skin was adjusted to be pale by MCH which was not affected by LL. Accumulation of α-MSH in the melanotrophs is caused by uncoupling of α-MSH synthesis and secretion due to inhibitory role of MCH on α-MSH secretion, which results in abnormal metamorphic pigmentation by affecting differentiation of adult-type melanophores. Our data demonstrate that continuous illumination at the post-embryonic stage has negative effects on the neuroendocrine system and pituitary in flounder.

  16. Aging-related dysregulation of dopamine and angiotensin receptor interaction.

    PubMed

    Villar-Cheda, Begoña; Dominguez-Meijide, Antonio; Valenzuela, Rita; Granado, Noelia; Moratalla, Rosario; Labandeira-Garcia, Jose L

    2014-07-01

    It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.

  17. Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release.

    PubMed

    Volkow, Nora D; Wang, Gene-Jack; Smith, Lisa; Fowler, Joanna S; Telang, Frank; Logan, Jean; Tomasi, Dardo

    2015-11-01

    Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [(11)C]cocaine to measure DAT, and with [(11)C]raclopride to measure dopamine release (assessed as changes in specific binding of [(11)C]raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.

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

    SciTech Connect

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

    1991-03-01

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

  19. Design, synthesis, radiolabeling and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential Positron Emission Tomography tracer for the dopamine D4 receptors

    PubMed Central

    Lacivita, Enza; De Giorgio, Paola; Lee, Irene T.; Rodeheaver, Sean I.; Weiss, Bryan A.; Fracasso, Claudia; Caccia, Silvio; Berardi, Francesco; Perrone, Roberto; Zhang, Ming-Rong; Maeda, Jun; Higuchi, Makoto; Suhara, Tetsuya; Schetz, John A.; Leopoldo, Marcello

    2010-01-01

    Here we describe the design, synthesis, physicochemical, and pharmacological evaluation of D4 dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D2 and sigma1 receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D4 receptor, > 100-fold selectivity over D2 and D3 dopamine receptor 5-HT1A, 5-HT2A and 5-HT2C serotonin receptors and sigma1 receptors, and logP = 2.37–2.55. Following intraperitoneal administration, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide (7) was radiolabelled with carbon-11 and subjected to PET analysis in non-human primate. [11C]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D4 receptors. PMID:20873719

  20. Synthesis and Characterization of Selective Dopamine D2 Receptor Antagonists. 2. Azaindole, Benzofuran, and Benzothiophene Analogs of L-741,626

    PubMed Central

    Vangveravong, Suwanna; Taylor, Michelle; Xu, Jinbin; Cui, Jinquan; Calvin, Wesley; Babic, Sonja; Luedtke, Robert R.; Mach, Robert H.

    2010-01-01

    A series of indole, 7-azaindole, benzofuran, and benzothiophene compounds have been prepared and evaluated for affinity at D2-like dopamine receptors. These compounds share structural elements with the classical D2-like dopamine receptor antagonists haloperidol, N-methylspiperone and benperidol. Two new compounds, 4-(4-iodophenyl)-1-((4-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (6) and 4-(4-iodophenyl)-1-((5-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (7), were found to have high affinity to and selectivity for D2 versus D3 receptors. Changing the aromatic ring system from an indole to other heteroaromatic ring systems reduced the D2 binding affinity and the D2 versus D3 selectivity. PMID:20542439

  1. Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

    PubMed

    Brindisi, Margherita; Butini, Stefania; Franceschini, Silvia; Brogi, Simone; Trotta, Francesco; Ros, Sindu; Cagnotto, Alfredo; Salmona, Mario; Casagni, Alice; Andreassi, Marco; Saponara, Simona; Gorelli, Beatrice; Weikop, Pia; Mikkelsen, Jens D; Scheel-Kruger, Jorgen; Sandager-Nielsen, Karin; Novellino, Ettore; Campiani, Giuseppe; Gemma, Sandra

    2014-11-26

    Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.

  2. Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson's disease.

    PubMed

    Jörg, Manuela; May, Lauren T; Mak, Frankie S; Lee, Kiew Ching K; Miller, Neil D; Scammells, Peter J; Capuano, Ben

    2015-01-22

    A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.

  3. Requirement for the eIF4E binding proteins for the synergistic down-regulation of protein synthesis by hypertonic conditions and mTOR inhibition.

    PubMed

    Clemens, Michael J; Elia, Androulla; Morley, Simon J

    2013-01-01

    The protein kinase mammalian target of rapamycin (mTOR) regulates the phosphorylation and activity of several proteins that have the potential to control translation, including p70S6 kinase and the eIF4E binding proteins 4E-BP1 and 4E-BP2. In spite of this, in exponentially growing cells overall protein synthesis is often resistant to mTOR inhibitors. We report here that sensitivity of wild-type mouse embryonic fibroblasts (MEFs) to mTOR inhibitors can be greatly increased when the cells are subjected to the physiological stress imposed by hypertonic conditions. In contrast, protein synthesis in MEFs with a double knockout of 4E-BP1 and 4E-BP2 remains resistant to mTOR inhibitors under these conditions. Phosphorylation of p70S6 kinase and protein kinase B (Akt) is blocked by the mTOR inhibitor Ku0063794 equally well in both wild-type and 4E-BP knockout cells, under both normal and hypertonic conditions. The response of protein synthesis to hypertonic stress itself does not require the 4E-BPs. These data suggest that under certain stress conditions: (i) translation has a greater requirement for mTOR activity and (ii) there is an absolute requirement for the 4E-BPs for regulation by mTOR. Importantly, dephosphorylation of p70S6 kinase and Akt is not sufficient to affect protein synthesis acutely.

  4. Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.

    PubMed

    Benskey, Matthew; Behrouz, Bahareh; Sunryd, Johan; Pappas, Samuel S; Baek, Seung-Hoon; Huebner, Marianne; Lookingland, Keith J; Goudreau, John L

    2012-06-01

    Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed in acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and rotenone rat models of degeneration. It is not known if the resistance of TIDA neurons is a constitutive or induced cell-autonomous phenotype for this unique subset of DA neurons. In the present study, treatment with a single injection of MPTP (20 mg/kg; s.c.) was employed to examine the response of TIDA versus NSDA neurons to acute injury. An acute single dose of MPTP caused an initial loss of DA from axon terminals of both TIDA and NSDA neurons, with recovery occurring solely in TIDA neurons by 16 h post-treatment. Initial loss of DA from axon terminals was dependent on a functional dopamine transporter (DAT) in NSDA neurons but DAT-independent in TIDA neurons. The active metabolite of MPTP, 1-methyl, 4-phenylpyradinium (MPP+), reached higher concentration and was eliminated slower in TIDA compared to NSDA neurons, which indicates that impaired toxicant bioactivation or distribution is an unlikely explanation for the observed resistance of TIDA neurons to MPTP exposure. Inhibition of protein synthesis prevented TIDA neuron recovery, suggesting that the ability to recover from injury was dependent on an induced, rather than a constitutive cellular mechanism. Further, there were no changes in total tyrosine hydroxylase (TH) expression following MPTP, indicating that up-regulation of the rate-limiting enzyme in DA synthesis does not account for TIDA neuronal recovery. Differential candidate gene expression analysis revealed a time-dependent increase in parkin and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) expression (mRNA and protein) in TIDA neurons during recovery from injury. Parkin expression was also found to increase with incremental

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

    PubMed

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

    2016-01-01

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

  6. Sport physiology, dopamine and nitric oxide - Some speculations and hypothesis generation.

    PubMed

    Landers, J G; Esch, Tobias

    2015-12-01

    Elite Spanish professional soccer players surprisingly showed a preponderance of an allele coding for nitric oxide synthase (NOS) that resulted in lower nitric oxide (NO) compared with Spanish endurance and power athletes and sedentary men. The present paper attempts a speculative explanation. Soccer is an "externally-paced" (EP) sport and team work dependent, requiring "executive function skills". We accept that time interval estimation skill is, in part, also an executive skill. Dopamine (DA) is prominent among the neurotransmitters with a role in such skills. Polymorphisms affecting dopamine (especially DRD2/ANKK1-Taq1a which leads to lower density of dopamine D2 receptors in the striatum, leading to increased striatal dopamine synthesis) and COMT val 158 met (which prolongs the action of dopamine in the cortex) feature both in the time interval estimation and the executive skills literatures. Our paper may be a pioneering attempt to stimulate empirical efforts to show how genotypes among soccer players may be connected via neurotransmitters to certain cognitive abilities that predict sporting success, perhaps also in some other externally-paced team sports. Graphing DA levels against time interval estimation accuracy and also against certain executive skills reveals an inverted-U relationship. A pathway from DA, via endogenous morphine and mu3 receptors on endothelia, to the generation of NO in tiny quantities has been demonstrated. Exercise up-regulates DA and this pathway. With somewhat excessive exercise, negative feedback from NO down-regulates DA, hypothetically keeping it near the peak of the inverted-U. Other research, not yet done on higher animals or humans, shows NO "fine-tuning" movement. We speculate that Caucasian men, playing soccer recreationally, would exemplify the above pattern and their nitric oxide synthase (NOS) would reflect the norm of their community, whereas professional players of soccer and perhaps other EP sports, with DA boosted by

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

    PubMed

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

    2015-09-28

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

  8. Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D₂/₃ receptors in their high-affinity state.

    PubMed

    van Wieringen, Jan-Peter; Shalgunov, Vladimir; Janssen, Henk M; Fransen, P Michel; Janssen, Anton G M; Michel, Martin C; Booij, Jan; Elsinga, Philip H

    2014-01-23

    Imaging of dopamine D2/3 receptors (D2/3R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D2/3R signaling is involved. Agonist D2/3 tracers for PET/SPECT imaging are considered to be superior to antagonists because they are more sensitive to dopamine concentrations and may selectively label the high-affinity receptor state. Carbon-11-labeled D2/3R agonists have been developed, but these short-lived tracers can be used only in centers with a cyclotron. Here, we report the development of a series of novel D2R agonist compounds based on the 2-aminomethylchromane (AMC) scaffold that provides ample opportunities for the introduction of longer-lived [(18)F] or [(123)I]. Binding experiments showed that several AMC compounds have a high affinity and selectivity for D2/3R and act as agonists. Two fluorine-containing compounds were [(18)F]-labeled, and both displayed specific binding to striatal D2/3R in rat brain slices in vitro. These findings encourage further in vivo evaluations.

  9. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells.

    PubMed

    Tang, Ruoping; Faussat, Anne-Marie; Majdak, Patricia; Marzac, Christophe; Dubrulle, Sabine; Marjanovic, Zora; Legrand, Ollivier; Marie, Jean-Pierre

    2006-03-01

    Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time- and dose-dependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia.

  10. Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release

    DOE PAGES

    Volkow, Nora D.; Wang, Gene-Jack; Smith, Lisa; ...

    2015-07-21

    Metamphetamine’s widepread abuse and concerns that it may increase Parkinson’s disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [11C]cocaine to measure DAT, and with [11C]raclopride to measure dopamine release (assessed as changes in specific binding of [11C]raclopride between placebo and methylphenidate), which was used as marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15).more » In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.« less

  11. Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release

    SciTech Connect

    Volkow, Nora D.; Wang, Gene-Jack; Smith, Lisa; Fowler, Joanna S.; Telang, Frank; Logan, Jean; Tomasi, Dardo

    2015-07-21

    Metamphetamine’s widepread abuse and concerns that it may increase Parkinson’s disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [11C]cocaine to measure DAT, and with [11C]raclopride to measure dopamine release (assessed as changes in specific binding of [11C]raclopride between placebo and methylphenidate), which was used as marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of

  12. Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.

    PubMed

    Lapinsky, David J; Velagaleti, Ranganadh; Yarravarapu, Nageswari; Liu, Yi; Huang, Yurong; Surratt, Christopher K; Lever, John R; Foster, James D; Acharya, Rejwi; Vaughan, Roxanne A; Deutsch, Howard M

    2011-01-01

    In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored. Towards addressing this knowledge gap, ligands were synthesized in which the piperidine nitrogen of 3- and 4-iodomethylphenidate was substituted with a benzyl group bearing a photoreactive azide. Analog (±)-3a demonstrated modest DAT affinity and a radioiodinated version was shown to bind covalently to rat striatal DAT and hDAT expressed in cultured cells. Co-incubation of (±)-3a with nonradioactive d-(+)-methylphenidate or (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT, WIN-35,428, a cocaine analog) blocked DAT labeling. Compound (±)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold. Such ligands are expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters.

  13. Azido-Iodo-N-Benzyl Derivatives of threo-Methylphenidate (Ritalin, Concerta): Rational Design, Synthesis, Pharmacological Evaluation, and Dopamine Transporter Photoaffinity Labeling

    PubMed Central

    Lapinsky, David J.; Velagaleti, Ranganadh; Yarravarapu, Nageswari; Liu, Yi; Huang, Yurong; Surratt, Christopher K.; Lever, John R.; Foster, James D.; Acharya, Rejwi; Vaughan, Roxanne A.; Deutsch, Howard M.

    2010-01-01

    In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored. Towards addressing this knowledge gap, ligands were synthesized in which the piperidine nitrogen of 3- and 4-iodomethylphenidate was substituted with a benzyl group bearing a photoreactive azide. Analog (±)-3a demonstrated modest DAT affinity and a radioiodinated version was shown to bind covalently to rat striatal DAT and hDAT expressed in cultured cells. Co-incubation of (±)-3a with nonradioactive D-(+)-methylphenidate or (−)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT, WIN-35,428, a cocaine analog) blocked DAT labeling. Compound (±)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold. Such ligands are expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters. PMID:21129986

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

    PubMed Central

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

    2014-01-01

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

  15. Microwave-assisted synthesis of a core-shell MWCNT/GONR heterostructure for the electrochemical detection of ascorbic acid, dopamine, and uric acid.

    PubMed

    Sun, Chia-Liang; Chang, Ching-Tang; Lee, Hsin-Hsien; Zhou, Jigang; Wang, Jian; Sham, Tsun-Kong; Pong, Way-Faung

    2011-10-25

    In this study, graphene oxide nanoribbons (GONRs) were synthesized from the facile unzipping of multiwalled carbon nanotubes (MWCNTs) with the help of microwave energy. A core-shell MWCNT/GONR-modified glassy carbon (MWCNT/GONR/GC) electrode was used to electrochemically detect ascorbic acid (AA), dopamine (DA), and uric acid (UA). In cyclic voltammograms, the MWCNT/GONR/GC electrode was found to outperform the MWCNT- and graphene-modified GC electrodes in terms of peak current. For the simultaneous sensing of three analytes, well-separated voltammetric peaks were obtained using a MWCNT/GONR/GC electrode in differential pulse voltammetry measurements. The corresponding peak separations were 229.9 mV (AA to DA), 126.7 mV (DA to UA), and 356.6 mV (AA to UA). This excellent electrochemical performance can be attributed to the unique electronic structure of MWCNTs/GONRs: a high density of unoccupied electronic states above the Fermi level and enriched oxygen-based functionality at the edge of the graphene-like structures, as revealed by X-ray absorption near-edge structure spectroscopy, obtained using scanning transmission X-ray microscopy.

  16. Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics*

    PubMed Central

    Moritz, Amy E.; Rastedt, Danielle E.; Stanislowski, Daniel J.; Shetty, Madhur; Smith, Margaret A.; Vaughan, Roxanne A.; Foster, James D.

    2015-01-01

    The dopamine transporter is a neuronal protein that drives the presynaptic reuptake of dopamine (DA) and is the major determinant of transmitter availability in the brain. Dopamine transporter function is regulated by protein kinase C (PKC) and other signaling pathways through mechanisms that are complex and poorly understood. Here we investigate the role of Ser-7 phosphorylation and Cys-580 palmitoylation in mediating steady-state transport kinetics and PKC-stimulated transport down-regulation. Using both mutational and pharmacological approaches, we demonstrate that these post-translational modifications are reciprocally regulated, leading to transporter populations that display high phosphorylation-low palmitoylation or low phosphorylation-high palmitoylation. The balance between the modifications dictates transport capacity, as conditions that promote high phosphorylation or low palmitoylation reduce transport Vmax and enhance PKC-stimulated down-regulation, whereas conditions that promote low phosphorylation or high palmitoylation increase transport Vmax and suppress PKC-stimulated down-regulation. Transitions between these functional states occur when endocytosis is blocked or undetectable, indicating that the modifications kinetically regulate the velocity of surface transporters. These findings reveal a novel mechanism for control of DA reuptake that may represent a point of dysregulation in DA imbalance disorders. PMID:26424792

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-07-09

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

  19. In situ electrochemical synthesis of highly loaded zirconium nanoparticles decorated reduced graphene oxide for the selective determination of dopamine and paracetamol in presence of ascorbic acid.

    PubMed

    Ezhil Vilian, A T; Rajkumar, Muniyandi; Chen, Shen-Ming

    2014-03-01

    Highly loaded zirconium oxide (ZrO2) nanoparticles were supported on graphene oxide (ERGO/ZrO2) via an in situ, simple and clean strategy on the basis of the electrochemical redox reaction between zirconyl chloride and graphene oxide (ZrOCl2 and GO). The electrochemical measurements and surface morphology of the as prepared nanocomposite were studied using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and field emission scanning electron microscopy (FESEM). This ZrO2 decorated reduced graphene oxide nanocomposite modified GCE (ERGO/ZrO2) exhibits a prominent electrocatalytic activity toward the selective detection and determination of dopamine (DA) and paracetamol (PA) in presence of ascorbic acid (AA). The peaks of linear sweep voltammetry (LSV) for DA and PA oxidation at ERGO/ZrO2 modified electrode surface were clearly separated from each other when they co-existed in the physiological pH (pH 7.0) with a potential value of 140 mV (between AA and DA) and 330 mV (between AA and PA). It was, therefore, possible to simultaneously determine DA and PA in the samples at ERGO/ZrO2 nanocomposite modified GCE. Linear calibration curves were obtained for 9-237 μM of PA and DA. The ERGO/ZrO2 nanocomposite electrode has been satisfactorily used for the determination of DA and PA in the presence of AA at pharmaceutical formulations in human urine samples with a linear range of 3-174 μM. The proposed biosensor shows a wide linear range, low detection limit, good reproducibility and acceptable stability, providing a biocompatible platform for bio sensing and bio catalysis.

  20. Click Synthesis of Hydrophilic Maltose-Functionalized Iron Oxide Magnetic Nanoparticles Based on Dopamine Anchors for Highly Selective Enrichment of Glycopeptides.

    PubMed

    Bi, Changfen; Zhao, Yingran; Shen, Lijin; Zhang, Kai; He, Xiwen; Chen, Langxing; Zhang, Yukui

    2015-11-11

    The development of methods to isolate and enrich low-abundance glycopeptides from biological samples is crucial to glycoproteomics. Herein, we present an easy and one-step surface modification strategy to prepare hydrophilic maltose functionalized Fe3O4 nanoparticles (NPs). First, based on the chelation of the catechol ligand with iron atoms, azido-terminated dopamine (DA) derivative was assembled on the surface of magnetic Fe3O4 nanoparticles by sonication. Second, the hydrophilic maltose-functionalized Fe3O4 (Fe3O4-DA-Maltose) NPs were obtained via copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). The morphology, structure, and composition of Fe3O4-DA-Maltose NPs were investigated by Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray powder diffraction (XRD), X-ray photoelectron spectrometer (XPS), and vibrating sample magnetometer (VSM). Meanwhile, hydrophilicity of the obtained NPs was evaluated by water contact angle measurement. The hydrophilic Fe3O4-DA-Maltose NPs were applied in isolation and enrichment of glycopeptides from horseradish peroxidase (HRP), immunoglobulin (IgG) digests. The MALDI-TOF mass spectrometric analysis indicated that the novel NPs exhibited high detection sensitivity in enrichment from HRP digests at concentration as low as 0.05 ng μL(-1), a large binding capacity up to 43 mg g(-1), and good recovery for glycopeptides enrichment (85-110%). Moreover, the Fe3O4-DA-Maltose NPs were applied to enrich glycopeptides from human renal mesangial cells (HRMC) for identification of N-glycosylation sites. Finally, we identified 115 different N-linked glycopeptides, representing 93 gene products and 124 glycosylation sites in HRMC.

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

    PubMed

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

    2007-02-28

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

  2. Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression.

    PubMed

    Liu, Guoxiang; Sgobio, Carmelo; Gu, Xinglong; Sun, Lixin; Lin, Xian; Yu, Jia; Parisiadou, Loukia; Xie, Chengsong; Sastry, Namratha; Ding, Jinhui; Lohr, Kelly M; Miller, Gary W; Mateo, Yolanda; Lovinger, David M; Cai, Huaibin

    2015-09-15

    Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release.

  3. An electrochemical sensor prepared by sonochemical one-pot synthesis of multi-walled carbon nanotube-supported cobalt nanoparticles for the simultaneous determination of paracetamol and dopamine.

    PubMed

    Kutluay, Aysegul; Aslanoglu, Mehmet

    2014-08-11

    Multi-walled carbon nanotubes (MWCNTs) functionalized by cobalt nanoparticles were obtained using a single step chemical deposition method in an ultrasonic bath. The composite material was characterized using scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX). The electroactivity of the cobalt-functionalized MWCNTs was assessed in respect to the electrooxidation of paracetamol (PAR) and dopamine (DA). It was found that the carbon nanotube supported cobalt nanoparticles have significantly higher catalytic properties. The proposed electrode has been applied for the simultaneous determination of PAR and DA. The modified electrode could resolve the overlapped voltammetric waves of PAR and DA into two well-defined voltammetric peaks with peak to peak separation of about 203 mV. On the other hand, the presence of potential drug interfering compounds AA and UA did not affect the voltammetric responses of PAR and DA. The current of oxidation peaks showed a linear dependent on the concentrations of PAR and DA in the range of 5.2×10(-9)-4.5×10(-7) M (R(2)=0.9987) and 5.0×10(-8)-3.0×10(-6) M (R(2)=0.9999), respectively. The detection limits of 1.0×10(-9) M and 1.5×10(-8) M were obtained for PAR and DA, respectively. The proposed electrode showed good stability (peak current change: 4.9% with and RSD of 2.6% for PAR; 5.5% with and RSD of 3.0% for DA over 3 weeks), reproducibility (RSD 2.3% for PAR and RSD 1.5% for DA), repeatability (RSD 2.25% for PAR and RSD 2.50% for DA) and high recovery (99.7% with an RSD of 1.3% for PAR; 100.8% with an RSD of 1.8% for DA). The proposed method was successfully applied to the determination of PAR and DA in pharmaceuticals.

  4. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine.

    PubMed

    Chase, T N

    1998-05-01

    Normal motor function is dependent on the highly regulated synthesis and release of the transmitter dopamine by neurons projecting from the substantia nigra to the corpus striatum. Parkinson's disease involves the progressive degeneration of these neurons. Its core symptoms are a direct consequence of a striatal insufficiency of intrasynaptic dopamine. Levodopa, the standard of care for the treatment of PD, acts after its conversion to dopamine by restoring striatal dopaminergic transmission. However, there are significant differences between the normally functioning dopamine system and the restoration of function provided by standard levodopa treatment. Increasing clinical and preclinical evidence suggests that the intermittent stimulation of dopamine receptors resulting from current therapeutic regimens contributes to the response complications that ultimately affect most parkinsonian patients. It now appears that chronic nonphysiologic stimulation of dopaminergic receptors on striatal GABAergic neurons activates characteristic signaling pathways, leading to a potentiation of the synaptic efficacy of adjacent glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype. As a result, function of these GABAergic efferent neurons changes in ways that favor the appearance of motor complications. Conceivably, use of dopaminomimetic replacement strategies that provide more continuous dopamine receptor stimulation will act to prevent or alleviate these disabling complications. A number of promising approaches to achieving this goal are now under development.

  5. Dopamine and anorexia nervosa.

    PubMed

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

    2016-01-01

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

  6. Knocking out the dopamine reuptake transporter (DAT) does not change the baseline brain arachidonic acid signal in the mouse

    PubMed Central

    Ramadan, Epolia; Chang, Lisa; Chen, Mei; Ma, Kaizong; Hall, F. Scott; Uhl, George R.; Rapoport, Stanley I.; Basselin, Mireille

    2012-01-01

    Background Dopamine transporter (DAT) homozygous knockout (DAT−/−) mice have a 10-fold higher extracellular DA concentration in the caudate-putamen and nucleus accumbens than do wildtype (DAT+/+) mice, but show reduced presynaptic DA synthesis and fewer postsynaptic D2 receptors. One aspect of neurotransmission involves DA binding to postsynaptic D2-like receptors coupled to cytosolic phospholipase A2 (cPLA2), releasing second messenger arachidonic acid (AA) from synaptic membrane phospholipid. We hypothesized that tonic overactivation of D2-like receptors in DAT−/− mice due to elevated DA would not increase brain AA signaling, because of compensatory downregulation of postsynaptic signaling mechanisms. Methods [1-14C]AA was infused intravenously for 3 min in unanesthetized DAT+/+, heterozygous (DAT+/−) and DAT−/− mice. AA incorporation coefficients k* and rates Jin, markers of AA metabolism and signaling, were imaged in 83 brain regions using quantitative autoradiography brain cPLA2-IV activity also was measured. Results Neither k* nor Jin for AA in any brain region, or in brain cPLA2-IV activity, differed significantly between DAT−/−, DAT+/− and DAT+/+ mice. Conclusions These results differ from reported increases in k* and Jin for AA, and brain cPLA2 expression, in serotonin reuptake transporter (5-HTT) knockout mice, and suggest that postsynaptic dopaminergic neurotransmission mechanisms involving AA are downregulated despite elevated DA in DAT−/− mice. PMID:22376027

  7. Growth of dopamine crystals

    NASA Astrophysics Data System (ADS)

    Patil, Vidya; Patki, Mugdha

    2016-05-01

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

  8. Updating dopamine reward signals

    PubMed Central

    Schultz, Wolfram

    2013-01-01

    Recent work has advanced our knowledge of phasic dopamine reward prediction error signals. The error signal is bidirectional, reflects well the higher order prediction error described by temporal difference learning models, is compatible with model-free and model-based reinforcement learning, reports the subjective rather than physical reward value during temporal discounting and reflects subjective stimulus perception rather than physical stimulus aspects. Dopamine activations are primarily driven by reward, and to some extent risk, whereas punishment and salience have only limited activating effects when appropriate controls are respected. The signal is homogeneous in terms of time course but heterogeneous in many other aspects. It is essential for synaptic plasticity and a range of behavioural learning situations. PMID:23267662

  9. Morbillivirus downregulation of CD46.

    PubMed

    Galbraith, S E; Tiwari, A; Baron, M D; Lund, B T; Barrett, T; Cosby, S L

    1998-12-01

    There is evidence that CD46 (membrane cofactor protein) is a cellular receptor for vaccine and laboratory-passaged strains of measles virus (MV). Following infection with these MV strains, CD46 is downregulated from the cell surface, and consequent complement-mediated lysis has been shown to occur upon infection of a human monocytic cell line. The MV hemagglutinin (H) protein alone is capable of inducing this downregulation. Some wild-type strains of MV fail to downregulate CD46, despite infection being prevented by anti-CD46 antibodies. In this study we show that CD46 is also downregulated to the same extent by wild-type, vaccine, and laboratory-passaged strains of rinderpest virus (RPV), although CD46 did not appear to be the receptor for RPV. Expression of the RPV H protein by a nonreplicating adenovirus vector was also found to cause this downregulation. A vaccine strain of peste des petits ruminants virus caused slight downregulation of CD46 in infected Vero cells, while wild-type and vaccine strains of canine distemper virus and a wild-type strain of dolphin morbillivirus failed to downregulate CD46. Downregulation of CD46 can, therefore, be a function independent of the use of this protein as a virus receptor.

  10. Immunomodulatory Effects Mediated by Dopamine.

    PubMed

    Arreola, Rodrigo; Alvarez-Herrera, Samantha; Pérez-Sánchez, Gilberto; Becerril-Villanueva, Enrique; Cruz-Fuentes, Carlos; Flores-Gutierrez, Enrique Octavio; Garcés-Alvarez, María Eugenia; de la Cruz-Aguilera, Dora Luz; Medina-Rivero, Emilio; Hurtado-Alvarado, Gabriela; Quintero-Fabián, Saray; Pavón, Lenin

    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.

  11. Immunomodulatory Effects Mediated by Dopamine

    PubMed Central

    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

  12. Genetics Home Reference: dopamine transporter deficiency syndrome

    MedlinePlus

    ... Genetics Home Health Conditions dopamine transporter deficiency syndrome dopamine transporter deficiency syndrome Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

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

    PubMed Central

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

    2014-01-01

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

  14. Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain

    PubMed Central

    Kubrusly, Regina C. C.; Bhide, Pradeep G.

    2009-01-01

    Exposure to cocaine during the fetal period can produce significant lasting changes in the structure and function of the brain. Cocaine exerts its effects on the developing brain by blocking monoamine transporters and impairing monoamine receptor signaling. Dopamine is a major central target of cocaine. In a mouse model, we show that cocaine exposure from embryonic day 8 (E8) to E14 produces significant reduction in dopamine transporter activity, attenuation of dopamine D1-receptor function and upregulation of dopamine D2-receptor function. Cocaine’s effects on the D1-receptor are at the level of protein expression as well as activity. The cocaine exposure also produces significant increases in basal cAMP levels in the striatum and cerebral cortex. The increase in the basal cAMP levels was independent of dopamine receptor activity. In contrast, blocking the adenosine A2a receptor downregulated of the basal cAMP levels in the cocaine-exposed brain to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine’s effects on the embryonic brain. In support of this suggestion, we found that the cocaine exposure downregulated adenosine transporter function. We also found that dopamine D2- and adenosine A2a-receptors antagonize each other’s function in the embryonic brain in a manner consistent with their interactions in the mature brain. Thus, our data show that prenatal cocaine exposure produces direct effects on both the dopamine and adenosine systems. Furthermore, the dopamine D2 and adenosine A2a receptor interactions in the embryonic brain discovered in this study unveil a novel substrate for cocaine’s effects on the developing brain. PMID:19765599

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

    SciTech Connect

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

    1988-05-01

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

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

    PubMed

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

    2016-03-01

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

  17. Quercetin-3-O-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside suppresses melanin synthesis by augmenting p38 MAPK and CREB signaling pathways and subsequent cAMP down-regulation in murine melanoma cells

    PubMed Central

    Jung, Hyun Gug; Kim, Han Hyuk; Paul, Souren; Jang, Jae Yoon; Cho, Yong Hun; Kim, Hyeon Jeong; Yu, Jae Myo; Lee, Eun Su; An, Bong Jeun; Kang, Sun Chul; Bang, Byung Ho

    2015-01-01

    In this study, the effect of purified quercetin-3-O-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosid (QCGG) on melanogenesis was investigated. QCGG was isolated from the calyx of a traditional Korean medicinal herb, Persimmon (Diospyros kaki). The hypopigmentation effects of QCGG were determined by examination of cellular melanin contents, tyrosinase activity assay, cAMP assay, and Western blotting of α-MSH-stimulated B16F10 mouse melanoma cells. Our results showed that QCGG inhibited both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly reduced the expression of melanogenic proteins such as microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1, tyrosinase-related protein-2, and tyrosinase. Moreover, QCGG inhibited intracellular cAMP levels, cAMP response element-binding protein (CREB), and p38 MAPK expression in α-MSH-stimulated B16F10 cells. Taken together, the suppressive effects of QCGG on melanogenesis may involve down-regulation of MITF and its downstream signaling pathway via phosphorylation of p38 MAPK and CREB along with reduced cAMP levels. These results indicate that QCGG reduced melanin synthesis by reducing expression of tyrosine and tyrosine-related proteins via extracellular signal-related protein kinase (ERK) activation, followed by down-regulation of CREB, p38, and MITF. PMID:26586997

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

    PubMed

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

    2016-01-01

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

  19. Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine.

    PubMed

    Peeters, Magali; Page, Guylène; Maloteaux, Jean-Marie; Hermans, Emmanuel

    2002-09-13

    Amantadine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to increase dopamine synthesis and release in the striatum, is frequently associated with L-DOPA in the treatment of Parkinson's disease. However, the biochemical mechanisms involved in the effect of amantadine and the consequences of its repetitive administration on the modulation of striatal dopamine transmission still need to be clarified. We have investigated the effects of short-term amantadine treatments on the expression of dopamine receptors and the functional coupling to G proteins in rat striatal membranes. Dopamine-induced stimulation of guanosine 5'-[gamma-35S]triphosphate ([35S]GTPgammaS) binding was significantly enhanced (40%) in striatum homogenates from rats treated for 4 days with amantadine (40 mg/kg, i.p.) compared to vehicle-treated animals. This effect was specific for dopamine receptors and was transient as no significant modifications were observed when animals were treated for either 2 or 7 days. Administration of amantadine did not directly affect the animal behaviour. However, treated animals exhibited hypersensitive dopamine transmission since rats treated for 4 days showed exacerbated responses to a single apomorphine administration (enhanced locomotor activity and reduced stereotypy). Since the effects of amantadine administration differ from those usually observed with direct dopamine receptor agonists or other NMDA receptor antagonists, we suggest that multiple biochemical mechanisms contribute to the modulation of dopamine transmission by amantadine.

  20. Complexity of dopamine metabolism

    PubMed Central

    2013-01-01

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

  1. Differences in Number of Midbrain Dopamine Neurons Associated with Summer and Winter Photoperiods in Humans

    PubMed Central

    Aumann, Tim D.; Raabus, Mai; Tomas, Doris; Prijanto, Agustinus; Churilov, Leonid; Spitzer, Nicholas C.; Horne, Malcolm K.

    2016-01-01

    Recent evidence indicates the number of dopaminergic neurons in the adult rodent hypothalamus and midbrain is regulated by environmental cues, including photoperiod, and that this occurs via up- or down-regulation of expression of genes and proteins that are important for dopamine (DA) synthesis in extant neurons (‘DA neurotransmitter switching’). If the same occurs in humans, it may have implications for neurological symptoms associated with DA imbalances. Here we tested whether there are differences in the number of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) and DA transporter (DAT) immunoreactive neurons in the midbrain of people who died in summer (long-day photoperiod, n = 5) versus winter (short-day photoperiod, n = 5). TH and DAT immunoreactivity in neurons and their processes was qualitatively higher in summer compared with winter. The density of TH immunopositive (TH+) neurons was significantly (~6-fold) higher whereas the density of TH immunonegative (TH-) neurons was significantly (~2.5-fold) lower in summer compared with winter. The density of total neurons (TH+ and TH- combined) was not different. The density of DAT+ neurons was ~2-fold higher whereas the density of DAT- neurons was ~2-fold lower in summer compared with winter, although these differences were not statistically significant. In contrast, midbrain nuclear volume, the density of supposed glia (small TH- cells), and the amount of TUNEL staining were the same in summer compared with winter. This study provides the first evidence of an association between environmental stimuli (photoperiod) and the number of midbrain DA neurons in humans, and suggests DA neurotransmitter switching underlies this association. PMID:27428306

  2. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts.

    PubMed

    Vousooghi, Nasim; Zarei, Seyed Zeinolabedin; Sadat-Shirazi, Mitra-Sadat; Eghbali, Fatemeh; Zarrindast, Mohammad Reza

    2015-10-01

    Excessive playing of computer games like some other behaviors could lead to addiction. Addictive behaviors may induce their reinforcing effects through stimulation of the brain dopaminergic mesolimbic pathway. The status of dopamine receptors in the brain may be parallel to their homologous receptors in peripheral blood lymphocytes (PBLs). Here, we have investigated the mRNA expression of dopamine D3, D4 and D5 receptors in PBLs of computer game addicts (n = 20) in comparison to normal subjects (n = 20), using a real-time PCR method. The results showed that the expression level of D3 and D4 dopamine receptors in computer game addicts were not statistically different from the control group. However, the expression of the mRNA of D5 dopamine receptor was significantly down-regulated in PBLs of computer game addicts and reached 0.42 the amount of the control group. It is concluded that unlike with drug addiction, the expression levels of the D3 and D4 dopamine receptors in computer game addicts are not altered compared to the control group. However, reduced level of the D5 dopamine receptor in computer game addicts may serve as a peripheral marker in studies where the confounding effects of abused drugs are unwanted.

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

    PubMed Central

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

    2016-01-01

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

  4. Dopamine reward prediction error coding.

    PubMed

    Schultz, Wolfram

    2016-03-01

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

  5. Dopamine reward prediction error coding

    PubMed Central

    Schultz, Wolfram

    2016-01-01

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

  6. Dopamine, Affordance and Active Inference

    PubMed Central

    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

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

    PubMed Central

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  9. Endogenous dopamine is involved in the herbicide paraquat-induced dopaminergic cell death.

    PubMed

    Izumi, Yasuhiko; Ezumi, Masayuki; Takada-Takatori, Yuki; Akaike, Akinori; Kume, Toshiaki

    2014-06-01

    The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50μM) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins.

  10. Dopamine Receptors and Neurodegeneration

    PubMed Central

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

    2015-01-01

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

  11. The nature of dopamine dysfunction in schizophrenia and what this means for treatment

    PubMed Central

    Howes, Oliver D; Kambeitz, Joseph; Kim, Euitae; Stahl, Daniel; Slifstein, Mark; Abi-Dargham, Anissa; Kapur, Shitij

    2013-01-01

    Context Current drug treatments for schizophrenia are inadequate for many patients and, despite five decades of drug discovery, all use the same mechanism-dopamine D2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. Objective To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. Data sources The MEDLINE, EMBASE and PsychINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Study selection Forty-four studies were identified that compared in vivo striatal dopaminergic function in 618 patients with schizophrenia with 606 controls using positron emission tomography or single photon emission computed tomography. Data extraction Demographic, clinical and imaging variables were extracted from each study and effect sizes determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function, and dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. Data synthesis There was a highly significant elevation (p<0.0001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen’s d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D2/3 receptor availability (Cohen’s d=0.26), but this was not evident in drug-naïve patients and was influenced by the imaging approach used. Conclusions The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic-affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release. Current drug treatments - which primarily act at D2/3 receptors - fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine

  12. Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells.

    PubMed

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

    2015-01-01

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

  13. Dopamine regulates body size in Caenorhabditis elegans.

    PubMed

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

    2016-04-01

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

  14. Dopamine, reward learning, and active inference

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    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.

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

    PubMed

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

    2014-09-01

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

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

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

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

  18. Chaotic behavior in dopamine neurodynamics.

    PubMed Central

    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 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. PMID:6583705

  19. Chaotic behavior in dopamine neurodynamics.

    PubMed

    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.

  20. Protein Kinase C Beta Regulates the D2-Like Dopamine Autoreceptor

    PubMed Central

    Luderman, Kathryn D.; Chen, Rong; Ferris, Mark J.; Jones, Sara R.; Gnegy, Margaret E.

    2014-01-01

    The focus of this study was the regulation of the D2-like dopamine autoreceptor (D2 autoreceptor) by protein kinase Cβ, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing autoreceptors to increase the release of several different neurotransmitters. Here, using both PKCβ−/− mice and specific PKCβ inhibitors, we demonstrated that a lack of PKCβ activity enhanced the D2 autoreceptor-stimulated decrease in dopamine release following both chemical and electrical stimulations. Inhibition of PKCβ increased surface localization of D2R in mouse striatal synaptosomes, which could underlie the greater sensitivity to quinpirole following inhibition of PKCβ. PKCβ−/− mice displayed greater sensitivity to the quinpirole-induced suppression of locomotor activity, demonstrating that the regulation of the D2 autoreceptor by PKCβ is physiologically significant. Overall, we have found that PKCβ downregulates the D2 autoreceptor, providing an additional layer of regulation for dopaminergic signaling. We propose that in the absence of PKCβ activity, surface D2 autoreceptor localization and thus D2 autoreceptor signaling is increased, leading to less dopamine in the extracellular space and attenuated dopaminergic signaling. PMID:25446677

  1. Early direct and transneuronal effects in mice with targeted expression of a toxin gene to D1 dopamine receptor neurons.

    PubMed

    Padungchaichot, P; Wong, J Y; Natoli, A L; Massalas, J S; Finkelstein, D I; Lawrence, A L; Drago, J

    2000-01-01

    The neurochemical profile was examined at postnatal day 3-4 in mutant mice generated by in vivo Cre mediated activation of an attenuated diphtheria toxin gene inserted into the D1 dopamine receptor gene locus. An earlier study of this model had shown that D1 dopamine receptor, substance P and dynorphin were not expressed in the striatum. Quantitative in situ hybridization analysis showed an increase in D2 dopamine receptor and enkephalin messenger RNA expression. The nigrostriatal pathway in the mutant pups was intact with a normal number of dopaminergic neurons in the substantia nigra and the ventral tegmental area in addition to a normal pattern of striatal dopamine transporter and tyrosine hydroxylase immunoreactivity. Quantitative analysis of striatal dopamine transporter density using [3H]mazindol showed a reduction of 26% suggesting a degree of transneuronal down-regulation. There was also a 49% reduction of striatal GABA receptor binding and a 36% reduction of striatal muscarinic receptor binding in mutant pups. The number of healthy striatal neuropeptide Y-containing interneurons was also substantially down-regulated in the mutant striatum. In contrast, there was an increase in the number of striatal cholinergic interneurons. Down-regulated cortical GABA receptor and muscarinic receptor binding was also observed in addition to subtle morphological changes in the neuropeptide Y-expressing population of cortical neurons. The changes reflect the early cascade of events which follows the ablation of D1 dopamine receptor-positive cells. Although extensive changes in a number of striatal and cortical neurons were demonstrated, only subtle transneuronal effects were seen in the nigrostriatal pathway.

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2015-10-05

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

  4. Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

    PubMed

    Schabram, Ina; Henkel, Karsten; Mohammadkhani Shali, Siamak; Dietrich, Claudia; Schmaljohann, Jörn; Winz, Oliver; Prinz, Susanne; Rademacher, Lena; Neumaier, Bernd; Felzen, Marc; Kumakura, Yoshitaka; Cumming, Paul; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

    2014-10-29

    Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

  5. Dopamine supports coupling of attention-related networks.

    PubMed

    Dang, Linh C; O'Neil, James P; Jagust, William J

    2012-07-11

    Attentional processing has been associated with the dorsal attention, default mode, and frontoparietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The frontoparietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network, depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used PET with 6-[(18)F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and fMRI to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the frontoparietal control network and the default mode network while reducing the coupling between the frontoparietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.

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

    PubMed

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

    2016-04-01

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

  7. Antiferroptotic activity of non-oxidative dopamine.

    PubMed

    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.

  8. Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons

    PubMed Central

    Chakraborty, Saikat; Rebecchi, Mario; Kaczocha, Martin

    2016-01-01

    Key points Transient receptor potential vanilloid type 1 (TRPV1) receptors transduce noxious thermal stimuli and are responsible for the thermal hyperalgesia associated with inflammatory pain.A large population of dorsal root ganglia (DRG) neurons, including the C low threshold mechanoreceptors (C‐LTMRs), express tyrosine hydroxylase, and probably release dopamine.We found that dopamine and SKF 81297 (an agonist at D1/D5 receptors), but not quinpirole (an agonist at D2 receptors), downregulate the activity of TRPV1 channels in DRG neurons.The inhibitory effect of SKF 81297 on TRPV1 channels was strongly dependent on external calcium and preferentially linked to calcium–calmodulin‐dependent protein kinase II (CaMKII).We suggest that modulation of TRPV1 channels by dopamine in nociceptive neurons may represent a way for dopamine to modulate incoming noxious stimuli. Abstract The transient receptor potential vanilloid type 1 (TRPV1) receptor plays a key role in the modulation of nociceptor excitability. To address whether dopamine can modulate the activity of TRPV1 channels in nociceptive neurons, the effects of dopamine and dopamine receptor agonists were tested on the capsaicin‐activated current recorded from acutely dissociated small diameter (<27 μm) dorsal root ganglia (DRG) neurons. Dopamine or SKF 81297 (an agonist at D1/D5 receptors), caused inhibition of both inward and outward currents by ∼60% and ∼48%, respectively. The effect of SKF 81297 was reversed by SCH 23390 (an antagonist at D1/D5 receptors), confirming that it was mediated by activation of D1/D5 dopamine receptors. In contrast, quinpirole (an agonist at D2 receptors) had no significant effect on the capsaicin‐activated current. Inhibition of the capsaicin‐activated current by SKF 81297 was mediated by G protein coupled receptors (GPCRs), and highly dependent on external calcium. The inhibitory effect of SKF 81297 on the capsaicin‐activated current was not affected when

  9. Identification of an intronic cis-acting element in the human dopamine transporter gene

    PubMed Central

    Zhao, Ying; Zhou, Yanhong; Lin, Zhicheng

    2017-01-01

    The human dopamine transporter gene (hDAT) encodes the dopamine transporter in dopamine (DA) neurons to regulate DA transmission. hDAT expression varies significantly from neuron to neuron, and from individual to individual so that dysregulation of hDAT is related to many neuropsychiatric disorders. It is critical to identify hDAT-specific cis-acting elements that regulate the hDAT expression. Previous studies showed that hDAT Intron 1 displayed inhibitory activity for reporter gene expression. Here we report that the hDAT Intron 1 contains a 121-bp fragment that down-regulated both SV40 and hDAT promoter activities by 80% in vitro. Subfragments of 121-bp still down-regulated the SV40 promoter but not the hDAT promoter, as supported by nuclear protein-binding activities. Collectively, 121-bp is a silencer in vitro that might coordinate with transcriptional activities both inside and outside 121-bp in regulation of hDAT. PMID:22160470

  10. Genetics Home Reference: dopamine beta-hydroxylase deficiency

    MedlinePlus

    ... Genetics Home Health Conditions dopamine beta-hydroxylase deficiency dopamine beta-hydroxylase deficiency Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Dopamine beta (β)-hydroxylase deficiency is a condition that ...

  11. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis.

    PubMed

    Seeman, Philip; Madras, Bertha

    2002-03-10

    How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2-0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.

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

    SciTech Connect

    Phillippe, M.; Niloff, J.M.

    1982-08-01

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

  13. Dopamine receptors – IUPHAR Review 13

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    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.

  15. Mesolimbic Dopamine Signals the Value of Work

    PubMed Central

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

    2015-01-01

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

  16. Effects of chronic methamphetamine on psychomotor and cognitive functions and dopamine signaling in the brain.

    PubMed

    Thanos, Panayotis K; Kim, Ronald; Delis, Foteini; Rocco, Mark J; Cho, Jacob; Volkow, Nora D

    2017-03-01

    Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed.

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

    NASA Astrophysics Data System (ADS)

    Uysal, Şaban; Koç, Ziya Erdem

    2016-04-01

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

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

    PubMed

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

    2015-03-31

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

  19. l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes

    PubMed Central

    Takeshima, Mika; Miyazaki, Ikuko; Murakami, Shinki; Kita, Taizo; Asanuma, Masato

    2016-01-01

    l-Theanine (γ-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of l-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with l-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with l-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to l-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from l-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of l-glutamate with l-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, l-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that l-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione. PMID:27698535

  20. l-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes.

    PubMed

    Takeshima, Mika; Miyazaki, Ikuko; Murakami, Shinki; Kita, Taizo; Asanuma, Masato

    2016-09-01

    l-Theanine (γ-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of l-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with l-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with l-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to l-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from l-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of l-glutamate with l-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, l-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that l-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione.

  1. Prenatal stress, moderate fetal alcohol, and dopamine system function in rhesus monkeys.

    PubMed

    Roberts, A D; Moore, C F; DeJesus, O T; Barnhart, T E; Larson, J A; Mukherjee, J; Nickles, R J; Schueller, M J; Shelton, S E; Schneider, M L

    2004-01-01

    This study examined the striatal dopamine system integrity and associated behavior in 5- to 7-year-old rhesus monkeys born from mothers that experienced stress and/or consumed moderate levels of alcohol during pregnancy. Thirty-one young adult rhesus monkeys were derived from females randomly assigned to one of four groups: (1) control group that consumed isocaloric sucrose solution throughout gestation; (2) stress group that experienced prenatal stress (10-min removal from home cage and exposure to three random loud noise bursts, gestational days 90 through 145); (3) alcohol group that consumed alcohol (0.6 g/kg/day) throughout gestation; or (4) combined alcohol plus stress group that received both treatments. The subjects were assessed for striatal dopamine system function using positron emission tomography (PET), in which the dopamine (DA)-rich striatum was evaluated in separate scans for the trapping of [(18)F]-Fallypride (FAL) and 6-[(18)F]fluoro-m-tyrosine (FMT) to assess dopamine D2 receptor binding potential (BP) and DA synthesis via dopa decarboxylase activity, respectively. Subjects were previously assessed for non-matching-to-sample (NMS) task acquisition, with ratings of behavioral inhibition, stereotypies, and activity made after each NMS testing session. Subjects from prenatal stress conditions (Groups 2 and 4) showed an increase in the ratio of striatal dopamine D2 receptor BP and DA synthesis compared to controls (Group 1). An increase in the radiotracer distribution volume ratios (DVRs), which is used to evaluate the balance between striatal DA synthesis and receptor availability, respectively, was significantly correlated with less behavioral inhibition. The latter supports a hypothesis linking striatal function to behavioral inhibitory control.

  2. [Role of DopR in the molecular mechanism of the dopamine control of juvenile hormone metabolism in female Drosophila].

    PubMed

    Karpova, E K; Bogomolova, E V; Romonova, I V; Gruntenko, N E; Raushenbakh, I Iu

    2012-08-01

    The effect of a decreased availability of the D1-like dopamine receptor (DopR) in Drosophila (caused by DopR antagonist added into food) on the juvenile hormone (JH) synthesis rate in young female D. melanogaster has been studied. The JH degradation rate and the alkaline phosphatase (ALP) and tyrosine decarboxylase (TDC) activities were used as indicators of the JH synthesis rate. Treatment of the flies with butaclamol, a specific DopR antagonist, has been demonstrated to increase the JH degradation rate, and the stress reactivity of the system of JH metabolism and decrease the ALP activity and stress reactivity, and increase the TDC activity and stress reactivity. As shown earlier, all this indicates a decrease in the JH synthesis rate in young female drosophila with a decreased DopR availability. It is concluded that the activating effect of dopamine on JH synthesis in Drosophila is mediated by D1-like receptors.

  3. Viral-mediated temporally controlled dopamine production in a rat model of Parkinson disease.

    PubMed

    Li, Xiao-Gang; Okada, Takashi; Kodera, Mika; Nara, Yuko; Takino, Naomi; Muramatsu, Chieko; Ikeguchi, Kunihiko; Urano, Fumi; Ichinose, Hiroshi; Metzger, Daniel; Chambon, Pierre; Nakano, Imaharu; Ozawa, Keiya; Muramatsu, Shin-Ichi

    2006-01-01

    Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor alpha (CreER(T2)) was delivered along with AAV vectors expressing dopamine-synthesizing enzymes to rats of a Parkinson disease model. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated Cre recombinase within the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence flanked by loxP sites, leading to a reduction in transgene-mediated dopamine synthesis. Using this strategy, aromatic L-amino acid decarboxylase (AADC) activity was retained so that l-3,4-dihydroxyphenylalanine (L-dopa), a substrate for AADC, could be converted to dopamine in the striatum and the therapeutic effects of L-dopa preserved, even after reduction of TH expression in the case of dopamine overproduction. Our data demonstrate that viral vector-mediated inducible Cre recombinase can serve as an in vivo molecular switch, allowing spatial and temporal control of transgene expression, thereby potentially increasing the safety of gene therapy.

  4. Metabolism of dopamine by the nasal mucosa.

    PubMed

    Chemuturi, Nagendra V; Donovan, Maureen D

    2006-11-01

    The nasal route of administration offers several advantages over oral and intravenous administration, including the ability to avoid hepatic first pass metabolism. Dopamine deficiency has been associated with several neurological disorders; it has been shown to have good systemic bioavailability and significant uptake into the CNS following intranasal administration. The purpose of these studies was to investigate the limiting role of mucosal metabolism of dopamine during nasal absorption. In vitro transport and initial rate studies were carried out using nasal mucosal explants to study dopamine permeability and metabolism. Dihydroxyphenylacetic acid (DOPAC) was the only metabolite detected. Monoamine oxidase (MAO), the enzyme responsible for DOPAC formation, was localized to the submucosal region of the nasal explants. The amount of DOPAC formed during the transport studies was less than 0.5% of the initial amount of dopamine placed into the system. Iproniazid, an MAO inhibitor, blocked DOPAC formation but had no effect on dopamine transport. The limited extent of dopamine metabolism compared to its mucosal transport demonstrates that nasal dopamine transport is not significantly reduced by mucosal metabolism and suggests that the nasal route may be promising for the efficient delivery of dopamine to the CNS.

  5. Synapsins Differentially Control Dopamine and Serotonin Release

    PubMed Central

    Kile, Brian M.; Guillot, Thomas S.; Venton, B. Jill; Wetsel, William C.; Augustine, George J.; Wightman, R. Mark

    2010-01-01

    Synapsins are a family of synaptic vesicle proteins that are important for neurotransmitter release. Here we have used triple knockout (TKO) mice lacking all three synapsin genes to determine the roles of synapsins in the release of two monoamine neurotransmitters, dopamine and serotonin. Serotonin release evoked by electrical stimulation was identical in substantia nigra pars reticulata slices prepared from TKO and wild-type mice. In contrast, release of dopamine in response to electrical stimulation was approximately doubled in striatum of TKO mice, both in vivo and in striatal slices, in comparison to wild-type controls. This was due to loss of synapsin III, because deletion of synapsin III alone was sufficient to increase dopamine release. Deletion of synapsins also increased the sensitivity of dopamine release to extracellular calcium ions. Although cocaine did not affect the release of serotonin from nigral tissue, this drug did enhance dopamine release. Cocaine-induced facilitation of dopamine release was a function of external calcium, an effect that was reduced in TKO mice. We conclude that synapsins play different roles in the control of release of dopamine and serotonin, with release of dopamine being negatively regulated by synapsins, specifically synapsin III, while serotonin release appears to be relatively independent of synapsins. These results provide further support for the concept that synapsin function in presynaptic terminals varies according to the neurotransmitter being released. PMID:20660258

  6. Going for broke: dopamine influences risky choice.

    PubMed

    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.

  7. GABA, glutamate, dopamine and serotonin transporters expression on forgetting.

    PubMed

    Tellez, Ruth; Gómez-Viquez, Leticia; Liy-Salmeron, Gustavo; Meneses, Alfredo

    2012-07-01

    Notwithstanding several neurotransmission systems are frequently related to memory formation; forgetting process and neurotransmission systems or their transporters; the role of γ-aminobutyric acid (GAT1), glutamate (EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper western-blot analysis was used to evaluate expression of GAT1, EAAC1, DAT and SERT during forgetting in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was determined in the hippocampus (HIP), prefrontal cortex (PFC) and striatum (STR). Results indicated that forgetting of Pavlovian/instrumental autoshaping was associated to up-regulation of GAT1 (PFC and HIP) and DAT (PFC) while SERT (HIP) was down-regulated; no-changes were observed in striatum. Methamphetamine administration did not affect forgetting at 216 h post-training but up-regulated hippocampal DAT and EACC, prefrontal cortex DAT and striatal GAT1 or EACC1. Fluoxetine alone prevented forgetting, which was associated to striatal GAT1 and hippocampal DAT up-regulation, but prefrontal cortex GAT1 down-regulation. Fluoxetine plus METH administration was also able to prevent forgetting, which was associated to hippocampal DAT, prefrontal cortex SERT and striatal GAT1, DAT or SERT up-regulation, but prefrontal cortex GAT1 down-regulation. Together these data show that forgetting provokes primarily hippocampal and prefrontal cortex transporters changes; forgetting represent a behavioral process hardly modifiable and its prevention could causes different transporters expression patterns.

  8. Metabolic hormones, dopamine circuits, and feeding

    PubMed Central

    Narayanan, Nandakumar S.; Guarnieri, Douglas J.; DiLeone, Ralph J.

    2009-01-01

    Recent evidence has emerged demonstrating that metabolic hormones such as ghrelin and leptin can act on ventral tegmental area (VTA) midbrain dopamine neurons to influence feeding. The VTA is the origin of mesolimbic dopamine neurons that project to the nucleus accumbens (NAc) to influence behavior. While blockade of dopamine via systemic antagonists or targeted gene delete can impair food intake, local NAc dopamine manipulations have little effect on food intake. Notably, non-dopaminergic manipulations in the VTA and NAc produce more consistent effects on feeding and food choice. More recent genetic evidence supports a role for the substantia nigra-striatal dopamine pathways in food intake, while the VTA-NAc circuit is more likely involved in higher-order aspects of food acquisition, such as motivation and cue associations. This rich and complex literature should be considered in models of how peripheral hormones influence feeding behavior via action on the midbrain circuits. PMID:19836414

  9. Dopamine transporter mutant animals: a translational perspective

    PubMed Central

    Efimova, Evgenia V.; Gainetdinov, Raul R.; Budygin, Evgeny A.; Sotnikova, Tatiana D.

    2016-01-01

    The dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby providing effective control over activity of dopaminergic transmission. Since brain dopamine is known to be involved in numerous neuropsychiatric disorders, investigations using mice with genetically altered DAT function and thus intensity of dopamine-mediated signaling have provided numerous insights into the pathology of these disorders and highlight novel pathological mechanisms that could be targeted to provide new therapeutic approaches for these disorders. In this brief overview we discuss recent investigations involving animals with genetically altered DAT function, particularly focusing on translational studies providing new insights into pathology and pharmacology of dopamine-related disorders. Perspective applications of these and newly developed models of DAT dysfunction are also discussed. PMID:27276191

  10. Dopamine agonist therapy in hyperprolactinemia.

    PubMed

    Webster, J

    1999-12-01

    Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice.

  11. Dopamine receptors in human gastrointestinal mucosa

    SciTech Connect

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

    1987-12-21

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

  12. Dopamine transporter: expression in Xenopus oocytes.

    PubMed

    Uhl, G R; O'Hara, B; Shimada, S; Zaczek, R; DiGiorgianni, J; Nishimori, T

    1991-01-01

    Xenopus oocytes can express biologically relevant transport activity after injection of mRNAs encoding several carrier molecules. mRNA from PC12 cells, as well as transcripts from a rat ventral midbrain library, can be expressed in these oocytes and allow them to display pharmacologically specific dopamine uptake. mRNA-injected oocytes incubated with tritiated dopamine contain tritiated dopamine and metabolites; lower amounts of radiolabeled dopamine and more radiolabeled metabolites are found in oocytes co-incubated with cocaine or in water-injected oocytes. Tritiated dopamine uptake into mRNA-injected oocytes is time, sodium, and temperature dependent. It is blocked by cocaine and mazindol, but not by haloperidol. It is not found after injection of mRNA from other brain regions. A size-selected rat midbrain library constructed in the plasma vector pCDM8 yields mRNA transcripts whose injection into oocytes causes cocaine-blockable [3H]dopamine uptake. These findings provide an assay for purification of the dopamine transporter cDNA by sib selection techniques.

  13. Stereoselectivity of presynaptic autoreceptors modulating dopamine release.

    PubMed

    Arbilla, S; Langer, S Z

    1981-12-17

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [3H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01--1 microM enhanced the electrically evoked release of [3H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.01--1 microM) but not to (R)-butaclamol (0.1--10 microM) enhanced the field-stimulated release of [3H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1 microM) of the stimulated release of [3H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [3H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective.

  14. Autoradiographic localization of benzodiazepine receptor downregulation

    SciTech Connect

    Tietz, E.I.; Rosenberg, H.C.; Chiu, T.H.

    1986-01-01

    Regional differences in downregulation of brain benzodiazepine receptors were studied using a quantitative autoradiographic method. Rats were given a 4-week flurazepam treatment known to cause tolerance and receptor downregulation. A second group of rats was given a similar treatment, but for only 1 week. A third group was given a single acute dose of diazepam to produce a brain benzodiazepine-like activity equivalent to that found after the chronic treatment. Areas studied included hippocampal formation, cerebral cortex, superior colliculus, substantia nigra, dorsal geniculate nucleus, lateral amygdala and lateral hypothalamus. There was a regional variation in the degree of downregulation after 1 week of flurazepam treatment, ranging from 12% to 25%. Extending the flurazepam treatment to 4 weeks caused little further downregulation in those areas studied, except for the pars reticulata of the substantia nigra, which showed a 13% reduction in (/sup 3/H)flunitrazepam binding after 1 week and a 40% reduction after 4 weeks of treatment. In a few areas, such as the lateral hypothalamus, no significant change in binding was found after 4 weeks. Acute diazepam treatment caused no change in binding. This latter finding as well as results obtained during the development of the methodology show that downregulation was not an artifact due to residual drug content of brain slices. The regional variations in degree and rate of downregulation suggest areas that may be most important for benzodiazepine tolerance and dependence and may be related to the varying time courses for tolerance to different benzodiazepine actions.

  15. Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling.

    PubMed

    Bergson, Clare; Levenson, Robert; Goldman-Rakic, Patricia S; Lidow, Michael S

    2003-09-01

    Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopamine-related drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptor-interacting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca(2+) sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca(2+) homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.

  16. Human dopamine receptor and its uses

    DOEpatents

    Civelli, Olivier; Van Tol, Hubert Henri-Marie

    1999-01-01

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

  17. Stress in adolescence and drugs of abuse in rodent models: Role of dopamine, CRF, and HPA axis

    PubMed Central

    Burke, Andrew R.; Miczek, Klaus A.

    2014-01-01

    Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534

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

    PubMed

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

    2016-01-15

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

  19. Phasic dopamine release in appetitive behaviors and drug abuse

    PubMed Central

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

    2010-01-01

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

  20. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

    PubMed

    Aumann, Tim D

    2016-04-01

    The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2

  1. Delusions, superstitious conditioning and chaotic dopamine neurodynamics.

    PubMed

    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.

  2. Detection of Dopamine Dynamics in the Brain.

    ERIC Educational Resources Information Center

    Wightman, R. Mark; And Others

    1988-01-01

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

  3. Dopamine-oxytocin interactions in penile erection.

    PubMed

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

    2009-12-03

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

  4. A model of dopamine modulated glutamatergic synapse.

    PubMed

    Di Maio, Vito; Ventriglia, Francesco; Santillo, Silvia

    2015-10-01

    The dopamine neurotransmitter regulates important neural pathways and its action in the brain is very complex. When dopaminergic neurons make synapses on spiny neurons of the striatum nucleus, they tune the responsiveness of glutamatergic synapses by means of the dopamine D1 and D2 receptors. We studied the effect of dopamine D1 receptors on glutamatergic synapse of GABAergic spiny neurons in striatum nucleus where they are located on the neck of the same spine. The action of dopamine consists essentially in promoting the phosphorylation of AMPA and NMDA receptors thus increasing the Excitatory Post Synaptic Current peak amplitude. The consequence is a cooperative effect of glutamatergic and dopaminergic synapses for the regulation of the GABAergic neuronal code. The mechanisms by which the phosphorylation induces the increase of the EPSC amplitude still remain unclear although the lack of this regulation can be involved in several pathologies as, for example, the Parkinson's disease. We tested, by computational experiments based on our model of glutamatergic synapse, three parameters of the synaptic function that could be involved in dopamine action: (a) time binding of glutamate to receptors; (b) open probability of the receptors; and (c) single receptor conductance. For different reasons, any of the three parameters could be responsible of the increased EPSC-dopamine-dependent. Our computational results were compared and discussed with experimental results found in literature. Although for our model both the open probability and the single receptor conductance can reproduce the phosphorylation effect of dopamine, we argue that the dopamine effect consists essentially in an increase of the single receptor conductance due to a 3D rearrangement of the phosphorylated receptors.

  5. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  6. Pharmacological characterization of renal vascular dopamine receptors.

    PubMed

    Schmidt, M; Imbs, J L

    1980-01-01

    We present an in vitro method for studying the renal effects of dopamine in the isolated rat kidney. The organ is perfused in an open circuit and can be maintained satisfactorily for up to 180 min. The responses to dopamine were studied in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M) while stable renal vasoconstriction was maintained by perfusion with prostaglandine F2 alpha. Dopamine induced dose-dependent renal vasodilation with an ED50 of 2.53 X 10(-6) moles/liter, which was not modified by reserpine pretreatment. (+) Butaclamol but not (-) butaclamol shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol and sulpiride at concentrations without intrinsic effect on vascular resistance also acted as competitive inhibitors for dopamine. Calculation of empirical pA2 values yielded the following relative potencies for these antagonists: (+) butaclamol greater than haloperidol greater than sulpiride. The renal vascular dopamine receptors are tentatively classified as being of the D1 type.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  10. [Study of extracellular concentration of dopamine and its metabolites in mice striatum by a microdialysis technique at intraperitoneal administration of MPTP].

    PubMed

    Averkin, R G; Korshunov, V A; Shchegolevskiĭ, N V; Mats, V N; Markevich, V A; Grigor'ian, G A; Bazian, A S

    2010-01-01

    In this paper a structure of a microdialytic cannula inserted into brain areas just before a microdialysis is described. The cannula used allowed to find out a correspondence of behavioral and biochemical changes in C57BL/6 mice at various time intervals after a single dose administration (20 mg/kg) of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, without any additional pharmacological actions enhancing an extracellular striatal dopamine concentration. Immediately after 1-methyl-4-phenyl-1.2,3.6-tetrahydropyridine administration an essential disturbance of mice behavior and a significant reduction of the extracellular concentration of dopamine and homovanillic acid were observed in striatum. A week after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration neither behavior nor the extracellular dopamine and homovanillic acid striatal concentration substantially differed from those of controls. 30 days after the neurotoxin administration there was again an essential disturbance of behavior and the large reduction of dopamine and its metabolite concentration in striatum. There was suggested that a reduction of the dopamine concentration immediately after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection connected with abnormalities of dopamine synthesis and metabolism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine whereas a reduction of the extracellular striatal dopamine concentration 30 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration related to damage of the nigrastriatal dopaminergic system.

  11. Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis

    PubMed Central

    Fino, Kristin K.; Matters, Gail L.; McGovern, Christopher O.; Gilius, Evan L.

    2012-01-01

    Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G1 to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer. PMID:22442157

  12. Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

    SciTech Connect

    Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan; Zhang, Jing; Chai, Hongyan; Tang, Tian; Chen, Honglei; Yue, Jiang; Li, Ying; Yang, Jing

    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

  13. Addiction: Beyond dopamine reward circuitry

    SciTech Connect

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

    2011-09-13

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

  14. Dopamine, behavioral economics, and effort.

    PubMed

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

    2009-01-01

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

  15. Dopamine, Behavioral Economics, and Effort

    PubMed Central

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

    2009-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  17. Selective Overexpression of Dopamine D3 Receptors in the Striatum Disrupts Motivation but not Cognition

    PubMed Central

    Simpson, Eleanor H.; Winiger, Vanessa; Biezonski, Dominik K.; Haq, Iram; Kandel, Eric R.; Kellendonk, Christoph

    2014-01-01

    Background Evidence indicating an increase in dopamine D2 receptor (D2R) density and occupancy in patients with schizophrenia comes from positron emission tomography studies using ligands that bind both D2Rs and dopamine D3 receptors (D3Rs), questioning the role of D3Rs in the pathophysiology of the disease. Dopamine D3 receptor positron emission tomography ligands have recently been developed and antagonists with preferential affinity for D3R versus D2R are undergoing clinical evaluation. To determine if an increase in D3Rs in the striatum could produce phenotypes relevant to schizophrenia, we generated a transgenic model of striatal D3R overexpression. Methods A bi-transgenic system was used to generate mice with increased D3Rs selectively in the striatum. Mice with overexpression of D3R were subjected to an extensive battery of behavioral tests, including several relevant to schizophrenia. Ligand binding and quantitative reverse transcription polymerase chain reaction methods were used to quantify the effect of D3R overexpression on dopamine D1 receptors (D1Rs) in the striatum. Results Mice with overexpression of D3R show no abnormalities in basic behavioral functions or cognitive tests but do display a deficit in incentive motivation. This was associated with a reduction in striatal D1R ligand binding, driven by a downregulation at the level of transcription. Both motivation and D1R expression were rescued by switching off the transgene in adulthood. Conclusions Overexpression of D3Rs in the striatum of mice does not elicit cognitive deficits but disrupts motivation, suggesting that changes in D3Rs may be involved in the negative symptoms of schizophrenia. These data imply that it will be important to evaluate the effects of D3R antagonists on motivational symptoms, which are not improved by currently available antipsychotic medications. PMID:24387821

  18. Role of dopamine in distal retina.

    PubMed

    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.

  19. Biochemical effects of baclofen (beta-parachlorophenyl-GABA) on the dopamine and the noradrenaline in the rat brain.

    PubMed

    Andén, N E; Wachtel, H

    1977-02-01

    Baclofen (beta-parachlorophenyl-GABA) caused an increase in the concentration of dopamine in the rat brain with a maximum of about 170% of the control value after 1 hr and after doses of 50 mg/kg or more intraperitoneally. The alpha-methyltyrosine-induced disappearance of dopamine was inhibited to about the same extent in the corpus striatum and in the limbic system by baclofen. The accumulation of DOPA following decarboxylase inhibition was stimulated more in the corpus striatum than in the limbic system by baclofen, thus accounting for the fact that the concentration of dopamine was elevated about three times as much in the corpus striatum as in the limbic system. Amphetamine almost completely inhibited the rise in dopamine produced by baclofen. Baclofen did not cause any consistent changes in the concentration, the synthesis and the utilization of noradrenaline. These effects of baclofen are similar to those described following gammahydroxybutyric acid or axotomy. Hence, baclofen might also interrupt the nerve impulse flow in central dopamine neurones, perhaps by stimulating a central GABA mechanism.

  20. Bromocryptine prevents the decline in tuberoinfundibular neuronal release of dopamine after removal of chronic estrogen treatment

    SciTech Connect

    Gottschall, P.E.; Meites, J.

    1987-11-01

    Prolonged exposure to estradiol 17-..beta.. (E/sub 2/) in rats has been shown to decrease dopamine (DA) synthesis in and release from tuberoinfundibular dopaminergic (TIDA) neurons in Fischer 344 rats. The objective of the present study was to determine whether inhibition of the E/sub 2/-induced increase in anterior pituitary (AP) weight and prolactin (PRL) secretion by concomitant administration of the dopaminergic agonist, bromocryptine, could prevent the decrease in TIDA neuronal function produced by chronic E/sub 2/ administration. TIDA neuronal function was evaluated by in vitro superfusion and electrical stimulation of median eminence (ME) tissue after allowing for accumulation of (/sup 3/H) dopamine (DA). The effect of chronic E/sub 2/ and/or bromocryptine treatment on catecholamine content in tuberohypophyseal neurons in the neurointermediate lobe was also measured to determine whether increased pituitary size possibly damaged the tuberohypophyseal neurons.

  1. Imbalance between nitric oxide and dopamine may underly aggression in acute neurological patients.

    PubMed

    Ramírez-Bermudez, J; Perez-Neri, I; Montes, S; Ramirez-Abascal, M; Nente, F; Abundes-Corona, A; Soto-Hernandez, J L; Rios, C

    2010-10-01

    The neurochemical basis of aggressive behavior in humans is not fully understood. In this study we explored the relationship between aggressiveness (as measured by the Overt Aggression Scale), cognitive performance (as measured by the Mini Mental State Examination), and biochemical markers of dopamine neurotransmission (homovanillic acid, HVA) and nitric oxide synthesis (nitrite plus nitrate, NO(x)) in cerebrospinal fluid from 70 patients with acute brain disorders, mainly brain infections. Aggressive behavior and cognitive performance showed an inverse correlation. NO(x)/HVA ratio was inversely correlated to aggressive behavior, and positively correlated to cognitive performance. A subanalysis with antipsychotic-naïve patients confirmed those results. The balance between nitric oxide and dopamine could be related to the cognitive control of aggressive impulse.

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

    PubMed

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

    2015-01-20

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

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

    SciTech Connect

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

    1990-02-02

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

  4. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

    PubMed Central

    Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Holmes Morton, D.; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.

    2014-01-01

    Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine ‘transportopathy’ to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5–34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having ‘juvenile parkinsonism’. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more

  5. Dopamine Uptake in the Somatic Cell Hybrid NX31

    DTIC Science & Technology

    1975-08-01

    AFRRI SR75-21 AUGUST 1975 AFRRI SCIENTIFIC REPORT CM CO DOPAMINE UPTAKE IN THE SOMATIC CELL HYBRID NX31 P. R. Myers W. G. Shaln, Jr...Sciences - National Research Council. AFRRI SR75-21 August 1975 DOPAMINE UPTAKE IN THE SOMATIC CELL HYBRID NX31 P. R. MYERS W. G. SHAIN...Introduction 1 II. Experimental Methods 2 Materials 2 Cell lines 2 Dopamine uptake experiments 3 Metabolism of accumulated dopamine 5

  6. Neuronal Source of Plasma Dopamine

    PubMed Central

    Goldstein, David S.; Holmes, Courtney

    2008-01-01

    BACKGROUND Determinants of plasma norepinephrine (NE) and epinephrine concentrations are well known; those of the third endogenous catecholamine, dopamine (DA), remain poorly understood. We tested in humans whether DA enters the plasma after corelease with NE during exocytosis from sympathetic noradrenergic nerves. METHODS We reviewed plasma catecholamine data from patients referred for autonomic testing and control subjects under the following experimental conditions: during supine rest and in response to orthostasis; intravenous yohimbine (YOH), isoproterenol (ISO), or glucagon (GLU), which augment exocytotic release of NE from sympathetic nerves; intravenous tri-methaphan (TRI) or pentolinium (PEN), which decrease exocytotic NE release; or intravenous tyramine (TYR), which releases NE by nonexocytotic means. We included groups of patients with pure autonomic failure (PAF), bilateral thoracic sympathectomies (SNS-x), or multiple system atrophy (MSA), since PAF and SNS-x are associated with noradrenergic denervation and MSA is not. RESULTS Orthostasis, YOH, ISO, and TYR increased and TRI/PEN decreased plasma DA concentrations. Individual values for changes in plasma DA concentrations correlated positively with changes in NE in response to orthostasis (r =0.72, P <0.0001), YOH (r = 0.75, P < 0.0001), ISO (r = 0.71, P < 0.0001), GLU (r = 0.47, P = 0.01), and TYR (r = 0.67, P < 0.0001). PAF and SNS-x patients had low plasma DA concentrations. We estimated that DA constitutes 2%– 4% of the catecholamine released by exocytosis from sympathetic nerves and that 50%–90% of plasma DA has a sympathoneural source. CONCLUSIONS Plasma DA is derived substantially from sympathetic noradrenergic nerves. PMID:18801936

  7. Imaging of Brain Dopamine Pathways

    PubMed Central

    Wang, Gene-Jack; Volkow, Nora D.; Thanos, Panayotis K.; Fowler, Joanna S.

    2011-01-01

    Obesity is typically associated with abnormal eating behaviors. Brain imaging studies in humans implicate the involvement of dopamine (DA)-modulated circuits in pathologic eating behavior(s). Food cues increase striatal extracellular DA, providing evidence for the involvement of DA in the nonhedonic motivational properties of food. Food cues also increase metabolism in the orbitofrontal cortex indicating the association of this region with the motivation for food consumption. Similar to drug-addicted subjects, striatal DA D2 receptor availability is reduced in obese subjects, which may predispose obese subjects to seek food as a means to temporarily compensate for understimulated reward circuits. Decreased DA D2 receptors in the obese subjects are also associated with decreased metabolism in prefrontal regions involved in inhibitory control, which may underlie their inability to control food intake. Gastric stimulation in obese subjects activates cortical and limbic regions involved with self-control, motivation, and memory. These brain regions are also activated during drug craving in drug-addicted subjects. Obese subjects have increased metabolism in the somatosensory cortex, which suggests an enhanced sensitivity to the sensory properties of food. The reduction in DA D2 receptors in obese subjects coupled with the enhanced sensitivity to food palatability could make food their most salient reinforcer putting them at risk for compulsive eating and obesity. The results from these studies suggest that multiple but similar brain circuits are disrupted in obesity and drug addiction and suggest that strategies aimed at improving DA function might be beneficial in the treatment and prevention of obesity. PMID:21603099

  8. Detection of cell surface dopamine receptors.

    PubMed

    Xiao, Jiping; Bergson, Clare

    2013-01-01

    Dopamine receptors are a class of metabotropic G protein-coupled receptors. Plasma membrane expression is a key determinant of receptor signaling, and one that is regulated both by extra and intracellular cues. Abnormal dopamine receptor signaling is implicated in several neuropsychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder, as well as drug abuse. Here, we describe in detail the application of two complementary applications of protein biotinylation and enzyme-linked immunoabsorbent assay (ELISA) for detecting and quantifying levels of dopamine receptors expressed on the cell surface. In the biotinylation method, cell surface receptors are labeled with Sulfo-NHS-biotin. The charge on the sulfonyl facilitates water solubility of the reactive biotin compound and prevents its diffusion across the plasma membrane. In the ELISA method, surface labeling is achieved with antibodies specific to extracellular epitopes on the receptors, and by fixing the cells without detergent such that the plasma membrane remains intact.

  9. Detection of Cell Surface Dopamine Receptors

    PubMed Central

    Xiao, Jiping; Bergson, Clare

    2014-01-01

    Dopamine receptors are a class of metabotropic G protein-coupled receptors. Plasma membrane expression is a key determinant of receptor signaling, and one that is regulated both by extra and intracellular cues. Abnormal dopamine receptor signaling is implicated in several neuropsychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder, as well as drug abuse. Here, we describe in detail the application of two complementary applications of protein biotinylation and enzyme-linked immunoabsorbant assay (ELISA) for detecting and quantifying levels of dopamine receptors expressed on the cell surface. In the biotinylation method, cell surface receptors are labeled with Sulfo-NHS-biotin. The charge on the sulfonyl facilitates water solubility of the reactive biotin compound and prevents its diffusion across the plasma membrane. In the ELISA method, cells surface labeling is achieved with antibodies specific to extracellular epitopes on the receptors, and by fixing the cells without detergent such that the plasma membrane remains intact. PMID:23296774

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

    PubMed

    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

  11. How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission

    PubMed Central

    Sulzer, David

    2011-01-01

    The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce non-exocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions on the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging. PMID:21338876

  12. Vascular dopamine receptors: Demonstration and characterization by in vitro studies.

    PubMed

    Brodde, O E

    1982-07-26

    Substantial evidence has accumulated that in certain vascular beds dopamine produces its relaxant effect through stimulation of specific dopamine receptors. The goal of this review is to describe several in vitro models (perfused mesenteric vessels of the dog; renal, mesenteric, splenic, coronary and cerebral arterial strips of rabbits, dogs and cats; perfused kidney of the rat) recently developed to demonstrate such specific relaxations induced by dopamine and dopaminomimetics. On these models studies on structure-activity relationship for activation of the dopamine receptor resulted in the following order of potency for agonists: SK&F 38393 (partial agonist) greater than epinine greater than A-6, 7-DTN greater than or equal to dopamine greater than N, N-di-n-propyl-dopamine (partial agonist) greater than apomorphine (partial agonist). The dopamine receptor antagonists (+)-butaclamol, cis-alpha-flupenthixol, metoclopramide, droperidol and bulbocapnine were found to competitively antagonize dopamine induced relaxation. In addition, in two isolated organ systems (rabbit mesenteric artery, rat perfused kidney) stereospecificity of the vascular dopamine receptor was demonstrated with the isomers of butaclamol. With the development of several in vitro models demonstrating a specific antagonism against dopamine induced relaxation an important requirement for definition of a specific dopamine receptor if fulfilled according to classical pharmacological criteria. Thus, there can be do doubt on the existence of post-synaptic dopamine receptors mediating vasodilation in certain vascular tissues.

  13. Dopamine receptors in a songbird brain

    PubMed Central

    Kubikova, Lubica; Wada, Kazuhiro; Jarvis, Erich D

    2010-01-01

    Dopamine is a key neuromodulatory transmitter in the brain. It acts through dopamine receptors to affect changes in neural activity, gene expression, and behavior. In songbirds, dopamine is released into the striatal song nucleus Area X, and the levels depend on social contexts of undirected and directed singing. This differential release is associated with differential expression of activity-dependent genes, such as egr1 (avian zenk), which in mammalian brain are modulated by dopamine receptors. Here we cloned from zebra finch brain cDNAs of all avian dopamine receptors: the D1 (D1A, D1B, D1D) and D2 (D2, D3, D4) families. Comparative sequence analyses of predicted proteins revealed expected phylogenetic relationships, in which the D1 family exists as single exon and the D2 family exists as spliced exon genes. In both zebra finch and chicken, the D1A, D1B, and D2 receptors were highly expressed in the striatum, the D1D and D3 throughout the pallium and within the mesopallium, respectively, and the D4 mainly in the cerebellum. Furthermore, within the zebra finch, all receptors, except for D4, showed differential expression in song nuclei relative to the surrounding regions and developmentally regulated expression that decreased for most receptors during the sensory acquisition and sensorimotor phases of song learning. Within Area X, half of the cells expressed both D1A and D2 receptors, and a higher proportion of the D1A-only-containing neurons expressed egr1 during undirected but not during directed singing. Our findings are consistent with hypotheses that dopamine receptors may be involved in song development and social context-dependent behaviors. J. Comp. Neurol. 518:741–769, 2010. © 2009 Wiley-Liss, Inc. PMID:20058221

  14. Downregulating the sucrose transporter VpSUT1 in Verbascum phoeniceum does not inhibit phloem loading

    PubMed Central

    Zhang, Cankui; Turgeon, Robert

    2009-01-01

    Sucrose is loaded into the phloem in the minor veins of leaves before export. Two active, species-specific loading mechanisms have been proposed. One involves transporter-mediated sucrose transfer from the apoplast into the sieve element-companion cell complex, so-called apoplastic loading. In the putative second mechanism, sucrose follows an entirely symplastic pathway, and the solute concentration is elevated by the synthesis of raffinose and stachyose in the phloem, not by transporter activity. Several sucrose-transporting plants have been shown to be apoplastic loaders by downregulating sucrose transporter 1 (SUT1), leading to accumulation of sugars and leaf chlorosis. In this study we compared the effect of downregulating SUT1 in Nicotiana tabacum, a sucrose transporter, and Verbascum phoeniceum, a species that transports raffinose and stachyose. To test the effectiveness of RNAi downregulation, we measured SUT1 mRNA levels and sucrose-H+ symport in leaf discs. Mild NtSUT1 downregulation in N. tabacum resulted in the pronounced phenotype associated with loading inhibition. In contrast, no such phenotype developed when VpSUT1 was downregulated in V. phoeniceum, leaving minimal sucrose transport activity. Only those plants with the most severe VpSUT1 downregulation accumulated more carbohydrate than usual and these plants were normal by other criteria: growth rate, photosynthesis, and ability to clear starch during the night. The results provide direct evidence that the mechanism of phloem loading in V. phoeniceum does not require active sucrose uptake from the apoplast and strongly supports the conclusion that the loading pathway is symplastic in this species. PMID:19846784

  15. PET evaluation of the dopamine system of the human brain

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Gatley, S. |

    1996-07-01

    Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.

  16. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells.

    PubMed

    Wang, Siyuan; Mou, Zhenzhen; Ma, Yuanheng; Li, Jian; Li, Jingyun; Ji, Xiwei; Wu, Kehua; Li, Liang; Lu, Wei; Zhou, Tianyan

    2015-05-15

    Growing evidence suggests that the efficacy of sunitinib in breast cancer may be limited by increasing the population of cancer stem-like cells (CSCs). Hence the concurrent use of CSCs-targeting agents is required. Previous results indicated that dopamine receptor (DR) may serve as a potential therapeutic target of anti-CSCs therapies. This study focused on evaluating the effect of dopamine (an agonist of DR) on the enhancement of sunitinib's efficacy in the treatment of drug-resistant breast cancer, investigating the involved activation type of DR pathway and exploring the underlying anti-CSCs mechanisms. MCF-7 cells, MCF-7/Adr cells and breast cancer stem-like cells (BCSCs) were used for in vitro study. Moreover, MCF-7/Adr cells and BCSCs were selected as drug-resistant cell lines and further used for in vivo development of the xenograft animal models. Our results showed that dopamine greatly synergized the inhibitory effect of sunitinib in the drug-resistant cells and strikingly enhanced the response of sunitinib in both xenograft models. It was found that dopamine significantly down-regulated the expression of BCSCs markers (CD44(+)/CD24(-)) in vitro and in vivo. In addition, dopamine remarkably induced the apoptosis of BCSCs, markedly inhibited the Wnt signaling pathway and activated the apoptotic associated signals. The activation of dopamine receptor D1 (D1DR) pathway may be involved in the underlying mechanism as D1DR's antagonist SCH23390 completely reversed the combined effects. In conclusion, dopamine may eradicate CSCs and it significantly enhances the response of sunitinib in the treatment of drug-resistant breast cancer.

  17. Quadruplex Integrated DNA (QuID) Nanosensors for Monitoring Dopamine

    PubMed Central

    Morales, Jennifer M.; Skipwith, Christopher G.; Clark, Heather A.

    2015-01-01

    Dopamine is widely innervated throughout the brain and critical for many cognitive and motor functions. Imbalances or loss in dopamine transmission underlie various psychiatric disorders and degenerative diseases. Research involving cellular studies and disease states would benefit from a tool for measuring dopamine transmission. Here we show a Quadruplex Integrated DNA (QuID) nanosensor platform for selective and dynamic detection of dopamine. This nanosensor exploits DNA technology and enzyme recognition systems to optically image dopamine levels. The DNA quadruplex architecture is designed to be compatible in physically constrained environments (110 nm) with high flexibility, homogeneity, and a lower detection limit of 110 µM. PMID:26287196

  18. Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [(18)F]DOPA PET Study.

    PubMed

    Kim, Euitae; Howes, Oliver D; Veronese, Mattia; Beck, Katherine; Seo, Seongho; Park, Jin Woo; Lee, Jae Sung; Lee, Yun-Sang; Kwon, Jun Soo

    2017-03-01

    Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment-resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment-resistant schizophrenia. However, in this study, the treatment-resistant patients were highly symptomatic, whereas the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus, we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment-resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls (n=12), patients treated with clozapine (n=12) who had not responded to first-line antipsychotics, and patients who had responded to first-line antipsychotics (n=12) were recruited. Participants were matched for age and sex and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [(18)F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment (Cohen's d=0.9191 (whole striatum), 0.7781 (associative striatum), 1.0344 (limbic striatum), and 1.0189 (sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment-resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.

  19. Mitochondrial reactive oxygen species mediate hypoxic down-regulation of hERG channel protein.

    PubMed

    Nanduri, Jayasri; Wang, Ning; Bergson, Pamela; Yuan, Guoxiang; Ficker, Eckhard; Prabhakar, Nanduri R

    2008-08-22

    Previous studies suggest that reactive oxygen species (ROS) play an important role in physiological responses to hypoxia. In the present study, we examined the effects of hypoxia on human ether-a-go-go related gene (hERG) channel protein expression and assessed the role of ROS. Hypoxia, in a stimulus- and time-dependent manner, decreased hERG protein with marked reduction in hERG K+ conductance in human embryonic kidney cells stably expressing the hERG alpha subunit. Down-regulation of hERG by hypoxia was not due to increased proteasomal degradation or decreased transcription but due to decreased synthesis of the protein. Hypoxia increased ROS in a time-dependent manner. Antioxidants prevented hypoxia-evoked down-regulation of hERG protein and exogenous oxidants mimicked the effects of hypoxia. Hypoxia-evoked down-regulation of hERG protein and elevation in ROS were absent in p(O) cells, which are devoid of mitochondrial DNA. Inhibitors of NADPH oxidase failed to prevent the effects of hypoxia. These results demonstrate that hypoxia enhances the production of ROS in the mitochondria, resulting in down-regulation of hERG translation and decreased hERG-mediated K+ conductance.

  20. Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783.

    PubMed

    Boulay, D; Leroux-Nicollet, I; Duterte-Boucher, D; Naudon, L; Costentin, J

    1994-01-01

    A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity. Forty-eight hours after the last administration, animals were sacrificed and 3H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.

  1. Dopamine-melanin nanofilms for biomimetic structural coloration.

    PubMed

    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.

  2. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

    PubMed Central

    Gironacci, M. M.

    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 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. PMID:27635280

  3. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney.

    PubMed

    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.

  4. Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans.

    PubMed

    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.

  5. Impulse control disorders and dopamine dysregulation syndrome associated with dopamine agonist therapy in Parkinson's disease.

    PubMed

    Fenu, Sandro; Wardas, Jadwiga; Morelli, Micaela

    2009-09-01

    Over the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders.

  6. Molecular model of the neural dopamine transporter

    NASA Astrophysics Data System (ADS)

    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.

  7. Dopamine receptor in anterior byssus retractor muscle of Mytilus edulis.

    PubMed

    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.

  8. Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

    PubMed Central

    Jinsmaa, Yunden; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J.; Sharabi, Yehonatan

    2016-01-01

    According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson’s disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The “cheese effect”—paroxysmal hypertension evoked by tyramine-containing foodstuffs—limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in

  9. Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells.

    PubMed

    Goldstein, David S; Jinsmaa, Yunden; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J; Sharabi, Yehonatan

    2016-02-01

    According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson

  10. The impact of FOXO on dopamine and octopamine metabolism in Drosophila under normal and heat stress conditions

    PubMed Central

    Adonyeva, Natalya V.; Burdina, Elena V.; Karpova, Evgenia K.; Andreenkova, Olga V.; Gladkikh, Daniil V.; Ilinsky, Yury Y.; Rauschenbach, Inga Yu

    2016-01-01

    ABSTRACT The forkhead boxO transcription factor (FOXO) is a component of the insulin signalling pathway and plays a role in responding to adverse conditions, such as oxidative stress and starvation. In stressful conditions, FOXO moves from the cytosol to the nucleus where it activates gene expression programmes. Here, we show that FOXO in Drosophila melanogaster responds to heat stress as it does to other stressors. The catecholamine signalling pathway is another component of the stress response. In Drosophila, dopamine and octopamine levels rise steeply under heat, nutrition and mechanical stresses, which are followed by a decrease in the activity of synthesis enzymes. We demonstrate that the nearly twofold decline of FOXO expression in foxoBG01018 mutants results in dramatic changes in the metabolism of dopamine and octopamine and the overall response to stress. The absence of FOXO increases tyrosine decarboxylase activity, the first enzyme in octopamine synthesis, and decreases the enzymatic activity of enzymes in dopamine synthesis, alkaline phosphatase and tyrosine hydroxylase, in young Drosophila females. We identified the juvenile hormone as a mediator of FOXO regulation of catecholamine metabolism. Our findings suggest that FOXO is a possible trigger for endocrinological stress reactions. PMID:27754851

  11. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    SciTech Connect

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-12-21

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 ..mu..M and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 ..mu..M and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 ..mu..M respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D/sub 2/-dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 ..mu..M. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, /sup 3/H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D/sup 1/- and D/sup 2/-dopamine receptors. 33 references, 3 figures, 2 tables.

  12. N-Nicotinoyl dopamine inhibits skin pigmentation by suppressing of melanosome transfer.

    PubMed

    Kim, Bora; Hwang, Jae Sung; Kim, Hyun-Soo

    2015-12-15

    We investigated the inhibitory effects of a niacinamide derivative, N-Nicotinoyl dopamine (NND) on melanogenesis. NND inhibits melanosome transfer in a normal human melanocyte-keratinocyte co-culture system and through phagocytic ability without affecting viability of cells while it did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. In addition, safety of NND was verified through performing neural stem cell morphology assay. Our findings indicate that NND may potentially be used for cosmetic industry for improvement of skin whitening and therapies related with several skin disorders, and the effect of NND may be acquired via reduction of melanosome transfer.

  13. PNA-Based Multivalent Scaffolds Activate the Dopamine D2 Receptor

    PubMed Central

    2015-01-01

    Peptide nucleic acid scaffolds represent a promising tool to interrogate the multivalent effects of ligand binding to a membrane receptor. Dopamine D2 receptors (D2R) are a class of G-protein coupled receptors (GPCRs), and the formation of higher-ordered structures of these receptors has been associated with the progression of several neurological diseases. In this Letter, we describe the synthesis of a library of ligand-modified PNAs bearing a known D2R agonist, (±)-PPHT. The D2R activity for each construct was assessed, and the multivalent effects were evaluated. PMID:25893044

  14. Sensorimotor impairment and elevated levels of dopamine metabolites in the neostriatum occur rapidly after intranigral injection of 6-hydroxydopamine or gamma-hydroxybutyrate in awake rats.

    PubMed

    Altar, C A; O'Neil, S; Marshall, J F

    1984-03-01

    The unilateral injection of 6-hydroxydopamine (8 micrograms) into the ventral tegmental area of awake rats produced a rapidly developing and irreversible sensory neglect to contralateral tactile stimuli. This neglect developed in a caudal to rostral direction on the affected body surface and coincided with significant elevation in the concentrations of dopamine and two of its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the ipsilateral neostriatum. The unilateral injection of procaine or gamma-hydroxybutyric acid (GHB) into the substantia nigra of awake animals also produced a contralateral neglect that developed in a caudal to rostral direction, but the behavioral effect of these drugs diminished within 1 hr. Concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid in the neostriatum were markedly elevated during continuous infusions of procaine or gamma-hydroxybutyric acid. The extent of sensory neglect and changes in dopamine metabolism in the neostriatum varied according to the amount of gamma-hydroxybutyric acid injected into the nigra and according to the proximity of injections of gamma-hydroxybutyric acid to the pars compacta. The rapid onset of sensory neglect following microinjections of 6-hydroxydopamine, procaine or gamma-hydroxybutyric acid is consistent with the ability of each of these drugs to block the conduction of impulses in mesostriatal neurons and suggests that concomitant increases in levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid in the neostriatum resulted from decreases in the release of dopamine coupled with increased synthesis of dopamine. These findings also indicate that the catabolism of dopamine to dihydroxyphenylacetic acid or homovanillic acid may originate intraneuronally, without prior release of dopamine and its recapture by mesostriatal terminals, if the flow of impulses in this pathway has been blocked.

  15. Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

    PubMed Central

    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

  16. Presynaptic recording of quanta from midbrain dopamine neurons and modulation of the quantal size.

    PubMed

    Pothos, E N; Davila, V; Sulzer, D

    1998-06-01

    The observation of quantal release from central catecholamine neurons has proven elusive because of the absence of evoked rapid postsynaptic currents. We adapted amperometric methods to observe quantal release directly from axonal varicosities of midbrain dopamine neurons that predominantly contain small synaptic vesicles. Quantal events were elicited by high K+ or alpha-latrotoxin, required extracellular Ca2+, and were abolished by reserpine. The events indicated the release of 3000 molecules over 200 microsec, much smaller and faster events than quanta associated with large dense-core vesicles previously recorded in vertebrate preparations. The number of dopamine molecules per quantum increased as a population to 380% of controls after glial-derived neurotrophic factor (GDNF) exposure and to 350% of controls after exposure to the dopamine precursor L-dihydroxyphenylalanine (L-DOPA). These results introduce a means to measure directly the number of transmitter molecules released from small synaptic vesicles of CNS neurons. Moreover, quantal size was not an invariant parameter in CNS neurons but could be modulated by neurotrophic factors and altered neurotransmitter synthesis.

  17. Pinolenic Acid Downregulates Lipid Anabolic Pathway in HepG2 Cells.

    PubMed

    Lee, Ah Ron; Han, Sung Nim

    2016-07-01

    Pine nut oil (PNO) was reported to reduce lipid accumulation in the liver. However, the specific effect of pinolenic acid (18:3, all-cis-Δ5,9,12), a unique component of PNO, on lipid metabolism has not been studied. We hypothesized that pinolenic acid downregulates the lipid anabolic pathway in HepG2 cells. HepG2 cells were incubated in serum-free medium supplemented with 50 μM bovine serum albumin (BSA), palmitic acid, oleic acid, γ-linolenic acid, pinolenic acid, eicosapentaenoic acid (EPA), or α-linolenic acid for 24 h. Lipid accumulation was determined by Oil Red O (ORO) staining. The mRNA levels of genes related to fatty acid biosynthesis (SREBP1c, FAS, SCD1, and ACC1), fatty acid oxidation (ACC2, PPARα, CPT1A, and ACADL), cholesterol synthesis (SREBP2 and HMGCR), and lipoprotein uptake (LDLr) and of genes that may be involved in the downregulation of the lipogenic pathway (ACSL3, ACSL4, and ACSL5) were determined by qPCR. LDLR protein levels were measured by Western blot analysis. The mRNA levels of SREBP1c, FAS, and SCD1 were significantly downregulated by pinolenic acid treatment compared to BSA control (53, 54, and 38 % lower, respectively). In addition, the mRNA levels of HMGCR, ACSL3, and LDLr were significantly lower (30, 30, and 43 % lower, respectively), and ACSL4 tended to be lower in the pinolenic acid group (20 % lower, P = 0.082) relative to the control group. In conclusion, pinolenic acid downregulated the lipid anabolic pathway in HepG2 cells by reducing expression of genes related to lipid synthesis, lipoprotein uptake, and the regulation of the lipogenic pathway.

  18. Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein.

    PubMed

    Werner, Ernst R; Bahrami, Soheyl; Heller, Regine; Werner-Felmayer, Gabriele

    2002-03-22

    GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclohydrolase I activity in dependence of tetrahydrobiopterin and phenylalanine concentrations, thus enabling stimulation of tetrahydrobiopterin biosynthesis by phenylalanine to ensure its efficient metabolism by phenylalanine hydroxylase. Here, we were interested in regulation of GFRP expression by proinflammatory cytokines and stimuli, which are known to induce GTP cyclohydrolase I expression. Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin. Levels of GFRP mRNA in human myelomonocytoma (THP-1) cells remained unaltered by treatment of cells with interferon-gamma or interleukin-1beta, but were significantly down-regulated by bacterial lipopolysaccharide (LPS, 1 microg/ml), without or with cotreatment by interferon-gamma, which strongly up-regulated GTP cyclohydrolase I expression and activity. GFRP expression was also suppressed in human umbilical vein endothelial cells treated with 1 microg/ml LPS, as well as in rat tissues 7 h post intraperitoneal injection of 10 mg/kg LPS. THP-1 cells stimulated with interferon-gamma alone showed increased pteridine synthesis by addition of phenylalanine to the culture medium. Cells stimulated with interferon-gamma plus LPS, in contrast, showed phenylalanine-independent pteridine synthesis. These results demonstrate that LPS down-regulates expression of GFRP, thus rendering pteridine synthesis independent of metabolic control by phenylalanine.

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

    PubMed Central

    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

  20. Pleiotrophin is downregulated in human keloids.

    PubMed

    Lee, Dong Hun; Jin, Cheng Long; Kim, Yeji; Shin, Mi Hee; Kim, Ji Eun; Kim, Minji; Lee, Min Jung; Cho, Soyun

    2016-10-01

    Keloid is an abnormal hyperproliferative scarring process with involvement of complex genetic and triggering environmental factors. Previously published dysregulated gene expression profile of keloids includes genes involved in tumor formation. Pleiotrophin (PTN) is a secreted, heparin-binding growth factor which is involved in various biological functions such as cell growth, differentiation, and tumor progression. Although PTN expression was reported to be increased in hypertrophic scars, there is no study on PTN expression in keloids, and previous microarray results are controversial. To clarify differential expression of PTN in keloids, we investigated the expression of PTN and its interacting molecules in keloid and control fibroblasts, and performed immunohistochemical staining of PTN using tissue arrays. The expressions of PTN, its upstream regulator platelet-derived growth factor subunit B (PDGF-B) and corresponding PDGF receptors were significantly downregulated in keloid fibroblasts compared to normal human fibroblasts, and the decreased PTN protein expression was confirmed by immunohistochemistry as well as Western blot. Moreover, functional downstream receptor protein tyrosine phosphatase β/ζ was significantly upregulated in keloid fibroblasts, supporting overall downregulation of PTN signaling pathway. The lowered PTN expression in keloids suggests a different pathomechanism from that of hypertrophic scars.

  1. Pharmacology of Signaling Induced by Dopamine D1-Like Receptor Activation

    PubMed Central

    Undieh, Ashiwel S.

    2010-01-01

    Dopamine D1-like receptors consisting of D1 and D5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D1-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D1-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D1-like receptor agonists is reliably associated with the D1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D5 receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D5 versus D1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D1 or D5 interactions with D2-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway. PMID:20547182

  2. A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake.

    PubMed

    Luk, Beryl; Mohammed, Mohinuddin; Liu, Fang; Lee, Frank J S

    2015-01-01

    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.

  3. A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake

    PubMed Central

    Luk, Beryl; Mohammed, Mohinuddin; Liu, Fang; Lee, Frank J. S.

    2015-01-01

    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. PMID:26305376

  4. Validation of an ELISA for urinary dopamine: applications in monitoring treatment of dopamine-related disorders.

    PubMed

    Nichkova, Mikaela; Wynveen, Paul M; Marc, David T; Huisman, Han; Kellermann, Gottfried H

    2013-06-01

    Dopamine is a catecholamine that serves as a neurotransmitter in the central and peripheral nervous system. Non-invasive, reliable, and high-throughput techniques for its quantification are needed to assess dysfunctions of the dopaminergic system and monitor therapies. We developed and validated a competitive ELISA for direct determination of dopamine in urine samples. The method provides high specificity, good accuracy, and precision (average inter-assay variation < 12%). The analysis is not affected by general urinary components and structurally related drugs and metabolites. The correlation between ELISA and LC-MS/MS analyses was very good (r = 0.986, n = 28). The reference range was 64-261 μg/g Cr (n = 64). Week-to-week biological variations of second morning urinary dopamine under free-living conditions were 23.9% for within- and 35.5% for between-subject variation (n = 10). The assay is applied in monitoring Parkinson's disease patients under different treatments. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. The present ELISA provides a cost-effective alternative to chromatographic methods to monitor patients receiving dopamine restoring treatment to ensure appropriate dosing and clinical efficacy. The method can be used in pathological research for the assessment of possible peripheral biological markers for disorders related to the dopaminergic system.

  5. Adenosine and dopamine receptors co-regulate photoreceptor coupling via gap junction phosphorylation in mouse retina

    PubMed Central

    Li, Hongyan; Zhang, Zhijing; Blackburn, Michael R.; Wang, Steven W.; Ribelayga, Christophe P.; O’Brien, John

    2013-01-01

    Gap junctions in retinal photoreceptors suppress voltage noise and facilitate input of rod signals into the cone pathway during mesopic vision. These synapses are highly plastic and regulated by light and circadian clocks. Recent studies have revealed an important role for connexin36 (Cx36) phosphorylation by protein kinase A (PKA) in regulating cell-cell coupling. Dopamine is a light-adaptive signal in the retina, causing uncoupling of photoreceptors via D4 receptors (D4R), which inhibits adenylyl cyclase (AC) and reduces PKA activity. We hypothesized that adenosine, with its extracellular levels increasing in darkness, may serve as a dark signal to co-regulate photoreceptor coupling through modulation of gap junction phosphorylation. Both D4R and A2a receptor (A2aR) mRNAs were present in photoreceptors, inner nuclear layer neurons, and ganglion cells in C57BL/6 mouse retina, and showed cyclic expression with partially overlapping rhythms. Pharmacologically activating A2aR or inhibiting D4R in light-adapted daytime retina increased photoreceptor coupling. Cx36 among photoreceptor terminals, representing predominantly rod-cone gap junctions but possibly including some rod-rod and cone-cone gap junctions, was phosphorylated in a PKA-dependent manner by the same treatments. Conversely, inhibiting A2aR or activating D4R in daytime dark-adapted retina decreased Cx36 phosphorylation with similar PKA dependence. A2a-deficient mouse retina showed defective regulation of photoreceptor gap junction phosphorylation, fairly regular dopamine release, and moderately down-regulated expression of D4R and AC type I mRNA. We conclude that adenosine and dopamine co-regulate photoreceptor coupling through opposite action on the PKA pathway and Cx36 phosphorylation. In addition, loss of the A2aR hampered D4R gene expression and function. PMID:23407968

  6. Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1-like receptors in neonatal rats

    PubMed Central

    Kawamoto, K; Otsuguro, K; Ishizuka, M; Ito, S

    2012-01-01

    BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways. PMID:22168428

  7. A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Schafer, William R.; Kenyon, Cynthia J.

    1995-05-01

    PROCESSING and storage of information by the nervous system requires the ability to modulate the response of excitable cells to neurotransmitter. A simple process of this type, known as adaptation or desensitization, occurs when prolonged stimulation triggers processes that attenuate the response to neurotransmitter. Here we report that the Caenorhabditis elegans gene unc-2 is required for adaptation to two neurotransmitters, dopamine and serotonin. A loss-of-function mutation in unc-2 resulted in failure to adapt either to paralysis by dopamine or to stimulation of egg laying by serotonin. In addition, unc-2 mutants displayed behaviours similar to those induced by serotonin treatment. We found that unc-2 encodes a homologue of a voltage-sensitive calcium-channel α-1 subunit. Expression of unc-2 occurs in two types of neurons implicated in the control of egg laying, a behaviour regulated by serotonin. Unc-2 appears to be required in modulatory neurons to downregulate the response of the egg-laying muscles to serotonin. We propose that adaptation to serotonin occurs through activation of an Unc-2-dependent calcium influx, which modulates the post-synaptic response to serotonin, perhaps by inhibiting the release of a potentiating neuropeptide.

  8. Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage.

    PubMed

    Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

    2006-03-01

    Microglia are the resident antigen-presenting cells within the central nervous system (CNS), and they serve immune-like functions in protecting the brain against injury and invading pathogens. By contrast, activated microglia can secrete numerous reactants that damage neurons. The pathogenesis of various neurodegenerative diseases has been associated with microglial activation, but the signaling pathways that program a neuronally protective or destructive phenotype in microglia are not known. To increase the understanding of microglial activation, microarray analysis was used to profile the transcriptome of BV-2 microglial cells after activation. Microglia were activated by lipopolysaccharide, the HIV neurotoxic protein TAT, and dopamine quinone, each of which has been linked to dopamine neuronal damage. We identified 210 of 9882 genes whose expression was differentially regulated by all activators (116 increased and 94 decreased in expression). Gene ontology analysis assigned up-regulated genes to a number of specific biological processes and molecular functions, including immune response, inflammation, and cytokine/chemokine activity. Genes down-regulated in expression contribute to conditions that are permissive of microglial migration, lowered adhesion to matrix, lessened phagocytosis, and reduction in receptors that oppose chemotaxis and inflammation. These results elaborate a broad profile of microglial genes whose expression is altered by conditions associated with both neurodegenerative diseases and microglial activation.

  9. Phosphorylation mechanisms in dopamine transporter regulation.

    PubMed

    Foster, James D; Vaughan, Roxanne A

    2016-11-09

    The dopamine transporter (DAT) is a plasma membrane phosphoprotein that actively translocates extracellular dopamine (DA) into presynaptic neurons. The transporter is the primary mechanism for control of DA levels and subsequent neurotransmission, and is the target for abused and therapeutic drugs that exert their effects by suppressing reuptake. The transport capacity of DAT is acutely regulated by signaling systems and drug exposure, providing neurons the ability to fine-tune DA clearance in response to specific conditions. Kinase pathways play major roles in these mechanisms, and this review summarizes the current status of DAT phosphorylation characteristics and the evidence linking transporter phosphorylation to control of reuptake and other functions. Greater understanding of these processes may aid in elucidation of their possible contributions to DA disease states and suggest specific phosphorylation sites as targets for therapeutic manipulation of reuptake.

  10. Ropinirole, a non-ergoline dopamine agonist.

    PubMed

    Jost, Wolfgang H; Angersbach, Dieter

    2005-01-01

    Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.

  11. Heart rate response to hypoxic exercise: role of dopamine D2-receptors and effect of oxygen supplementation.

    PubMed

    Lundby, C; Møller, P; Kanstrup, I L; Olsen, N V

    2001-10-01

    This study examined the effects of dopamine D(2)-receptor blockade on the early decrease in maximal heart rate at high altitude (4559 m). We also attempted to clarify the time-dependent component of this reduction and the extent to which it is reversed by oxygen breathing. Twelve subjects performed two consecutive maximal exercise tests, without and with oxygen supplementation respectively, at sea level and after 1, 3 and 5 days at altitude. On each study day, domperidone (30 mg; n=6) or no medication (n=6) was given 1 h before the first exercise session. Compared with sea level, hypoxia progressively decreased the maximal heart rate from day 1 and onwards; also, hypoxia by itself increased plasma noradrenaline levels after maximal exercise. Domperidone further increased maximal noradrenaline concentrations, but had no effect on maximal heart rate. On each study day at altitude, oxygen breathing completely reversed the decrease in maximal heart rate to values not different from those at sea level. In conclusion, dopamine D(2)-receptor blockade with domperidone demonstrates that hypoxic exercise in humans activates D(2)-receptors, resulting in a decrease in circulating levels of noradrenaline. However, dopamine D(2)-receptors are not involved in the hypoxia-induced decrease in the maximal heart rate. These data suggest that receptor uncoupling, and not down-regulation, of cardiac adrenoreceptors, is responsible for the early decrease in heart rate at maximal hypoxic exercise.

  12. Alcohol-induced alterations in dopamine modulation of prefrontal activity.

    PubMed

    Trantham-Davidson, Heather; Chandler, L Judson

    2015-12-01

    Long-term alcohol use leads to persistent cognitive deficits that may be associated with maladaptive changes in the neurocircuitry that mediates executive functions. Impairments caused by these changes can persist well into abstinence and have a negative impact on quality of life and job performance, and can increase the probability of relapse. Many of the changes that affect cognitive function appear to involve dysregulation of the mesocortical dopamine system. This includes changes in dopamine release and alterations in dopamine receptor expression and function in the medial prefrontal cortex (PFC). This review summarizes the cellular effects of acute and chronic ethanol exposure on dopamine release and dopamine receptor function in the PFC with the goal of providing greater understanding of the effects of alcohol-use disorders on the dopamine system and how this relates to deficits in the executive function of the PFC.

  13. Alcohol-induced alterations in dopamine modulation of prefrontal activity

    PubMed Central

    Trantham-Davidson, Heather; Chandler, L. Judson

    2015-01-01

    Long-term alcohol use leads to persistent cognitive deficits that may be associated with maladaptive changes in the neurocircuitry that mediates executive functions. Impairments caused by these changes can persist well into abstinence and have a negative impact on quality of life and job performance, and can increase the probability of relapse. Many of the changes that affect cognitive function appear to involve dysregulation of the mesocortical dopamine system. This includes changes in dopamine release and alterations in dopamine receptor expression and function in the medial prefrontal cortex (PFC). This review summarizes the cellular effects of acute and chronic ethanol exposure on dopamine release and dopamine receptor function in the PFC with the goal of providing greater understanding of the effects of alcohol-use disorders on the dopamine system and how this relates to deficits in the executive function of the PFC. PMID:26558348

  14. Dopamine neurons share common response function for reward prediction error

    PubMed Central

    Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

    2016-01-01

    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 striking 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 could 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. PMID:26854803

  15. mTORC2/Rictor Signaling Disrupts Dopamine-Dependent Behaviors via Defects in Striatal Dopamine Neurotransmission

    PubMed Central

    Dadalko, Olga I.; Siuta, Michael; Poe, Amanda; Erreger, Kevin; Matthies, Heinrich J.G.; Niswender, Kevin

    2015-01-01

    Disrupted neuronal protein kinase B (Akt) signaling has been associated with dopamine (DA)-related neuropsychiatric disorders, including schizophrenia, a devastating mental illness. We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function. Akt is activated by phosphorylation of two key residues: Thr308 and Ser473. Blunted Akt phosphorylation at Ser473 (pAkt-473) has been observed in lymphocytes and postmortem brains of schizophrenia patients, and psychosis-prone normal individuals. Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multiprotein complex that is responsible for phosphorylation of Akt at Ser473 (pAkt-473). We demonstrate that mice with disrupted mTORC2 signaling in brain exhibit altered striatal DA-dependent behaviors, such as increased basal locomotion, stereotypic counts, and exaggerated response to the psychomotor effects of amphetamine (AMPH). Combining in vivo and ex vivo pharmacological, electrophysiological, and biochemical techniques, we demonstrate that the changes in striatal DA neurotransmission and associated behaviors are caused, at least in part, by elevated D2 DA receptor (D2R) expression and upregulated ERK1/2 activation. Haloperidol, a typical antipsychotic and D2R blocker, reduced AMPH hypersensitivity and elevated pERK1/2 to the levels of control animals. By viral gene delivery, we downregulated mTORC2 solely in the dorsal striatum of adult wild-type mice, demonstrating that striatal mTORC2 regulates AMPH-stimulated behaviors. Our findings implicate mTORC2 signaling as a novel pathway regulating striatal DA tone and D2R signaling. PMID:26063917

  16. Dopamine D1-like receptors agonist SKF 38393 increases cFOS expression in the paraventricular nucleus of the hypothalamus--impact of acute and chronic cocaine.

    PubMed

    Chocyk, A; Czyrak, A; Wedzony, K

    2008-09-01

    The present study indicates that activation of dopamine D1-like receptors by administration of SKF 38393 leads to dose-dependent (doses: 5, 10 and 20 mg/kg) increases in the expression of cFos proteins in the rat paraventricular nucleus of the hypothalamus (PVN). This effect was abolished by administration of SCH 23390, a dopamine D1-like receptor antagonist (0.5 and 1 mg/kg, given 30 min before SKF 38393--10 mg/kg), suggesting that the apparent effect is specific for activation of dopamine D1-like receptors. Expression of cFos after SKF 38393 (10 mg/kg) was observed in some, but not all, CRF-immunoreactive neurons, as well as in small portion of oxytocin- but not vasopressin-immunoreactive neurons (double-immunofluorescence experiments). There were also certain populations of nuclei that showed expression of cFos but did not co-localize with the above markers. We also found that both acute and repeated (once daily for 5 consecutive days) exposure to cocaine (25 mg/kg) attenuated the induction of cFos expression triggered by SKF 38393 when administered 24 hours after single or the last dose of cocaine (25 mg/kg). Attenuation was observed at the same level after single and chronic exposure to cocaine, indicating a rapid functional down-regulation of dopamine D1-like receptors that are resistant to subsequent doses of cocaine. These data provide evidence for the functional role of dopamine D1-like receptors in the PVN and indicate a functional adaptation of dopamine D1-like receptors following a single dose of cocaine without further progression of adaptation or resistance of D1-like receptor-mediated genomic function in the course of repeated cocaine intake.

  17. Dopamine Modulates Reward-Related Vigor

    PubMed Central

    Beierholm, Ulrik; Guitart-Masip, Marc; Economides, Marcos; Chowdhury, Rumana; Düzel, Emrah; Dolan, Ray; Dayan, Peter

    2013-01-01

    Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence. PMID:23419875

  18. Linking unfounded beliefs to genetic dopamine availability

    PubMed Central

    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

  19. Linking unfounded beliefs to genetic dopamine availability.

    PubMed

    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 val (158) met) 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.

  20. DOPAMINE AND FOOD ADDICTION: LEXICON BADLY NEEDED

    PubMed Central

    Salamone, John D.; Correa, Mercè

    2012-01-01

    Over the last few years, the concept of food addiction has become a common feature in the scientific literature, as well as the popular press. Nevertheless, the use of the term “addiction” to describe pathological aspects of food intake in humans remains controversial, and even among those who affirm the validity of the concept, there is considerable disagreement about its utility for explaining the increasing prevalence of obesity throughout much of the world. An examination of the literature on food addiction indicates that mesolimbic and nigrostriatal dopamine systems often are cited as mechanisms that contribute to the establishment of food addiction. However, in reviewing this literature, it is important to have a detailed consideration of the complex nature of dopaminergic involvement in motivational processes. For example, although it is often stated that mesolimbic dopamine mediates “reward”, there is no standard or consistent technical meaning of this term. Moreover, there is a persistent tendency to link dopamine transmission with pleasure or hedonia, as opposed to other aspects of motivation or learning. The present paper provides a critical discussion of some aspects of the food addiction literature, viewed through the lens of recent findings and current theoretical views of dopaminergic involvement in food motivation. Furthermore, compulsive food intake and binge eating will be considered from an evolutionary perspective, in terms of the motivational subsystems that are involved in adaptive patterns of food consumption and seeking behaviors, and a consideration of how these could be altered in pathological conditions. PMID:23177385

  1. Safety out of control: dopamine and defence.

    PubMed

    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.

  2. Metabolic sensing in brain dopamine systems.

    PubMed

    de Araujo, Ivan E; Ren, Xueying; Ferreira, Jozélia G

    2010-01-01

    The gustatory system allows the brain to monitor the presence of chemicals in the oral cavity and initiate appropriate responses of acceptance or rejection. Among such chemicals are the nutrients that must be rapidly recognized and ingested for immediate oxidation or storage. In the periphery, the gustatory system consists of a highly efficient sensing mechanism, where distinct cell types express receptors that bind specifically to chemicals associated with one particular taste quality. These specialized receptors connect to the brain via dedicated pathways, the stimulation of which triggers stereotypic behavioral responses as well as neurotransmitter release in brain reward dopamine systems. However, evidence also exists in favor of the concept that the critical regulators of long-term nutrient choice are physiological processes taking place after ingestion and independently of gustation. We will appraise the hypothesis that organisms can develop preferences for nutrients independently of oral taste stimulation. Of particular interest are recent findings indicating that disrupting nutrient utilization interferes with activity in brain dopamine pathways. These findings establish the metabolic fate of nutrients as previously unanticipated reward signals that regulate the reinforcing value of foods. In particular, it suggests a role for brain dopamine reward systems as metabolic sensors, allowing for signals generated by the metabolic utilization of nutrients to regulate neurotransmitter release and food reinforcement.

  3. Suppression of Dopamine Neurons Mediates Reward

    PubMed Central

    Yamagata, Nobuhiro; Abe, Ayako; Tanimoto, Hiromu

    2016-01-01

    Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM-γ3, mediates sugar reward by suppressing their own activity. PAM-γ3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-γ3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM-γ3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-γ3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation. PMID:27997541

  4. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.

    PubMed

    Felger, Jennifer C; Treadway, Michael T

    2017-01-01

    Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

  5. Dopamine regulates termite soldier differentiation through trophallactic behaviours

    PubMed Central

    Yaguchi, Hajime; Inoue, Takaya; Sasaki, Ken; Maekawa, Kiyoto

    2016-01-01

    Caste polyphenism in social insects is regulated by social interactions among colony members. Trophallaxis is one of the most frequently observed interactions, but no studies have been conducted identifying the intrinsic factors involved in this behaviour and caste differentiation. Dopamine (DA) has multiple roles in the modulation of behaviours and physiology, and it produces species-specific behaviours in animals. Here, to verify the role of DA in termite soldier differentiation, we focused on the first soldier in an incipient colony of Zootermopsis nevadensis, which always differentiates from the oldest 3rd instar (No. 1 larva) via a presoldier. First, brain DA levels of the No. 1 larva at day 3 after its appearance were significantly higher than day 0. Second, DA synthesis gene expression levels were extraordinarily high in the No. 1 larva at day 0–1 after appearance. Finally, injection of a DA receptor antagonist into the No. 1 larva resulted in the inhibition of presoldier differentiation. Behavioural observations of the antagonist or control-injected larvae suggested that brain DA and signalling activity regulate the frequencies of trophallaxis from reproductives and presoldier differentiation. Because trophallaxis is a social behaviour frequently observed in natural conditions, the role of DA should be investigated in other social insects with frequent trophallactic and allogrooming behaviour. PMID:26998327

  6. Phencyclidine: behavioral and biochemical evidence supporting a role for dopamine.

    PubMed

    Johnson, K M

    1983-06-01

    Pharmacological studies of phencyclidine (PCP)-induced behaviors such as stereotypy and turning suggest that PCP is an indirectly acting dopamine (DA) agonist with some anticholinergic potential. In vitro studies show that PCP is a potent, competitive inhibitor of monoamine uptake. PCP has also been shown to stimulate synaptosomal striatal tyrosine hydroxylase activity via a release of DA (which normally inhibits this enzyme). The mechanism by which PCP releases DA is unknown, but is similar to that of methylphenidate and distinct from that of amphetamine. In vivo studies also show similarities between PCP and the nonamphetamine class of stimulants. For example, PCP and amfonelic acid, but not amphetamine, potentiate haloperidol-induced DA metabolism. This effect can be blocked by baclofen, which suggests a dependence on nigrostriatal impulse flow. Other studies suggest that PCP releases a pool of DA that is in rapid equilibrium with the vesicular compartment, thereby activating a feedback mechanism (probably transsynaptic) that inhibits the synthesis of DA. Despite the similarities between PCP and nonamphetamine stimulants, there are both behavioral and biochemical anomalies that caution against the strict classification of PCP as a nonamphetamine stimulant.

  7. Dopamine Modulates Cell Cycle in the Lateral Ganglionic Eminence

    PubMed Central

    Ohtani, Nobuyo; Goto, Tomohide; Waeber, Christian; Bhide, Pradeep G.

    2005-01-01

    Dopamine is a neuromodulator the functions of which in the regulation of complex behaviors such as mood, motivation, and attention are well known. Dopamine appears in the brain early in the embryonic period when none of those behaviors is robust, raising the possibility that dopamine may influence brain development. The effects of dopamine on specific developmental processes such as neurogenesis are not fully characterized. The neostriatum is a dopamine-rich region of the developing and mature brain. If dopamine influenced neurogenesis, the effects would likely be pronounced in the neostriatum. Therefore, we examined whether dopamine influenced neostriatal neurogenesis by influencing the cell cycle of progenitor cells in the lateral ganglionic eminence (LGE), the neuroepithelial precursor of the neostriatum. We show that dopamine arrives in the LGE via the nigrostriatal pathway early in the embryonic period and that neostriatal neurogenesis progresses in a dopamine-rich milieu. Dopamine D1-like receptor activation reduces entry of progenitor cells from the G1-to S-phase of the cell cycle, whereas D2-like receptor activation produces the opposite effects by promoting G1- to S-phase entry. D1-like effects are prominent in the ventricular zone, and D2-like effects are prominent in the subventricular zone. The overall effects of dopamine on the cell cycle are D1-like effects, most likely because of the preponderance of D1-like binding sites in the embryonic neostriatum. These data reveal a novel developmental role for dopamine and underscore the relevance of dopaminergic signaling in brain development. PMID:12684471

  8. Interactions of taurine and dopamine in the striatum.

    PubMed

    Kontro, P

    1987-01-01

    Both spontaneous and K+-stimulated taurine release from rat striatal slices were affected by dopamine and apomorphine, suggesting that dopaminergic systems are able to modulate taurine release. K+-stimulated dopamine release was potentiated by taurine, which effect may not involve dopamine autoreceptors. Taurine was able to inhibit spiperone binding to striatal membranes in a uncompetitive manner and thus interfere with the function of dopaminergic receptors.

  9. The dopamine transporter: role in neurotoxicity and human disease

    SciTech Connect

    Bannon, Michael J. . E-mail: mbannon@med.wayne.edu

    2005-05-01

    The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

  10. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug.

    PubMed

    Mizushima, Jin; Takahata, Keisuke; Kawashima, Noriko; Kato, Motoichiro

    2012-07-07

    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.

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

    NASA Astrophysics Data System (ADS)

    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.

  12. Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

    PubMed

    Thomas, Roshni Baby; Joy, Shilpa; Ajayan, M S; Paulose, C S

    2013-11-01

    Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.

  13. Dopamine release in rat striatum - Physiological coupling to tyrosine supply

    NASA Technical Reports Server (NTRS)

    During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

    1989-01-01

    Intracerebral microdialysis was used to monitor dopamine release in rat striatal extracellular fluid following the intraperitoneal administration of dopamine's precursor amino acid, L-tyrosine. Dopamine concentrations in dialysates increased transiently after tyrosine (50-100 mg/kg) administration. Pretreatment with haloperidol or the partial lesioning of nigrostriatal neurons enhanced the effect of tyrosine on dopamine release, and haloperidol also prolonged this effect. These data suggest that nigrostriatal dopaminergic neurons are responsive to changes in precursor availability under basal conditions, but that receptor-mediated feedback mechanisms limit the magnitude and duration of this effect.

  14. Reinforcement signalling in Drosophila; dopamine does it all after all.

    PubMed

    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.

  15. Cross-hemispheric dopamine projections have functional significance

    PubMed Central

    Fox, Megan E.; Mikhailova, Maria A.; Bass, Caroline E.; Takmakov, Pavel; Gainetdinov, Raul R.; Budygin, Evgeny A.; Wightman, R. Mark

    2016-01-01

    Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson’s disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine–lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres. PMID:27298371

  16. Cloning of the cocaine-sensitive bovine dopamine transporter

    SciTech Connect

    Usdin, T.B.; Chen, C.; Brownstein, M.J.; Hoffman, B.J. ); Mezey, E. )

    1991-12-15

    A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat {gamma}-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. ({sup 3}H)Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transports, including GBR12909.

  17. The action of dopamine and vascular dopamine (DA1) receptor agonists on human isolated subcutaneous and omental small arteries.

    PubMed Central

    Hughes, A. D.; Sever, P. S.

    1989-01-01

    1. Human small arteries were obtained from surgical specimens and studied in vitro by use of a myograph technique. Following induction of tone with a potassium depolarizing solution, dopamine in the presence of beta-adrenoceptor and catecholamine uptake blockade relaxed isolated omental and subcutaneous arteries. Preincubation of tissues with phentolamine increased the maximum relaxation in response to dopamine. 2. The selective vascular dopamine receptor agonists, fenoldopam and SKF 38393 also relaxed isolated subcutaneous and omental arteries in a concentration-dependent manner. The order of potency for agonists was dopamine greater than fenoldopam greater than SKF 38393. 3. Dopamine-induced relaxation was competitively antagonized by SCH 23390, (R)- and (S)-sulpiride, and fenoldopam induced relaxation by SCH 23390 and (+)- but not (-)-butaclamol. 4. These results indicate the presence of vascular dopamine receptors (DA1 subtype) on human isolated resistance arteries from omental and subcutaneous sites. PMID:2474354

  18. [Dopamine content in blood and activity of alcohol-transforming enzymes in alcoholism].

    PubMed

    Kharchenko, N K

    1997-01-01

    An increase of alcohol dehydrogenase activity is observed in patients with chronic alcoholism at the first stage of the disease under normal indices of activity of aldehyde dehydrogenase, aspartate- and alanine aminotransferase and thymol sample that evidences for the induction of alcohol dehydrogenase synthesis in the liver. At the second stage of alcoholism the activity of alcohol dehydrogenase, aspartate- and alanine aminotransferase, the index of thymol sample increase while activity of aldehyde dehydrogenase decreases that indicates to organic destructive changes in the liver. At the third stage of alcoholism one can observe the decrease in activity of alcohol dehydrogenase, aldehyde dehydrogenase and alanine aminotransferase relative to activity of these enzymes at the second stage, that can evidence for the increase of the possibility of the processes of synthesis of the liver. The correlation of alcohol dehydrogenase activity to that of aldehyde dehydrogenase in the process of formation and development of alcoholism is shifted towards the progressive accumulation of acetaldehyde. Parallel increase of dopamine concentration in blood creates conditions for formation of morphine-like alcaloides--products of condensation of acetaldehide with dopamine.

  19. Amygdala Dopamine Receptors Are Required for the Destabilization of a Reconsolidating Appetitive Memory(1,2).

    PubMed

    Merlo, Emiliano; Ratano, Patrizia; Ilioi, Elena C; Robbins, Miranda A L S; Everitt, Barry J; Milton, Amy L

    2015-01-01

    Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation.

  20. Doping Polypyrrole Films with 4-N-Pentylphenylboronic Acid to Enhance Affinity towards Bacteria and Dopamine

    PubMed Central

    Padiolleau, Laurence; Chen, Xi; Jafari, Mohammad Javad; Sheikhzadeh, Elham; Turner, Anthony P. F.; Jager, Edwin W. H.; Beni, Valerio

    2016-01-01

    Here we demonstrate the use of a functional dopant as a fast and simple way to tune the chemical affinity and selectivity of polypyrrole films. More specifically, a boronic-functionalised dopant, 4-N-Pentylphenylboronic Acid (PBA), was used to provide to polypyrrole films with enhanced affinity towards diols. In order to prove the proposed concept, two model systems were explored: (i) the capture and the electrochemical detection of dopamine and (ii) the adhesion of bacteria onto surfaces. The chemisensor, based on overoxidised polypyrrole boronic doped film, was shown to have the ability to capture and retain dopamine, thus improving its detection; furthermore the chemisensor showed better sensitivity in comparison with overoxidised perchlorate doped films. The adhesion of bacteria, Deinococcus proteolyticus, Escherichia coli, Streptococcus pneumoniae and Klebsiella pneumoniae, onto the boric doped polypyrrole film was also tested. The presence of the boronic group in the polypyrrole film was shown to favour the adhesion of sugar-rich bacterial cells when compared with a control film (Dodecyl benzenesulfonate (DBS) doped film) with similar morphological and physical properties. The presented single step synthesis approach is simple and fast, does not require the development and synthesis of functional monomers, and can be easily expanded to the electrochemical, and possibly chemical, fabrication of novel functional surfaces and interfaces with inherent pre-defined sensing and chemical properties. PMID:27875555

  1. Doping Polypyrrole Films with 4-N-Pentylphenylboronic Acid to Enhance Affinity towards Bacteria and Dopamine.

    PubMed

    Golabi, Mohsen; Padiolleau, Laurence; Chen, Xi; Jafari, Mohammad Javad; Sheikhzadeh, Elham; Turner, Anthony P F; Jager, Edwin W H; Beni, Valerio

    2016-01-01

    Here we demonstrate the use of a functional dopant as a fast and simple way to tune the chemical affinity and selectivity of polypyrrole films. More specifically, a boronic-functionalised dopant, 4-N-Pentylphenylboronic Acid (PBA), was used to provide to polypyrrole films with enhanced affinity towards diols. In order to prove the proposed concept, two model systems were explored: (i) the capture and the electrochemical detection of dopamine and (ii) the adhesion of bacteria onto surfaces. The chemisensor, based on overoxidised polypyrrole boronic doped film, was shown to have the ability to capture and retain dopamine, thus improving its detection; furthermore the chemisensor showed better sensitivity in comparison with overoxidised perchlorate doped films. The adhesion of bacteria, Deinococcus proteolyticus, Escherichia coli, Streptococcus pneumoniae and Klebsiella pneumoniae, onto the boric doped polypyrrole film was also tested. The presence of the boronic group in the polypyrrole film was shown to favour the adhesion of sugar-rich bacterial cells when compared with a control film (Dodecyl benzenesulfonate (DBS) doped film) with similar morphological and physical properties. The presented single step synthesis approach is simple and fast, does not require the development and synthesis of functional monomers, and can be easily expanded to the electrochemical, and possibly chemical, fabrication of novel functional surfaces and interfaces with inherent pre-defined sensing and chemical properties.

  2. Dopamine and dopamine receptor D1 associated with decreased social interaction.

    PubMed

    Liu, Qiang; Shi, Jieyun; Lin, Rongfei; Wen, Tieqiao

    2017-02-13

    Deficits in social interaction are hallmarks of neurological and psychiatric disorders. However, its underlying mechanism is still unclear. Here, we show that the loss of dendritic cell factor 1 (Dcf1) in the nervous system of mice induces social interaction deficiency, autism-like behaviour, and influences social interaction via the dopamine system. Dopamine receptor D1 agonist rescues this social cognition phenotype, and improves short-term plasticity. Together, this study presents a new genetic mechanism that affects social interaction and may provide a new way to improve positive social interaction and treat autism spectrum disorders.

  3. Monitoring Dopamine Quinone-Induced Dopaminergic Neurotoxicity Using Dopamine Functionalized Quantum Dots.

    PubMed

    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.

  4. Effects of dopamine and dopamine-active compounds on oxytocin and vasopressin production in rat neurohypophyseal tissue cultures.

    PubMed

    Gálfi, M; Janáky, T; Tóth, R; Prohászka, G; Juhász, A; Varga, C; László, F A

    2001-04-02

    The effects of dopamine (DA) or DA-active drugs on the synthesis of neurohypophyseal (NH) hormones were studied in 13-14 day cultures of isolated NH tissue from rats. The following DA-active compounds were used (10(-6) M in each medium): DA, apomorphine (APM), Pro-Lys-Gly (PLG), butaclamol (B), haloperidol (HP), chlorpromazine (CPZ) and sulpiride (SP). The oxytocin (OT) and vasopressin (VP) contents of the condensed media were determined by RIA after a 1 or 2 h incubation. Significantly increased contents of OT and VP were detected in the tissue culture media following DA, APM or PLG administration. This elevation of NH hormone production could be blocked by previous administration of B or the DA receptor antagonists HP, CPZ or SP. The application of B after DA agonists proved ineffective. The results indicate that NH hormone production can be directly influenced by the DA-ergic system. The DA-ergic control of NH hormone secretion in rats can occur independently of the hypothalamus, at the level of the posterior pituitary.

  5. Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity

    PubMed Central

    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. PMID:25402186

  6. Facilitatory effect of dopamine on neuromuscular transmission mediated via dopamine D1-like receptors and prospective interaction with nicotine.

    PubMed

    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.

  7. Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity.

    PubMed

    Bradner, Joshua M; Suragh, Tiffany A; Wilson, W Wyatt; Lazo, Carlos R; Stout, Kristen A; Kim, Hye Mi; Wang, Min Z; Walker, Douglas I; Pennell, Kurt D; Richardson, Jason R; Miller, Gary W; Caudle, W Michael

    2013-03-01

    In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson's disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders.

  8. Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain.

    PubMed

    Hall, H; Sedvall, G; Magnusson, O; Kopp, J; Halldin, C; Farde, L

    1994-12-01

    Densities and distribution of D1-dopamine and D2-dopamine receptors were investigated in vitro using [3H]SCH 23390 and [3H]raclopride in receptor binding assays and autoradiography on human post mortem whole hemisphere slices to serve as anatomical correlates to PET studies using [11C]SCH 23390 and [11C]raclopride. In addition, the levels of dopamine and its metabolites were determined by HPLC in various brain regions. Both dopamine receptor subtypes, as well as dopamine, HVA and DOPAC, were primarily found in the basal ganglia. Very high densities of D1-dopamine receptors were found particularly in the medial caudate nucleus, whereas D2-dopamine receptors were evenly distributed throughout the caudate. The densities of D1- and D2-dopamine receptors were similar in the caudate nucleus and the putamen, whereas there were 4 to 7 times higher densities of the D1- than of the D2-dopamine receptors in several limbic and neocortical regions. The receptor distribution in the autoradiographic study was consistent with that demonstrated in the living human brain using [11C]SCH 23390 and [11C]raclopride.

  9. Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats

    PubMed Central

    Sun, Jianjun; Kouranova, Evguenia; Cui, Xiaoxia; Mach, Robert H.; Xu, Jinbin

    2014-01-01

    Pathogenic autosomal recessive mutations in the DJ-1 (Park7) or the PTEN-induced putative kinase 1 (Pink1 or PARK6) genes are associated with familial Parkinson’s disease (PD). It is not well known regarding the pathological mechanisms involving the DJ-1 and Pink1 mutations. Here we characterized DJ-1 and Pink1 knockout rats both through expression profiling and using quantitative autoradiography to measure the densities of the dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) in the striatum of transgenic rats and wild type controls. Expression profiling with a commercially available array of 84 genes known to be involved in PD indicated that only the target gene was significantly downregulated in each transgenic rat model. D1 receptor, VMAT2, and DAT were measured using [3H]SCH23390, [3H]dihydrotetrabenazine, and [3H]WIN35428, respectively. No significant changes were observed in the density of DAT in either model. Although the densities of VMAT2 and D1 receptor were unchanged in Pink1 knockout, but both were increased in DJ-1 knockout rats. The densities of D2 and D3 receptors, determined by mathematical analysis of binding of radioligands [3H]WC-10 and [3H]raclopride, were significantly increased in both knockout models. These distinctive changes in the expression of dopamine presynaptic markers and receptors in the striatum may reflect different compensatory regulation of dopamine system in DJ-1 versus Pink1 knockout rat models of familial PD. PMID:24157858

  10. A proposed resolution to the paradox of drug reward: Dopamine's evolution from an aversive signal to a facilitator of drug reward via negative reinforcement.

    PubMed

    Ting-A-Kee, Ryan; Heinmiller, Andrew; van der Kooy, Derek

    2015-09-01

    The mystery surrounding how plant neurotoxins came to possess reinforcing properties is termed the paradox of drug reward. Here we propose a resolution to this paradox whereby dopamine - which has traditionally been viewed as a signal of reward - initially signaled aversion and encouraged escape. We suggest that after being consumed, plant neurotoxins such as nicotine activated an aversive dopaminergic pathway, thereby deterring predatory herbivores. Later evolutionary events - including the development of a GABAergic system capable of modulating dopaminergic activity - led to the ability to down-regulate and 'control' this dopamine-based aversion. We speculate that this negative reinforcement system evolved so that animals could suppress aversive states such as hunger in order to attend to other internal drives (such as mating and shelter) that would result in improved organismal fitness.

  11. Influence of Lead on Repetitive Behavior and Dopamine Metabolism in a Mouse Model of Iron Overload

    PubMed Central

    Kueon, Chojin; Kim, Jonghan

    2014-01-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  12. Serotonin-S2 and dopamine-D2 receptors are the same size in membranes

    SciTech Connect

    Brann, M.R.

    1985-12-31

    Target size analysis was used to compare the sizes of serotonin-S2 and dopamine-D2 receptors in rat brain membranes. The sizes of these receptors were standardized by comparison with the muscarinic receptor, a receptor of known size. The number of serotonin-S2 receptors labeled with (3H)ketanserin or (3H)spiperone in frontal cortex decreased as an exponential function of radiation dose, and receptor affinity was not affected. The number of dopamine-D2 receptors labeled with (3H)spiperone in striatum also decreased as an exponential function of radiation dose, and D2 and S2 receptors were equally sensitive to radiation. In both striatum and frontal cortex, the number of muscarinic receptors labeled with (3H)QNB decreased as an exponential function of radiation dose, and were much less sensitive to radiation than S2 and D2 receptors. These data indicate that in rat brain membranes, S2 and D2 receptors are of similar size, and both molecules are much larger than the muscarinic receptor.

  13. Interaction of structural analogs of dopamine, chlorpromazine and sulpiride with striatal dopamine receptors

    SciTech Connect

    Wallace, R.A.

    1987-01-01

    The objectives of these studies were to determine if the nitrogen atom of dopaminergic agonists and antagonists drugs is required for interaction with the D-1 and D-2 dopamine receptors and whether the positively charged or uncharged molecular species interacts with these receptors. To address these issues, permanently charged analogs of dopamine, chlorpromazine and sulpiride were synthesized in which a dimethylsulfonium, dimethylselenonium or quaternary ammonium group replaced the amine group. Permanently uncharged analogs which contained a methylsulfide, methylselenide and sulfoxide group instead of an amine group were also synthesized. The interactions of these compounds with striatal dopamine receptors were studied. We found that the permanently charged dopamine analogs bound to the D-2 receptor of striatal membranes like conventional dopaminergic agonists and displayed agonist activity at the D-2 receptor regulating potassium-evoked (/sup 3/H) acetylcholine release. In contrast, the permanently uncharged analogs bound only to the high affinity state of the D-2 receptor and had neither agonist or antagonist activity.

  14. Positron-labeled dopamine agonists for probing the high affinity states of dopamine subtype 2 receptors.

    PubMed

    Hwang, Dah-Ren; Narendran, Raj; Laruelle, Marc

    2005-01-01

    It is well documented that guanidine nucleotide-coupled dopamine subtype 2 receptors (D2) are configured in high and low affinity states for the dopamine agonist in vitro. However, it is still unclear whether these functional states exist in vivo. We hypothesized that positron-labeled D2 agonist and Positron Emission Tomography can be used to probe these functional states noninvasively. Recently, we demonstrated in nonhuman primates that N-[11C]propyl-norapomorphine (NPA), a full D2 agonist, is a suitable tracer for imaging the high affinity states of D2 receptors in vivo. We also developed kinetic modeling method to derive receptor parameters, such as binding potential (BP) and specific uptake ratios (V3''). When coupled with a dopamine releasing drug, amphetamine, NPA was found to be more sensitive than antagonist tracers, such as [11C]raclopride (RAC), to endogenous dopamine concentration changes (by about 42%). This finding suggests that NPA is a superior tracer for reporting endogenous DA concentration. In addition, the difference of the BP or V3'' of NPA and RAC under control and amphetamine challenge conditions could be used to estimate the functional states of D2 receptors in vivo. On the basis of our findings and the assumptions that NPA binds only to the high affinity states and RAC binds equally to both affinity states, we proposed that about 70% of the D2 receptors are configured in the high affinity states in vivo.

  15. Cell wall modifications triggered by the down-regulation of Coumarate 3-hydroxylase-1 in maize.

    PubMed

    Fornalé, Silvia; Rencoret, Jorge; Garcia-Calvo, Laura; Capellades, Montserrat; Encina, Antonio; Santiago, Rogelio; Rigau, Joan; Gutiérrez, Ana; Del Río, José-Carlos; Caparros-Ruiz, David

    2015-07-01

    Coumarate 3-hydroxylase (C3H) catalyzes a key step of the synthesis of the two main lignin subunits, guaiacyl (G) and syringyl (S) in dicotyledonous species. As no functional data are available in regards to this enzyme in monocotyledonous species, we generated C3H1 knock-down maize plants. The results obtained indicate that C3H1 participates in lignin biosynthesis as its down-regulation redirects the phenylpropanoid flux: as a result, increased amounts of p-hydroxyphenyl (H) units, lignin-associated ferulates and the flavone tricin were detected in transgenic stems cell walls. Altogether, these changes make stem cell walls more degradable in the most C3H1-repressed plants, despite their unaltered polysaccharide content. The increase in H monomers is moderate compared to C3H deficient Arabidopsis and alfalfa plants. This could be due to the existence of a second maize C3H protein (C3H2) that can compensate the reduced levels of C3H1 in these C3H1-RNAi maize plants. The reduced expression of C3H1 alters the macroscopic phenotype of the plants, whose growth is inhibited proportionally to the extent of C3H1 repression. Finally, the down-regulation of C3H1 also increases the synthesis of flavonoids, leading to the accumulation of anthocyanins in transgenic leaves.

  16. Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors.

    PubMed

    Hedlund, Eva; Belnoue, Laure; Theofilopoulos, Spyridon; Salto, Carmen; Bye, Chris; Parish, Clare; Deng, Qiaolin; Kadkhodaei, Banafsheh; Ericson, Johan; Arenas, Ernest; Perlmann, Thomas; Simon, András

    2016-06-01

    Degeneration of dopamine neurons in the midbrain causes symptoms of the movement disorder, Parkinson disease. Dopamine neurons are generated from proliferating progenitor cells localized in the embryonic ventral midbrain. However, it remains unclear for how long cells with dopamine progenitor character are retained and if there is any potential for reactivation of such cells after cessation of normal dopamine neurogenesis. We show here that cells expressing Lmx1a and other progenitor markers remain in the midbrain aqueductal zone beyond the major dopamine neurogenic period. These cells express dopamine receptors, are located in regions heavily innervated by midbrain dopamine fibres and their proliferation can be stimulated by antagonizing dopamine receptors, ultimately leading to increased neurogenesis in vivo. Furthermore, treatment with dopamine receptor antagonists enhances neurogenesis in vitro, both from embryonic midbrain progenitors as well as from embryonic stem cells. Altogether our results indicate a potential for reactivation of resident midbrain cells with dopamine progenitor potential beyond the normal period of dopamine neurogenesis.

  17. Imaging dopamine receptors in the human brain by position tomography

    SciTech Connect

    Wagner, H.N. Jr.; Burns, H.D.; Dannals, R.F.; Wong, D.F.; Langstrom, B.; Duelfer, T.; Frost, J.J.; Ravert, H.T.; Links, J.M.; Rosenbloom, S.B.

    1983-01-01

    Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-(/sup 11/C)methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

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

    PubMed

    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.

  19. PKCβ Inhibitors Attenuate Amphetamine-Stimulated Dopamine Efflux.

    PubMed

    Zestos, Alexander G; Mikelman, Sarah R; Kennedy, Robert T; Gnegy, Margaret E

    2016-06-15

    Amphetamine abuse afflicts over 13 million people, and there is currently no universally accepted treatment for amphetamine addiction. Amphetamine serves as a substrate for the dopamine transporter and reverses the transporter to cause an increase in extracellular dopamine. Activation of the beta subunit of protein kinase C (PKCβ) enhances extracellular dopamine in the presence of amphetamine by facilitating the reverse transport of dopamine and internalizing the D2 autoreceptor. We previously demonstrated that PKCβ inhibitors block amphetamine-stimulated dopamine efflux in synaptosomes from rat striatum in vitro. In this study, we utilized in vivo microdialysis in live, behaving rats to assess the effect of the PKCβ inhibitors, enzastaurin and ruboxistaurin, on amphetamine-stimulated locomotion and increases in monoamines and their metabolites. A 30 min perfusion of the nucleus accumbens core with 1 μM enzastaurin or 1 μM ruboxistaurin reduced efflux of dopamine and its metabolite 3-methoxytyramine induced by amphetamine by approximately 50%. The inhibitors also significantly reduced amphetamine-stimulated extracellular levels of norepinephrine. The stimulation of locomotor behavior by amphetamine, measured simultaneously with the analytes, was comparably reduced by the PKCβ inhibitors. Using a stable isotope label retrodialysis procedure, we determined that ruboxistaurin had no effect on basal levels of dopamine, norepinephrine, glutamate, or GABA. In addition, normal uptake function through the dopamine transporter was unaltered by the PKCβ inhibitors, as measured in rat synaptosomes. Our results support the utility of using PKCβ inhibitors to reduce the effects of amphetamine.

  20. Dopamine receptor genes: new tools for molecular psychiatry.

    PubMed Central

    Niznik, H B; Van Tol, H H

    1992-01-01

    For over a decade it has been generally assumed that all the pharmacological and biochemical actions of dopamine within the central nervous system and periphery were mediated by two distinct dopamine receptors. These receptors, termed D1 and D2, were defined as those coupled to the stimulation or inhibition of adenylate cyclase, respectively, and by their selectivity and avidity for various drugs and compounds. The concept that two dopamine receptors were sufficient to account for all the effects mediated by dopamine was an oversimplification. Recent molecular biological studies have identified five distinct genes which encode at least eight functional dopamine receptors. The members of the expanded dopamine receptor family, however, can still be codifed by way of the original D1 and D2 receptor dichotomy. These include two genes encoding dopamine D1-like receptors (D1 [D1A]/D5 [D1B]) and three genes encoding D2-like receptors (D2/D3/D4). We review here our recent work on the cloning and characterization of some of the members of the dopamine receptor gene family (D1, D2, D4, D5), their relationship to neuropsychiatric disorders and their potential role in antipsychotic drug action. Images Fig. 1 PMID:1450188

  1. The dopamine transporter and attention-deficit/hyperactivity disorder.

    PubMed

    Madras, Bertha K; Miller, Gregory M; Fischman, Alan J

    2005-06-01

    The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.

  2. Hub and switches: endocannabinoid signalling in midbrain dopamine neurons.

    PubMed

    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.

  3. Dopamine receptor oligomerization visualized in living cells.

    PubMed

    O'Dowd, Brian F; Ji, Xiaodong; Alijaniaram, Mohammad; Rajaram, Ryan D; Kong, Michael M C; Rashid, Asim; Nguyen, Tuan; George, Susan R

    2005-11-04

    G protein-coupled receptors occur as dimers within arrays of oligomers. We visualized ensembles of dopamine receptor oligomers in living cells and evaluated the contributions of receptor conformation to the dynamics of oligomer association and dissociation, using a strategy of trafficking a receptor to another cellular compartment. We incorporated a nuclear localization sequence into the D1 dopamine receptor, which translocated from the cell surface to the nucleus. Receptor inverse agonists blocked this translocation, retaining the modified receptor, D1-nuclear localization signal (NLS), at the cell surface. D1 co-translocated with D1-NLS to the nucleus, indicating formation of homooligomers. (+)-Butaclamol retained both receptors at the cell surface, and removal of the drug allowed translocation of both receptors to the nucleus. Agonist-nonbinding D1(S198A/S199A)-NLS, containing two substituted serine residues in transmembrane 5 also oligomerized with D1, and both were retained on the cell surface by (+)-butaclamol. Drug removal disrupted these oligomerized receptors so that D1 remained at the cell surface while D1(S198A/S199A)-NLS trafficked to the nucleus. Thus, receptor conformational differences permitted oligomer disruption and showed that ligand-binding pocket occupancy by the inverse agonist induced a conformational change. We demonstrated robust heterooligomerization between the D2 dopamine receptor and the D1 receptor. The heterooligomers could not be disrupted by inverse agonists targeting either one of the receptor constituents. However, D2 did not heterooligomerize with the structurally modified D1(S198A/S199A), indicating an impaired interface for their interaction. Thus, we describe a novel method showing that a homogeneous receptor conformation maintains the structural integrity of oligomers, whereas conformational heterogeneity disrupts it.

  4. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.

    PubMed

    Masoud, S T; Vecchio, L M; Bergeron, Y; Hossain, M M; Nguyen, L T; Bermejo, M K; Kile, B; Sotnikova, T D; Siesser, W B; Gainetdinov, R R; Wightman, R M; Caron, M G; Richardson, J R; Miller, G W; Ramsey, A J; Cyr, M; Salahpour, A

    2015-02-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease.

  5. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and L-DOPA reversible motor deficits

    PubMed Central

    Masoud, ST; Vecchio, LM; Bergeron, Y; Hossain, MM; Nguyen, LT; Bermejo, MK; Kile, B; Sotnikova, TD; Siesser, WB; Gainetdinov, RR; Wightman, RM; Caron, MG; Richardson, JR; Miller, GW; Ramsey, AJ; Cyr, M; Salahpour, A

    2015-01-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with L-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and LDOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson’s disease. PMID:25447236

  6. Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation.

    PubMed

    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

  7. Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction.

    PubMed

    Rivera, Alicia; Gago, Belén; Suárez-Boomgaard, Diana; Yoshitake, Takashi; Roales-Buján, Ruth; Valderrama-Carvajal, Alejandra; Bilbao, Ainhoa; Medina-Luque, José; Díaz-Cabiale, Zaida; Craenenbroeck, Kathleen Van; Borroto-Escuela, Dasiel O; Kehr, Jan; Rodríguez de Fonseca, Fernando; Santín, Luis; de la Calle, Adelaida; Fuxe, Kjell

    2016-05-22

    Morphine is one of the most effective drugs used for pain management, but it is also highly addictive. Morphine elicits acute and long-term adaptive changes at cellular and molecular level in the brain, which play a critical role in the development of tolerance, dependence and addiction. Previous studies indicated that the dopamine D4 receptor (D4 R) activation counteracts morphine-induced adaptive changes of the μ opioid receptor (MOR) signaling in the striosomes of the caudate putamen (CPu), as well as the induction of several Fos family transcription factors. Thus, it has been suggested that D4 R could play an important role avoiding some of the addictive effects of morphine. Here, using different drugs administration paradigms, it is determined that the D4 R agonist PD168,077 prevents morphine-induced activation of the nigrostriatal dopamine pathway and morphological changes of substantia nigra pars compacta (SNc) dopamine neurons, leading to a restoration of dopamine levels and metabolism in the CPu. Results from receptor autoradiography indicate that D4 R activation modulates MOR function in the substantia nigra pars reticulata (SNr) and the striosomes of the CPu, suggesting that these regions are critically involved in the modulation of SNc dopamine neuronal function through a functional D4 R/MOR interaction. In addition, D4 R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. These results provide a novel role of D4 R agonist as a pharmacological strategy to prevent the adverse effects of morphine in the treatment of pain.

  8. GABA, glutamate, dopamine and serotonin transporters expression on memory formation and amnesia.

    PubMed

    Tellez, Ruth; Gómez-Víquez, Leticia; Meneses, Alfredo

    2012-02-01

    Notwithstanding several neurotransmission systems are frequently related to memory formation, amnesia and/or therapeutic targets for memory alterations, the role of transporters γ-aminobutyric acid (GABA, GAT1), glutamate (neuronal glutamate transporter excitatory amino acid carrier; EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper Western-blot analysis was used to evaluate expression changes on them during memory formation in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was evaluated in the hippocampus, prefrontal cortex and striatum. Data indicated that in addition of memory performance other behavioral parameters (e.g., explorative behavior, food-intake, etc.) that memory formation was recorded. Thus, memory formation in a Pavlovian/instrumental autoshaping was associated to up-regulation of prefrontal cortex GAT1 and EAAC1, striatal SERT, DAT and EACC1; while, hippocampal EACC1, GAT1 and SERT were down-regulated. METH impaired short (STM) and long-term memory (LTM), at 24 or 48h. The METH-induced amnesia down-regulated SERT, DAT, EACC1 and GAT1 in hippocampus and the GAT1 in striatum; no-changes were observed in prefrontal cortex. Post-training administration of fluoxetine improved LTM (48h), which was associated to DAT, GAT1 (prefrontal cortex) up-regulation, but GAT1 (striatum) and SERT (hippocampus) down-regulation. Fluoxetine plus METH administration was able to prevent amnesia, which was associated to DAT, EACC1 and GAT1 (prefrontal cortex), SERT and DAT (hippocampus) and EACC1 or DAT (striatal) up-regulation. Together these data show that memory formation, amnesia and anti-amnesic effects are associated to specific patters of transporters expression.

  9. Personality, addiction, dopamine: insights from Parkinson's disease.

    PubMed

    Dagher, Alain; Robbins, Trevor W

    2009-02-26

    In rare instances, patients with Parkinson's disease (PD) may become addicted to their own medication or develop behavioral addictions such as pathological gambling. This is surprising because PD patients typically have a very low incidence of drug abuse and display a personality type that is the polar opposite of the addictive personality. These rare addictive syndromes, which appear to result from excessive dopaminergic medication use, illustrate the link between dopamine, personality, and addiction. We describe the clinical phenomena and attempt to relate them to current models of learning and addiction. We conclude that persistently elevated dopaminergic stimulation promotes the development and maintenance of addictive behaviors.

  10. Effect of three anorectic drugs on central catecholamine levels and synthesis in the Zucker rat.

    PubMed

    Orosco, M; Bremond, J; Jacquot, C; Cohen, Y

    1983-01-01

    1. Genetically obese Zucker rats and their lean littermates were treated during 5 days with fenfluramine, mazindol or amphetamine. Norepinephrine and dopamine levels were assayed in the hypothalamus, striatum, medulla-oblongata pons and remainder of the brain, and the amine synthesis was estimated, when possible. 2. Fenfluramine acted especially on norepinephrine in the obese rat hypothalamus. 3. Mazindol was active on norepinephrine and dopamine levels only in obese animals. 4. Amphetamine acted on norepinephrine levels only in obese rats and on dopamine levels in both obese and lean rats.

  11. Renal tubular vasopressin receptors downregulated by dehydration

    SciTech Connect

    Steiner, M.; Phillips, M.I. )

    1988-03-01

    Receptors for arginine vasopressin (AVP) were characterized in tubular epithelial basolateral membranes (BL membranes) prepared from the kidneys of male Spraque-Dawley rats. Association of ({sup 3}H)AVP was rapid, reversible, and specific. Saturation studies revealed a single class of saturable binding sites with a maximal binding (B{sub max}) of 184 {plus minus} 15 fmol/mg protein. The V{sub 2} receptor antagonist was more than 3,700 times as effective in displacing ({sup 3}H)AVP than was the V{sub 1} antagonist. To investigate the physiological regulation of vasopressin receptors, the effects of elevated levels of circulating AVP on receptor characteristics were studied. Seventy-two-hour water deprivation significantly elevated plasma osmolality and caused an 11.5-fold increase in plasma (AVP). Scatchard analysis revealed a 38% decreased in the number of AVP receptors on the BL membranes from dehydrated animals. The high-affinity binding sites on the BL membranes fit the pharmacological profile for adenylate cyclase-linked vasopressin receptors (V{sub 2}), which mediate the antidiuretic action of the hormone. The authors conclude that physiologically elevated levels of AVP can downregulate vasopressin receptors in the kidney.

  12. Poly-L-histidine downregulates fibrinolysis.

    PubMed

    Chu, Arthur J; Mathews, Suresh T

    2003-10-01

    The elevated level of histidine-rich glycoprotein was considered a risk factor of inherited thrombophilia. However, the mode of action remains largely unclear. In the current study, we employ poly-l-histidine (PLH) mimicking the histidine-rich region and determine whether PLH modulates urokinase (uPA)-dependent fibrinolysis. In an in vitro model, turbidity appearance and clearance monitored fibrin polymer formation and lysis, respectively. Fibrin polymer formed upon fibrinogen incubation with thrombin. In the presence of uPA or plasmin, fibrin polymer lysis took place in a dose-dependent manner as a function of time. We demonstrated that PLH significantly downregulated uPA-dependent fibrinolysis. PLH had no effect on plasminogen activation, as evidenced by no inhibitions on either uPA amidolytic activity or plasmin formation derived from its zymogen. Nor did PLH show any inhibition on plasmin amidolytic activity. PLH caused a profound delay of plasmin-dependent fibrinolysis upon pre-incubation of either plasmin or fibrinogen with PLH. The observations taken together suggest that the complex [plasmin-PLH-fibrin] formation significantly delayed plasmin-dependent fibrinolysis.

  13. CDK5 downregulation enhances synaptic plasticity.

    PubMed

    Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen; Inestrosa, Nibaldo C; Bodaleo, Felipe; González-Billault, Christian; Kirkwood, Alfredo; Cardona-Gómez, Gloria Patricia

    2017-01-01

    CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity-such as long-term potentiation (LTP)-have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca(2+) signaling and BDNF/CREB activation.

  14. [Multiple Dopamine Signals and Their Contributions to Reinforcement Learning].

    PubMed

    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.

  15. Role of brain dopamine in food reward and reinforcement

    PubMed Central

    Wise, Roy A

    2006-01-01

    The ability of food to establish and maintain response habits and conditioned preferences depends largely on the function of brain dopamine systems. While dopaminergic transmission in the nucleus accumbens appears sufficient for some forms of reward, the role of dopamine in food reward does not appear to be restricted to this region. Dopamine plays an important role in both the ability to energize feeding and to reinforce food-seeking behaviour; the role in energizing feeding is secondary to the prerequisite role in reinforcement. Dopaminergic activation is triggered by the auditory and visual as well as the tactile, olfactory, and gustatory stimuli of foods. While dopamine plays a central role in the feeding and food-seeking of normal animals, some food rewarded learning can be seen in genetically engineered dopamine-deficient mice. PMID:16874930

  16. Arithmetic and local circuitry underlying dopamine prediction errors

    PubMed Central

    Eshel, Neir; Bukwich, Michael; Rao, Vinod; Hemmelder, Vivian; Tian, Ju; Uchida, Naoshige

    2015-01-01

    Dopamine neurons are thought to facilitate learning by comparing actual and expected reward1,2. 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 (VTA) while mice engaged in classical conditioning. By manipulating the temporal expectation of reward, we demonstrate 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 neurons in the VTA 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 VTA 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. PMID:26322583

  17. ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

    PubMed Central

    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

  18. Characterization of pre- and postsynaptic dopamine receptors in Lymnaea.

    PubMed

    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.

  19. Striatal Dopamine Links Gastrointestinal Rerouting to Altered Sweet Appetite.

    PubMed

    Han, Wenfei; Tellez, Luis A; Niu, Jingjing; Medina, Sara; Ferreira, Tatiana L; Zhang, Xiaobing; Su, Jiansheng; Tong, Jenny; Schwartz, Gary J; van den Pol, Anthony; de Araujo, Ivan E

    2016-01-12

    Reductions in calorie intake contribute significantly to the positive outcome of bariatric surgeries. However, the physiological mechanisms linking the rerouting of the gastrointestinal tract to reductions in sugar cravings remain uncertain. We show that a duodenal-jejunal bypass (DJB) intervention inhibits maladaptive sweet appetite by acting on dopamine-responsive striatal circuitries. DJB disrupted the ability of recurrent sugar exposure to promote sweet appetite in sated animals, thereby revealing a link between recurrent duodenal sugar influx and maladaptive sweet intake. Unlike ingestion of a low-calorie sweetener, ingestion of sugar was associated with significant dopamine effluxes in the dorsal striatum, with glucose infusions into the duodenum inducing greater striatal dopamine release than equivalent jejunal infusions. Consistently, optogenetic activation of dopamine-excitable cells of the dorsal striatum was sufficient to restore maladaptive sweet appetite in sated DJB mice. Our findings point to a causal link between striatal dopamine signaling and the outcomes of bariatric interventions.

  20. Striatal Dopamine Links Gastrointestinal Rerouting to Altered Sweet Appetite

    PubMed Central

    Han, Wenfei; Tellez, Luis A; Niu, Jingjing; Medina, Sara; Ferreira, Tatiana L; Zhang, Xiaobing; Su, Jiansheng; Tong, Jenny; Schwartz, Gary J; van den Pol, Anthony; de Araujo, Ivan E

    2015-01-01

    Reductions in calorie intake contribute significantly to the positive outcome of bariatric surgeries. However, the physiological mechanisms linking the rerouting of the gastrointestinal tract to reductions in sugar cravings remain uncertain. We show that a duodenal-jejunal bypass (DJB) intervention inhibits maladaptive sweet appetite by acting on dopamine-responsive striatal circuitries. DJB disrupted the ability of recurrent sugar exposure to promote sweet appetite in sated animals, thereby revealing a link between recurrent duodenal sugar influx and maladaptive sweet intake. Unlike ingestion of a low-calorie sweetener, ingestion of sugar was associated with significant dopamine effluxes in dorsal striatum, with glucose infusions into the duodenum inducing greater striatal dopamine release than equivalent jejunal infusions. Consistently, optogenetic activation of dopamine-excitable cells of dorsal striatum was sufficient to restore maladaptive sweet appetite in sated DJB mice. Our findings point to a causal link between striatal dopamine signaling and the outcomes of bariatric interventions. PMID:26698915

  1. A descending dopamine pathway conserved from basal vertebrates to mammals

    PubMed Central

    Ryczko, Dimitri; Cone, Jackson J.; Alpert, Michael H.; Goetz, Laurent; Auclair, François; Dubé, Catherine; Parent, Martin; Roitman, Mitchell F.; Alford, Simon; Dubuc, Réjean

    2016-01-01

    Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson’s disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine’s role in locomotion. PMID:27071118

  2. Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training.

    PubMed

    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.

  3. Multiple functionalization of fluorescent nanoparticles for specific biolabeling and drug delivery of dopamine

    NASA Astrophysics Data System (ADS)

    Malvindi, Maria Ada; di Corato, Riccardo; Curcio, Annalisa; Melisi, Daniela; Rimoli, Maria Grazia; Tortiglione, Claudia; Tino, Angela; George, Chandramohan; Brunetti, Virgilio; Cingolani, Roberto; Pellegrino, Teresa; Ragusa, Andrea

    2011-12-01

    The development of fluorescent biolabels for specific targeting and controlled drug release is of paramount importance in biological applications due to their potential in the generation of novel tools for simultaneous diagnosis and treatment of diseases. Dopamine is a neurotransmitter involved in several neurological diseases, such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD), and the controlled delivery of its agonists already proved to have beneficial effects both in vitro and in vivo. Here, we report the synthesis and multiple functionalization of highly fluorescent CdSe/CdS quantum rods for specific biolabeling and controlled drug release. After being transferred into aqueous media, the nanocrystals were made highly biocompatible through PEG conjugation and covered by a carbohydrate shell, which allowed specific GLUT-1 recognition. Controlled attachment of dopamine through an ester bond also allowed hydrolysis by esterases, yielding a smart nanotool for specific biolabeling and controlled drug release.The development of fluorescent biolabels for specific targeting and controlled drug release is of paramount importance in biological applications due to their potential in the generation of novel tools for simultaneous diagnosis and treatment of diseases. Dopamine is a neurotransmitter involved in several neurological diseases, such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD), and the controlled delivery of its agonists already proved to have beneficial effects both in vitro and in vivo. Here, we report the synthesis and multiple functionalization of highly fluorescent CdSe/CdS quantum rods for specific biolabeling and controlled drug release. After being transferred into aqueous media, the nanocrystals were made highly biocompatible through PEG conjugation and covered by a carbohydrate shell, which allowed specific GLUT-1 recognition. Controlled attachment of dopamine through an ester bond also allowed

  4. Endogenous dopamine increases extracellular concentrations of glutamate and GABA in striatum of the freely moving rat: involvement of D1 and D2 dopamine receptors.

    PubMed

    Expósito, I; Del Arco, A; Segovia, G; Mora, F

    1999-07-01

    Interactions between endogenous dopamine, glutamate, GABA, and taurine were investigated in striatum of the freely moving rat by using microdialysis. Intrastriatal infusions of the selective dopamine uptake inhibitor nomifensine (NMF) were used to increase the endogenous extracellular dopamine. NMF produced a dose-related increase in extracellular dopamine and also increased extracellular concentrations of glutamate, GABA, and taurine. Extracellular increases of dopamine were significantly correlated with extracellular increases of glutamate and GABA, but not taurine. To investigate whether the increased extracellular dopamine produced by NMF was responsible for the concomitant increase of glutamate and GABA, D1, and D2 receptor antagonists were used. Dopamine receptor antagonists D1 (SCH23390) and D2 (sulpiride) significantly attenuated the increases of glutamate and GABA produced by NMF. These data suggest that endogenous dopamine, through both D1 and D2 dopamine receptors, plays a role in releasing glutamate and GABA in striatum of the freely moving rat.

  5. Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

    PubMed Central

    Chang, Lisa; Chen, Mei; Bell, Jane M.; Rapoport, Stanley I.

    2016-01-01

    Observations that dopaminergic antagonists are beneficial in bipolar disorder and that dopaminergic agonists can produce mania suggest that bipolar disorder involves excessive dopaminergic transmission. Thus, mood stabilizers used to treat the disease might act in part by downregulating dopaminergic transmission. In agreement, we reported that dopamine D2-like receptor mediated signaling involving arachidonic acid (AA, 20:4n-6) was downregulated in rats chronically treated with lithium. To see whether chronic carbamazepine, another mood stabilizer, did this as well, we injected i.p. saline or the D2-like receptor agonist, quinpirole (1 mg/kg), into unanesthetized rats that had been pretreated for 30 days with i.p. carbamazepine (25 mg/kg/day) or vehicle, and used quantitative autoradiography to measure regional brain incorporation coefficients (k*) for AA, markers of signaling. We also measured brain prostaglandin E2 (PGE2), an AA metabolite. In vehicle-treated rats, quinpirole compared with saline significantly increased k* for AA in 35 of 82 brain regions examined, as well as brain PGE2 concentration. Affected regions belong to dopaminergic circuits and have high D2-like receptor densities. Chronic carbamazepine pretreatment prevented the quinpirole-induced increments in k* and in PGE2. These findings are consistent with the hypothesis that effective mood stabilizers generally downregulate brain AA signaling via D2-like receptors, and that this signaling is upregulated in bipolar disorder. PMID:18302021

  6. MTOR downregulates iodide uptake in thyrocytes.

    PubMed

    de Souza, Elaine Cristina Lima; Padrón, Alvaro Souto; Braga, William Miranda Oliveira; de Andrade, Bruno Moulin; Vaisman, Mário; Nasciutti, Luiz Eurico; Ferreira, Andrea Claudia Freitas; de Carvalho, Denise Pires

    2010-07-01

    Phosphoinositide-3-kinase (PI3K) inhibition increases functional sodium iodide symporter (NIS) expression in both FRTL-5 rat thyroid cell line and papillary thyroid cancer lineages. In several cell types, the stimulation of PI3K results in downstream activation of the mechanistic target of rapamycin (MTOR), a serine-threonine protein kinase that is a critical regulator of cellular metabolism, growth, and proliferation. MTOR activation is involved in the regulation of thyrocyte proliferation by TSH. Here, we show that MTOR inhibition by rapamycin increases iodide uptake in TSH-stimulated PCCL3 thyroid cell line, although the effect of rapamycin was less pronounced than PI3K inhibition. Thus, NIS inhibitory pathways stimulated by PI3K might also involve the activation of proteins other than MTOR. Insulin downregulates iodide uptake and NIS protein expression even in the presence of TSH, and both effects are counterbalanced by MTOR inhibition. NIS protein expression levels were correlated with iodide uptake ability, except in cells treated with TSH in the absence of insulin, in which rapamycin significantly increased iodide uptake, while NIS protein levels remained unchanged. Rapamycin avoids the activation of both p70 S6 and AKT kinases by TSH, suggesting the involvement of MTORC1 and MTORC2 in TSH effect. A synthetic analog of rapamycin (everolimus), which is clinically used as an anticancer agent, was able to increase rat thyroid iodide uptake in vivo. In conclusion, we show that MTOR kinase participates in the control of thyroid iodide uptake, demonstrating that MTOR not only regulates cell survival, but also normal thyroid cell function both in vitro and in vivo.

  7. UV-triggered dopamine polymerization: control of polymerization, surface coating, and photopatterning.

    PubMed

    Du, Xin; Li, Linxian; Li, Junsheng; Yang, Chengwu; Frenkel, Nataliya; Welle, Alexander; Heissler, Stefan; Nefedov, Alexei; Grunze, Michael; Levkin, Pavel A

    2014-12-17

    UV irradiation is demonstrated to initiate dopamine polymerization and deposition on different surfaces under both acidic and basic pH. The observed acceleration of the dopamine polymerization is explained by the UV-induced formation of reactive oxygen species that trigger dopamine polymerization. The UV-induced dopamine polymerization leads to a better control over polydopamine deposition and formation of functional polydopamine micropatterns.

  8. Exchange diffusion of dopamine induced in planar lipid bilayer membranes by the ionophore X537A

    PubMed Central

    Holz, RW

    1977-01-01

    The ionophore X537A causes a large increase in the [(14)C]dopamine (a catecholamine) permeability of planar bilayer membranes. Dopamine transport increases linearly with the ionophore concentration. At relatively high concentrations in the presence of dopamine, the ionophore omdices a conductance which is nearly ideally selective for the dopamine cation. However, the total dopamine flux as determined in tracer experiments is not affected by an electric field and is over 10(5) times larger than predicted from the estimated dopamine conductance. Increasing the dopamine concentration on the side containing radioactive dopamine (the cis side) saturates the dopamine transport. This saturation is relieved by trans addition of nonradioactive dopamine, tyramine, H(+), or K(+). With unequal concentrations of dopamine cis and trans (49 and 12.5 mM), the unidirectional dopamine fluxes are equal. Increasing H(+) cis and trans decreases dopamine transport. It is concluded that at physiological pH, the X537A-induced transport of dopamine occurs via an electrically silent exchange diffusion of dopamine cation with another cation (e.g., dopamine(+), H(+), or K(+)). X537A induces a Ca(++)-independent release of catecholamines from sympathetic nerves by interfering with intracellular storage within storage vesicles (R.W. Holz. 1975. Biochim. Biophys. Acta. 375:138-152). It is suggested that X537A causes an exchange of intravesicular catecholamine with a cytoplasmic cation (perhaps K(+) or H(+)) across the storage vesicle membrane. PMID:16982

  9. Kinetic Diversity of Striatal Dopamine: Evidence from a Novel Protocol for Voltammetry.

    PubMed

    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.

  10. Dopamine depresses cholinergic oscillatory network activity in rat hippocampus.

    PubMed

    Weiss, Torsten; Veh, Rüdiger W; Heinemann, Uwe

    2003-11-01

    The dopaminergic neuronal system is implicated in cognitive processes in a variety of brain regions including the mesolimbic system. We have investigated whether dopamine also affects synchronized network activity in the hippocampus, which has been ascribed to play a pivotal role in memory formation. Gamma frequency (20-80 Hz) oscillations were induced by the cholinergic agonist carbachol. Oscillatory activity was examined in area CA3 of Wistar rat hippocampal slices, employing field potential and intracellular recordings. Application of carbachol initiated synchronized population activity in the gamma band at 40 Hz. Induced gamma activity persisted over hours and required GABAA receptors. Dopamine reversibly decreased the integrated gamma band power of the carbachol rhythm by 62%, while its frequency was not changed. By contrast, individual pyramidal cells recorded during carbachol-induced field gamma activity exhibited theta frequency (5-15 Hz) membrane potential oscillations that were not altered by dopamine. The dopamine effect on the field gamma activity was mimicked by the D1 receptor agonist SKF-383393 and partially antagonized by the D1 antagonist SCH-23390. Conversely, the D2 receptor agonist quinpirole failed to depress the oscillations, and the D2 antagonist sulpiride did not prevent the suppressive dopamine effect. The data indicate that dopamine strongly depresses cholinergic gamma oscillations in area CA3 of rat hippocampus by activation of D1-like dopamine receptors and that this effect is most likely mediated via impairment of interneurons involved in generation and maintenance of the carbachol-induced network rhythm.

  11. Dopamine function and the efficiency of human movement.

    PubMed

    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.

  12. The primate thalamus is a key target for brain dopamine.

    PubMed

    Sánchez-González, Miguel Angel; García-Cabezas, Miguel Angel; Rico, Beatriz; Cavada, Carmen

    2005-06-29

    The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.

  13. Dopamine uptake dynamics are preserved under isoflurane anesthesia.

    PubMed

    Brodnik, Zachary D; España, Rodrigo A

    2015-10-08

    Fast scan cyclic voltammetry is commonly used for measuring the kinetics of dopamine release and uptake. For experiments using an anesthetized preparation, urethane is preferentially used because it does not alter dopamine uptake kinetics compared to freely moving animals. Unfortunately, urethane is highly toxic, can induce premature death during experiments, and cannot be used for recovery surgeries. Isoflurane is an alternative anesthetic that is less toxic than urethane, produces a stable level of anesthesia over extended periods, and is often used for recovery surgeries. Despite these benefits, the effects of isoflurane on dopamine release and uptake have not been directly characterized. In the present studies, we assessed the utility of isoflurane for voltammetry experiments by testing dopamine signaling parameters under baseline conditions, after treatment with the dopamine uptake inhibitor cocaine, and after exposure to increasing concentrations of isoflurane. Our results indicate that surgical levels of isoflurane do not significantly alter terminal mechanisms of dopamine release and uptake over prolonged periods of time. Consequently, we propose that isoflurane is an acceptable anesthetic for voltammetry experiments, which in turn permits the design of studies in which dopamine signaling is examined under anesthesia prior to recovery and subsequent experimentation in the same animals.

  14. Dopamine modulates metabolic rate and temperature sensitivity in Drosophila melanogaster.

    PubMed

    Ueno, Taro; Tomita, Jun; Kume, Shoen; Kume, Kazuhiko

    2012-01-01

    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.

  15. Prefrontal cortical dopamine transmission is decreased in alcoholism

    PubMed Central

    Narendran, Rajesh; Mason, Neale Scott; Paris, Jennifer; Himes, Michael L.; Douaihy, Antoine B.; Frankle, W. Gordon

    2014-01-01

    Objective Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such working memory, attention, inhibitory control and risk/reward decisions--all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies in alcoholics that have demonstrated less dopamine in the striatum, we hypothesized decreased dopamine transmission in the prefrontal cortex in alcoholism. To test this hypothesis, we used amphetamine and [11C]FLB 457 positron emission tomography (PET) to measure cortical dopamine transmission in a group of 21 recently abstinent alcoholics and matched healthy controls. Methods [11C]FLB 457 binding potential (BPND) was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg−1 of d-amphetamine. Results Amphetamine-induced displacement of [11C]FLB 457 binding potential (Δ BPND) was significantly smaller in the cortical regions in alcoholics compared to healthy controls. Cortical regions that demonstrated lower dopamine transmission in alcoholics included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex and medial temporal lobe. Conclusions The results of this study for the first time unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism. PMID:24874293

  16. Dopamine alleviates salt-induced stress in Malus hupehensis.

    PubMed

    Li, Chao; Sun, Xiangkai; Chang, Cong; Jia, Dongfeng; Wei, Zhiwei; Li, Cuiying; Ma, Fengwang

    2015-04-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, ion homeostasis and the response to salinity in Malus hupehensis Rehd. Both hydroponics and field-pot experiments were conducted under saline conditions. Salt-stressed plants had reduced growth and a marked decline in their net photosynthetic rates, values for Fv /Fm and chlorophyll contents. However, pretreatment with 100 or 200 μM dopamine significantly alleviated this inhibition and enabled plants to maintain their photosynthetic capacity. In addition to changing stomatal behavior, supplementation with dopamine positively influenced the uptake of K, N, P, S, Cu and Mn ions but had an inhibitory effect on Na and Cl uptake, the balance of which is responsible for managing the response to salinity by Malus plants. Dopamine pretreatment also controlled the burst of hydrogen peroxide, possibly through direct scavenging and by enhancing the activities of antioxidative enzymes and the capacity of the ascorbate-glutathione cycle. We also investigated whether dopamine might regulate salt overly sensitive pathway genes under salinity. Here, MdHKT1, MdNHX1 and MdSOS1 were greatly upregulated in roots and leaves, which possibly contributed to the maintenance of ion homeostasis and, thus, improved salinity resistance in plants exposed earlier to exogenous dopamine. These results support our conclusion that dopamine alleviates salt-induced stress not only at the level of antioxidant defense but also by regulating other mechanisms of ion homeostasis.

  17. Dopamine-resistant hypotension and severe retinopathy of prematurity

    PubMed Central

    Catenacci, Melissa; Miyagi, Shogo; Wickremasinghe, Andrea C.; Lucas, Sarah Scarpace; de Alba Campomanes, Alejandra G.; Good, William V.; Clyman, Ronald I.

    2013-01-01

    Objective To examine the relationship between the cause or severity of hypotension and the development of severe retinopathy of prematurity (sROP) (≥ stage 3 or stage 2 with plus disease in Zone I or II).. Study design Infants (<28 weeks’ gestation, n=242) were observed for hypotension and treated with a standardized hypotension-treatment protocol. Hypotension was classified as resulting from one of the following causes: (a) culture-positive infection and/or necrotizing enterocolitis, (b) PDA ligation, or (c) “idiopathic” (no cause identified other than prematurity), and as being either dopamine-responsive or dopamine-resistant. Cortisol levels were measured for infants with dopamine-resistant hypotension. Eye examinations were performed until the ROP resolved or the vasculature matured. Multivariable logistic regression analysis was performed to determine the relationship between the cause/severity of hypotension and sROP. Results Overall, 66% of infants developed hypotension (41% were dopamine-responsive and 25% were dopamine-resistant). sROP developed in 19% of infants. “Idiopathic” dopamine-resistant hypotension was the only cause significantly related to sROP. 66% of infants with dopamine-resistant hypotension had low serum cortisol (≤10 μg/dL). Low cortisol, in the presence of dopamine-resistant hypotension, was significantly associated with sROP and accounted for the relationship between “idiopathic” hypotension and sROP. When low cortisol was included in statistical models, other known risk factors, such as immature gestation, were no longer significantly related to sROP. Conclusion Low cortisol, in the presence of dopamine-resistant hypotension, has the greatest magnitude of association with sROP. PMID:23465406

  18. Regulation of bat echolocation pulse acoustics by striatal dopamine

    PubMed Central

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

    2011-01-01

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

  19. Regulation of bat echolocation pulse acoustics by striatal dopamine.

    PubMed

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

    2011-10-01

    The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.

  20. Methamphetamine Regulation of Firing Activity of Dopamine Neurons.

    PubMed

    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.

  1. Enhanced downregulation of the p75 nerve growth factor receptor by cholesteryl and bis-cholesteryl antisense oligonucleotides.

    PubMed

    Epa, W R; Rong, P; Bartlett, P F; Coulson, E J; Barrett, G L

    1998-12-01

    The effects of conjugating cholesterol to either or both ends of a phosphorothioate (PS) oligonucleotide were analyzed in terms of cellular uptake and antisense efficacy. The oligo sequence was directed against the p75 nerve growth factor receptor (p75), and was tested in differentiated PC12 cells, which express high levels of this protein. The addition of a single cholesteryl group to the 5'-end significantly increased cellular uptake and improved p75 mRNA downregulation compared with the unmodified PS oligo. However, only a minor degree of downregulation of p75 protein was obtained with 5' cholesteryl oligos. Three different linkers was used to attach the 5' cholesteryl group but were found not to have any impact on efficacy. Addition of a single cholesteryl group to the 3'-end led to greater p75 mRNA downregulation (31%) and p75 protein downregulation (28%) than occurred with the 5' cholesteryl oligos. The biggest improvement in antisense efficacy, both at the mRNA and protein levels, was obtained from the conjugation of cholesterol to both ends of the oligo. One of the bischolesteryl oligos was nearly as effective as cycloheximide at decreasing synthesis of p75. The bis-cholesteryl oligos also displayed significant efficacy at 1 microM, whereas the other oligos required 5 microM to be effective. The enhanced efficacy of bis-cholesteryl oligos is likely to be due to a combination of enhanced cellular uptake and resistance to both 5' and 3' exonucleases.

  2. Effect of downregulation of germline transcripts on immunoglobulin A isotype differentiation

    PubMed Central

    1993-01-01

    In this study we determined the role of immunoglobulin (Ig) germline transcripts in the isotype switch differentiation of the cloned lymphoma B cell line CH12.LX. In initial studies, we showed that addition of transforming growth factor beta (TGF-beta) and interleukin 4 (IL-4), either alone or in combination, augment switching from membrane (m)IgM+ to mIgA+ cells, and that increased switching is preceded and paralleled by an increase in the steady-state level of alpha germline transcripts (alpha GLT). Interestingly, TGF-beta and IL- 4 affect switching in different ways, as shown by the fact that IL-4 increases and TGF-beta decreases the number of dual-positive (mIgM+/mIgA+) cells; in addition, TGF-beta and IL-4 have different effects on the time course of induction of alpha GLT. In subsequent studies, we established that we could downregulate alpha GLT levels in CH12.LX B cells by transfecting an expression vector that can be induced to produce transcripts antisense to the I alpha exon. Using this approach we downregulated alpha GLT in CH12.LX B cells undergoing switching in the presence of TGF-beta and IL-4 and showed that such downregulation led to decreased switching, as evidenced by decreased appearance of dual-positive B cells as well as decreased IgA synthesis relative to IgM synthesis. This result was corroborated by the fact that incubation of CH12.LX cells with phosphorothio-oligo antisense DNA to I alpha sequence also led to a decrease in the number of dual- positive cells and in the IgA/IgM secretion ratio. In summary, IgA isotype differentiation in CH12.LX B cell, particularly the steps necessary for the elaboration of mIgM+/mIgA+ switch intermediate cells, is inhibited by downregulation of alpha GLT; it is therefore apparent that alpha GLT plays a key role in the initial stage of isotype switch differentiation. PMID:8315375

  3. Dopamine does double duty in motivating cognitive effort

    PubMed Central

    Westbrook, Andrew; Braver, Todd S.

    2015-01-01

    Cognitive control is subjectively costly, suggesting that engagement is modulated in relationship to incentive state. Dopamine appears to play key roles. In particular, dopamine may mediate cognitive effort by two broad classes of functions: 1) modulating the functional parameters of working memory circuits subserving effortful cognition, and 2) mediating value-learning and decision-making about effortful cognitive action. Here we tie together these two lines of research, proposing how dopamine serves “double duty”, translating incentive information into cognitive motivation. PMID:26889810

  4. Monitoring dopamine release from single living vesicles with nanoelectrodes.

    PubMed

    Wu, Wen-Zhan; Huang, Wei-Hua; Wang, Wei; Wang, Zong-Li; Cheng, Jie-Ke; Xu, Tao; Zhang, Rong-Ying; Chen, Yu; Liu, Jie

    2005-06-29

    Carbon fiber nanoelectrodes (tip diameter = ca. 100 nm) have been first used to monitor real-time dopamine release from single living vesicles of single rat pheochromocytoma (PC12) cells. The experiments show that active and inactive release sites exist on the surface of cells, and the spatial distributions have been differentiated even in the same active release zone. It is first demonstrated that multiple vesicles can sequentially release dopamine at the same site of the cell surface, which possibly plays the main role in the dopamine release from PC12 cells.

  5. Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

    PubMed Central

    Bayliss, Jacqueline A.; Lemus, Moyra B.; Santos, Vanessa V.; Deo, Minh; Davies, Jeffrey S.; Kemp, Bruce E.; Elsworth, John D.

    2016-01-01

    Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson’s Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin’s neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD. PMID:27467571

  6. Dopamine suppresses persistent network activity via D1-like dopamine receptors in rat medial entorhinal cortex

    PubMed Central

    Mayne, Elizabeth W; Craig, Michael T; McBain, Chris J; Paulsen, Ole

    2013-01-01

    Cortical networks display persistent activity in the form of periods of sustained synchronous depolarizations (‘UP states’) punctuated by periods of relative hyperpolarization (‘DOWN states’), which together form the slow oscillation. UP states are known to be synaptically generated and are sustained by a dynamic balance of excitation and inhibition, with fast ionotropic glutamatergic excitatory and GABAergic inhibitory conductances increasing during the UP state. Previously, work from our group demonstrated that slow metabotropic GABA receptors also play an important role in terminating the UP state, but the effects of other neuromodulators on this network phenomenon have received little attention. Given that persistent activity is a neural correlate of working memory and that signalling through dopamine receptors has been shown to be critical for working memory tasks, we examined whether dopaminergic neurotransmission affected the slow oscillation. Here, using an in vitro model of the slow oscillation in rat medial entorhinal cortex, we showed that dopamine strongly and reversibly suppressed cortical UP states. We showed that this effect was mediated through D1-like and not D2-like dopamine receptors, and we found no evidence that tonic dopaminergic transmission affected UP states in our model. PMID:23336973

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

    PubMed Central

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

    2016-01-01

    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. PMID:27250920

  8. Exposure to the Polybrominated Diphenyl Ether Mixture DE-71 Damages the Nigrostriatal Dopamine System: Role of Dopamine Handling in Neurotoxicity

    PubMed Central

    Bradner, Joshua M.; Suragh, Tiffany A.; Wilson, W. Wyatt; Lazo, Carlos R.; Stout, Kristen A.; Kim, Hye Mi; Wang, Min Z.; Walker, Douglas I.; Pennell, Kurt D.; Richardson, Jason R.; Miller, Gary W.; Caudle, W. Michael

    2013-01-01

    In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson’s disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH+ neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders. PMID:23287494

  9. Whole organic electronic synapses for dopamine detection

    NASA Astrophysics Data System (ADS)

    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.

  10. Glutamate and dopamine components in schizophrenia

    PubMed Central

    Seeman, Philip

    2009-01-01

    The treatment of schizophrenia for the last half century has been with dopamine (DA) D2 receptor blockers, implicating a hyperdopamine basis for psychosis. However, a 2007 report found that the glutamate agonist LY404039 was effective in schizophrenia, suggesting a hypoglutamate state for the illness. Although phencyclidine psychosis also supports a hypoglutamate cause, assessing the basic and clinical findings shows that phencyclidine has DA D2 agonist actions as well. Accurate Dreiding models of phencyclidine and the LY glutamate agonists precisely fit the known tetrahedral model of the D2 receptor that accommodates all DA agonists. A further view is that metabotropic glutamate agonists also exert D2 agonism, and their antipsychotic doses (about 100 mg/d) are predicted by their dissociation constants (about 20 nM) for D2. Hence, the clinical antipsychotic action of a glutamate agonist may depend on its ability to interfere with DA neurotransmission by its DA partial agonism. PMID:19270765

  11. The immunoregulatory role of dopamine: an update

    PubMed Central

    Sarkar, Chandrani; Basu, Biswarup; Chakroborty, Debanjan; Dasgupta, Partha Sarthi; Basu, Sujit

    2009-01-01

    The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson’s disease. These results suggest an immunoregulatory role of DA. Therefore targeting DA receptors and their signaling pathways in these cells by using DA receptor agonists and antagonists may be useful for the treatment of diseases where DA induced altered immunity play a pathogenic role. PMID:19896530

  12. Enhanced Dopamine Transporter Activity in Middle-Aged Gdnf Heterozygous Mice

    PubMed Central

    Littrell, Ofelia M.; Pomerleau, Francois; Huettl, Peter; Surgener, Stewart; McGinty, Jacqueline F.; Middaugh, Lawrence D.; Granholm, Ann-Charlotte; Gerhardt, Greg A.; Boger, Heather A.

    2010-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the viability of midbrain dopamine (DA) neurons that degenerate in Parkinson’s disease. Middle aged, 12-month-old, Gdnf heterozygous (Gdnf+/−) mice have diminished spontaneous locomotor activity and enhanced synaptosomal DA uptake compared to wildtype mice. In this study, dopamine transporter (DAT) function in middle-aged, 12-month-old Gdnf+/− mice was more thoroughly investigated using in vivo electrochemistry. Gdnf+/− mice injected with the DAT inhibitor, nomifensine, exhibited significantly more locomotor activity than wildtype mice. In vivo electrochemistry with carbon fiber microelectrodes demonstrated enhanced clearance of DA in the striatum of Gdnf+/− mice, suggesting greater surface expression of DAT than in wildtype littermates. Additionally, 12 month old Gdnf+/− mice expressed greater D2 receptor mRNA and protein in the striatum than wildtype mice. Neurochemical analyses of striatal tissue samples indicated significant reductions in DA and a faster DA metabolic rate in Gdnf+/− mice than in wildtype mice. Altogether, these data support an important role for GDNF in the regulation of uptake, synthesis, and metabolism of DA during aging. PMID:21144620

  13. Evidence that dopamine within motivation and song control brain regions regulates birdsong context-dependently.

    PubMed

    Heimovics, Sarah A; Riters, Lauren V

    2008-09-03

    Vocal communication is critical for successful social interactions among conspecifics, but little is known about how the brain regulates context-appropriate communication. The neurotransmitter dopamine (DA) is involved in modulating highly motivated, goal-directed behaviors (including sexually motivated singing behavior), and emerging data suggest that the role of DA in vocal communication may differ depending on the context in which it occurs. To address this possibility, relationships between immunolabeled tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine synthesis) and song produced within versus outside of a breeding context were explored in male European starlings (Sturnus vulgaris). Immunocytochemistry for dopamine beta-hydroxylase (DBH; the enzyme that converts DA to norepinephrine) was also performed to provide insight into whether relationships between song and TH immunoreactivity reflected dopaminergic or noradrenergic neurotransmission. Measures of TH and DBH were quantified in song control regions (HVC, Area X, robust nucleus of the acropallium) and regions implicated in motivation (medial preoptic nucleus (POM), ventral tegmental area (VTA), and midbrain central gray). In Area X, POM, and VTA measures of TH correlated with song produced within, but not outside of a breeding context. DBH in these regions did not correlate with song in either context. Together, these data suggest DA in both song control and motivation brain regions may be more tightly linked to the regulation of highly goal-directed, sexually motivated vocal behavior.

  14. Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release.

    PubMed

    Romanò, Nicola; Yip, Siew H; Hodson, David J; Guillou, Anne; Parnaudeau, Sébastien; Kirk, Siobhan; Tronche, François; Bonnefont, Xavier; Le Tissier, Paul; Bunn, Stephen J; Grattan, Dave R; Mollard, Patrice; Martin, Agnès O

    2013-03-06

    Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretion. Their extensive functional plasticity allows a change from low PRL secretion in the non-pregnant state to the condition of hyperprolactinemia that characterizes lactation. To allow this rise in PRL, TIDA neurons are thought to become unresponsive to PRL at lactation and functionally silenced. Here we show that, contrary to expectations, the electrical properties of the system were not modified during lactation and that the neurons remained electrically responsive to a PRL stimulus, with PRL inducing an acute increase in their firing rate during lactation that was identical to that seen in non-pregnant mice. Furthermore, we show a long-term organization of TIDA neuron electrical activity with an harmonization of their firing rates, which remains intact during lactation. However, PRL-induced secretion of dopamine (DA) at the median eminence was strongly blunted during lactation, at least in part attributable to lack of phosphorylation of tyrosine hydroxylase, the key enzyme involved in DA synthesis. We therefore conclude that lactation, rather than involving electrical silencing of TIDA neurons, represents a condition of decoupling between electrical activity at the cell body and DA secretion at the median eminence.

  15. Water Extract of Fructus Hordei Germinatus Shows Antihyperprolactinemia Activity via Dopamine D2 Receptor

    PubMed Central

    Wang, Xiong; Ma, Li; Zhang, En-jing; Zou, Ji-li; Guo, Hao; Peng, Si-wei; Wu, Jin-hu

    2014-01-01

    Objective. Fructus Hordei Germinatus is widely used in treating hyperprolactinemia (hyperPRL) as a kind of Chinese traditional herb in China. In this study, we investigated the anti-hyperPRL activity of water extract of Fructus Hordei Germinatus (WEFHG) and mechanism of action. Methods. Effect of WEFHG on serum prolactin (PRL), estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and hypothalamus protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) levels of hyperPRL rats were investigated. And effect of WEFHG on PRL secretion, D2 receptors, and dopamine transporters (DAT) was studied in MMQ, GH3, and PC12 cells, respectively. Results. WEFHG reduced the secretion of PRL in hyperPRL rats effectively. In MMQ cell, treatment with WEFHG at 1–5 mg/mL significantly suppressed PRL secretion and synthesis. Consistent with a D2-action, WEFHG did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D2 receptor expression but significantly increased the expression of D2 receptors and DAT in PC12 cells. In addition, WEFHG reduced the cAMP and PKA levels of hypothalamus in hyperPRL rats significantly. Conclusions. WEFHG showed anti-hyperPRL activity via dopamine D2 receptor, which was related to the second messenger cAMP and PKA. PMID:25254056

  16. Adult rat bone marrow stromal cells express genes associated with dopamine neurons

    SciTech Connect

    Kramer, Brian C.; Woodbury, Dale . E-mail: WOODBURYDL@AOL.COM; Black, Ira B.

    2006-05-19

    An intensive search is underway to identify candidates to replace the cells that degenerate in Parkinson's disease (PD). To date, no suitable substitute has been found. We have recently found that adult rat bone marrow stromal cells (MSCs) can be induced to assume a neuronal phenotype in vitro. These findings may have particular relevance to the treatment of PD. We now report that adult MSCs express multiple dopaminergic genes, suggesting that they are potential candidates for cell therapy. Using RT-PCR, we have examined families of genes that are associated with the development and/or survival of dopaminergic neurons. MSCs transcribe a variety of dopaminergic genes including patched and smoothened (components of the Shh receptor), Gli-1 (downstream mediator of Shh), and Otx-1, a gene associated with formation of the mesencephalon during development. Furthermore, Shh treatment elicits a 1.5-fold increase in DNA synthesis in cultured MSCs, suggesting the presence of a functional Shh receptor complex. We have also found that MSCs transcribe and translate Nurr-1, a nuclear receptor essential for the development of dopamine neurons. In addition, MSCs express a variety of growth factor receptors including the glycosyl-phosphatidylinositol-anchored ligand-binding subunit of the GDNF receptor, GFR{alpha}1, as well as fibroblast growth factor receptors one and four. The expression of genes that are associated with the development and survival of dopamine neurons suggests a potential role for these cells in the treatment of Parkinson's disease.

  17. Separate enrichment analysis of pathways for up- and downregulated genes.

    PubMed

    Hong, Guini; Zhang, Wenjing; Li, Hongdong; Shen, Xiaopei; Guo, Zheng

    2014-03-06

    Two strategies are often adopted for enrichment analysis of pathways: the analysis of all differentially expressed (DE) genes together or the analysis of up- and downregulated genes separately. However, few studies have examined the rationales of these enrichment analysis strategies. Using both microarray and RNA-seq data, we show that gene pairs with functional links in pathways tended to have positively correlated expression levels, which could result in an imbalance between the up- and downregulated genes in particular pathways. We then show that the imbalance could greatly reduce the statistical power for finding disease-associated pathways through the analysis of all-DE genes. Further, using gene expression profiles from five types of tumours, we illustrate that the separate analysis of up- and downregulated genes could identify more pathways that are really pertinent to phenotypic difference. In conclusion, analysing up- and downregulated genes separately is more powerful than analysing all of the DE genes together.

  18. Dopamine effects on identified rat vagal motoneurons

    PubMed Central

    Zheng, Zhongling; Travagli, R. Alberto

    2011-01-01

    Catecholaminergic neurons of the A2 area play a prominent role in brain stem vagal circuits. It is not clear, however, whether these neurons are noradrenergic or adrenergic, i.e., display tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DβH) immunoreactivity (-IR) or dopaminergic (i.e., TH- but not DβH-IR). Our aims were to investigate whether a subpopulation of neurons in the A2 area was dopaminergic and, if so, to investigate the effects of dopamine (DA) on the membrane of gastric-projecting vagal motoneurons. We observed that although the majority of A2 neurons were both TH- and DβH-IR, a small percentage of nucleus tractus solitarius neurons were TH-IR only, suggesting that DA itself may play role in these circuits. Whole cell recordings from thin brain stem slices showed that 71% of identified gastric-projecting motoneurons responded to DA (1–300 µM) with either an excitation (28%) or an inhibition (43%) of the membrane; the remaining 29% of the neurons were unresponsive. The DA-induced depolarization was mimicked by SK 38393 and prevented by pretreatment with SCH 23390. Conversely, the DA-induced inhibition was mimicked by bromoergocryptine and prevented by pretreatment with L741626. When tested on the same neuron, the effects of DA and NE were not always similar. In fact, in neurons in which DA induced a membrane depolarization, 77% were inhibited by NE, whereas 75% of neurons unresponsive to DA were inhibited by NE. Our data suggest that DA modulates the membrane properties of gastric-projecting motoneurons via D1- and D2-like receptors, and DA may play different roles than norepinephrine in brain stem vagal circuits. PMID:17170022

  19. Enhanced electrochemiluminescence sensor for detecting dopamine based on gold nanoflower@graphitic carbon nitride polymer nanosheet-polyaniline hybrids.

    PubMed

    Lu, Qiyi; Zhang, Juanjuan; Liu, Xiaofang; Wu, Yuanya; Yuan, Ruo; Chen, Shihong

    2014-12-21

    In this work, an enhanced electrochemiluminescence (ECL) sensor based on gold nanoflower@graphitic carbon nitride polymer nanosheet-polyaniline hybrids (AuNF@g-C3N4-PANI) was prepared for the detection of dapamine (DA). First, the bulk g-C3N4 was prepared through polymerizing melamine under 600 °C. And then the g-C3N4 nanosheet was obtained by ultrasonication-assisted liquid exfoliation of bulk g-C3N4. Finally, polyaniline (PANI) and gold nanoflowers (AuNFs) were successively formed on the g-C3N4 nanosheet through an in situ synthesis method. The resulting AuNF@g-C3N4-PANI hybrids were modified onto the surface of glassy carbon electrode to achieve a sensor (AuNF@g-C3N4-PANI/GCE) for detecting dopamine. Under the optimal conditions, the ECL signal increased linearly with the concentration of dopamine. The linear range of 5.0 × 10(-9) to 1.6 × 10(-6) M was obtained, while the detection limit was 1.7 × 10(-9) M. The prepared sensor exhibited a low detection limit and high sensitivity for the determination of dopamine. The combination of g-C3N4 nanosheet, PANI and AuNF would provide a new opportunity for the ECL sensor.

  20. Incorporating β-cyclodextrin with ZnO nanorods: a potentiometric strategy for selectivity and detection of dopamine.

    PubMed

    Elhag, Sami; Ibupoto, Zafar Hussain; Nur, Omer; Willander, Magnus

    2014-01-17

    We describe a chemical sensor based on a simple synthesis of zinc oxide nanorods (ZNRs) for the detection of dopamine molecules by a potentiometric approach. The polar nature of dopamine leads to a change of surface charges on the ZNR surface via metal ligand bond formation which results in a measurable electrical signal. ZNRs were grown on a gold-coated glass substrate by a low temperature aqueous chemical growth (ACG) method. Polymeric membranes incorporating β-cyclodextrin (β-CD) and potassium tetrakis (4-chlorophenyl) borate was immobilized on the ZNR surface. The fabricated electrodes were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. The grown ZNRs were well aligned and exhibited good crystal quality. The present sensor system displays a stable potential response for the detection of dopamine in 10(-2) mol·L(-1) acetic acid/sodium acetate buffer solution at pH 5.45 within a wide concentration range of 1 × 10(-6) M(-1) × 10(-1) M, with sensitivity of 49 mV/decade. The electrode shows a good response time (less than 10 s) and excellent repeatability. This finding can contribute to routine analysis in laboratories studying the neuropharmacology of catecholamines. Moreover, the metal-ligand bonds can be further exploited to detect DA receptors, and for bio-imaging applications.

  1. Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling.

    PubMed

    Wang, Hong; Yuan, Guoxiang; Prabhakar, Nanduri R; Boswell, Mark; Katz, David M

    2006-02-01

    Expression of brain-derived neurotrophic factor (BDNF) is sensitive to changes in oxygen availability, suggesting that BDNF may be involved in adaptive responses to oxidative stress. However, it is unknown whether or not oxidative stress actually increases availability of BDNF by stimulating BDNF secretion. To approach this issue we examined BDNF release from PC12 cells, a well-established model of neurosecretion, in response to hypoxic stimuli. BDNF secretion from neuronally differentiated PC12 cells was strongly stimulated by exposure to intermittent hypoxia (IH). This response was inhibited by N-acetyl-l-cysteine, a potent scavenger of reactive oxygen species (ROS) and mimicked by exogenous ROS. IH-induced BDNF release requires activation of tetrodotoxin sensitive Na+ channels and Ca2+ influx through N- and L-type channels, as well as mobilization of internal Ca2+ stores. These results demonstrate that oxidative stress can stimulate BDNF release and that underlying mechanisms are similar to those previously described for activity-dependent BDNF secretion from neurons. Surprisingly, we also found that IH-induced secretion of BDNF was blocked by dopamine D2 receptor antagonists or by inhibition of dopamine synthesis with alpha-methyl-p-tyrosine. These data indicate that oxidative stress can stimulate BDNF release through an autocrine or paracrine loop that requires dopamine receptor activation.

  2. FGFR4 Downregulation of Cell Adhesion in Prostate Cancer

    DTIC Science & Technology

    2007-03-01

    AD_________________ Award Number: W81XWH-06-1-0385 TITLE: FGFR4 Downregulation of Cell Adhesion...2007 2. REPORT TYPE Annual 3. DATES COVERED 1 Mar 2006 – 28 Feb 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER FGFR4 Downregulation of Cell...our project to examine the role of FGFR4 G388R in altering cell adhesion in prostate cancer. This includes acquiring expertise in the passage and

  3. Striatal Dopamine and the Interface between Motivation and Cognition

    PubMed Central

    Aarts, Esther; van Holstein, Mieke; Cools, Roshan

    2011-01-01

    Brain dopamine has long been known to be implicated in the domains of appetitive motivation and cognition. Recent work indicates that dopamine also plays a role in the interaction between appetitive motivation and cognition. Here we review this work. Animal work has revealed an arrangement of spiraling connections between the midbrain and the striatum that subserves a mechanism by which dopamine can direct information flow from ventromedial to more dorsal regions in the striatum. In line with current knowledge about dopamine's effects on cognition, we hypothesize that these striato-nigro-striatal connections provide the basis for functionally specific effects of appetitive motivation on cognition. One implication of this hypothesis is that appetitive motivation can induce cognitive improvement or impairment depending on task demands. PMID:21808629

  4. Iron oxide magnetic nanoparticles with versatile surface functions based on dopamine anchors

    NASA Astrophysics Data System (ADS)

    Mazur, Mykola; Barras, Alexandre; Kuncser, Victor; Galatanu, Andrei; Zaitzev, Vladimir; Turcheniuk, Kostiantyn V.; Woisel, Patrice; Lyskawa, Joel; Laure, William; Siriwardena, Aloysius; Boukherroub, Rabah; Szunerits, Sabine

    2013-03-01

    The synthesis of multifunctional magnetic nanoparticles (MF-MPs) is one of the most active research areas in advanced materials as their multifunctional surfaces allow conjugation of biological and chemical molecules, thus making it possible to achieve target-specific diagnostic in parallel to therapeutics. We report here a simple strategy to integrate in a one-step reaction several reactive sites onto the particles. The preparation of MF-MPs is based on their simultaneous modification with differently functionalized dopamine derivatives using simple solution chemistry. The formed MF-MPs show comparable magnetic properties to those of naked nanoparticles with almost unaltered particle size of around 25 nm. The different termini, amine, azide and maleimide functions, enable further functionalization of MF-MPs by the grafting-on approach. Michael addition, Cu(i) catalyzed « click » chemistry and amidation reactions are performed on the MF-MPs integrating subsequently 6-(ferrocenyl)-hexanethiol, horseradish peroxidase (HRP) and mannose.

  5. Dopamine Dynamics and Signaling in Drosophila: An Overview of Genes, Drugs and Behavioral Paradigms

    PubMed Central

    Yamamoto, Shinya; Seto, Elaine S.

    2014-01-01

    Changes in dopamine (DA) signaling have been implicated in a number of human neurologic and psychiatric disorders. Similarly, defects in DA signaling in the fruit fly, Drosophila melanogaster, have also been associated with several behavioral defects. As most genes involved in DA synthesis, transport, secretion, and signaling are conserved between species, Drosophila is a powerful genetic model organism to study the regulation of DA signaling in vivo. In this review, we will provide an overview of the genes and drugs that regulate DA biology in Drosophila. Furthermore, we will discuss the behavioral paradigms that are regulated by DA signaling in flies. By analyzing the genes and neuronal circuits that govern such behaviors using sophisticated genetic, pharmacologic, electrophysiologic, and imaging approaches in Drosophila, we will likely gain a better understanding about how this neuromodulator regulates motor tasks and cognition in humans. PMID:24770636

  6. N-Nicotinoyl dopamine, a novel niacinamide derivative, retains high antioxidant activity and inhibits skin pigmentation.

    PubMed

    Kim, Bora; Kim, Jin Eun; Lee, Su Min; Lee, Soung-Hoon; Lee, Jin Won; Kim, Myung Kyoo; Lee, Kye Jong; Kim, Hyuk; Lee, Joo Dong; Choi, Kang-Yell

    2011-11-01

    We synthesized a novel derivative of a well-known skin-lightening compound niacinamide, N-nicotinoyl dopamine (NND). NND did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. However, NND retains high antioxidant activity without affecting viability of cells. In a reconstructed skin model, topical applications of 0.05% and 0.1% NND induced skin lightening and decreased melanin production without affecting the viability and morphology of melanocytes and overall tissue histology. Moreover, no evidence for skin irritation or sensitization was observed when 0.1% NND emulsion was applied onto the skin of 52 volunteers. The effect of NND on skin lightening was further revealed by pigmented spot analyses of human clinical trial. Overall, NND treatment may be a useful trial for skin lightening and treating pigmentary disorders.

  7. Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability

    PubMed Central

    Jiang, Cheng; Levant, Beth; Li, Xiaoqin; Zhao, Ting; Wen, Bo; Luo, Ruijuan; Sun, Duxin

    2014-01-01

    We report herein the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective dopamine-3 (D3) receptor agonists. A number of these new compounds bind to the D3 receptor with subnanomolar affinities and show excellent selectivity (>10,000) for the D3 receptor over the D1 and D2 receptors. Compound 23 for example, binds to the D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20,000 over the D2 receptor and the D1 receptor in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes and in vitro functional assays showed it to be a full agonist for the human D3 receptor. PMID:25338762

  8. State-dependent effect of dopamine D₁/D₅ receptors inactivation on memory destabilization and reconsolidation.

    PubMed

    Rossato, Janine I; Köhler, Cristiano A; Radiske, Andressa; Lima, Ramón H; Bevilaqua, Lia R M; Cammarota, Martín

    2015-05-15

    Object recognition memories (ORM) can incorporate new information upon reactivation. This update initially involves destabilization of the original memory, which is followed by restabilization of the upgraded engram through a reconsolidation process that requires gene expression and protein synthesis in the hippocampus. We found that when given in dorsal CA1 either immediately after training or 15 min before ORM reactivation in the presence of a novel object, the dopamine D1/D5 receptor antagonist SCH23390 did not affect ORM consolidation, expression or retention but impeded the amnesia caused by the post-retrieval administration of the mRNA synthesis inhibitor α-amanitin or the protein synthesis blocker anisomycin. This anti-amnesic effect was not observed when SCH23390 was given immediately after training and again 15 min before memory reactivation. Our results demonstrate that hippocampal D1/D5 receptors are not needed for formation, retrieval or post-retrieval restabilization of the ORM trace but are essential for its destabilization when reactivation occurs together with the incorporation of new information into the original memory. Importantly, they also suggest that reenactment of the animal's post-learning neurochemical milieu at the moment of memory reactivation can be a boundary condition for reconsolidation.

  9. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  10. Differentiating Siblings: The Case of Dopamine and Norepinephrine.

    PubMed

    Nakatsuka, Nako; Andrews, Anne M

    2017-02-15

    Monitoring dopamine and norepinephrine (or other structurally similar neurotransmitters) in the same brain region necessitates selective sensing. In this Viewpoint, we highlight electrochemical and optical strategies for advancing simultaneous real-time measurements of dopamine and norepinephrine transmission. The potential for DNA aptamers as recognition elements in the context of field-effect transistor sensing for selective and simultaneous neurotransmitter monitoring in vivo is also discussed.

  11. Is schizophrenia a dopamine supersensitivity psychotic reaction?☆

    PubMed Central

    Seeman, Mary V.; Seeman, Philip

    2013-01-01

    Adolf Meyer (1866–1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans. It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or fiight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia. PMID:24128684

  12. The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D[subscript 1]-Type, D[subscript 2]-Type, and Nonselective Dopamine Receptor Agonists

    ERIC Educational Resources Information Center

    Bratcher, Natalie A.; Farmer-Dougan, Valeri; Dougan, James D.; Heidenreich, Byron A.; Garris, Paul A.

    2005-01-01

    Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D[subscript 1]-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D[subscript…

  13. Dopamine in the medial amygdala network mediates human bonding

    PubMed Central

    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

  14. Is dopamine a physiological natriuretic hormone in the dog?

    PubMed

    Cuche, J L; Selz, F; Ruget, G; Jondeau, G; Guedon, J

    1983-11-01

    Both plasma and urinary dopamine and noradrenaline were measured as free and sulphate conjugates, by a radioenzymatic method, before and during extracellular volume expansion (ECVE) with hypo-, iso- or hyper-tonic fluid (usually sodium chloride solution) in dogs. During ECVE there was a decrease in plasma catecholamine concentration. For all cases except noradrenaline, this is probably due to a dilution phenomenon since when results were expressed as pg/mg of protein, ECVE had no effect. This change in noradrenaline accounted for the increase in the dopamine/noradrenaline ratio. As expected, there was an increase in the urinary excretion of dopamine during ECVE with both iso- and hyper-tonic fluid. This increase was not observed in the group of dogs given hypotonic fluid, although the increase of fractional excretion of sodium was of a similar order of magnitude. The increase in the urinary excretion of dopamine was apparently not affected by an increase in plasma sodium concentration and/or osmolality. The demonstrated dissociation between sodium and dopamine in urine does not support a physiological role for dopamine in renal handling of sodium during ECVE, and raises the question of its specificity.

  15. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

    PubMed

    Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

    2015-12-01

    Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

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

    PubMed

    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.

  17. Fibromyalgia patients show an abnormal dopamine response to pain.

    PubMed

    Wood, Patrick B; Schweinhardt, Petra; Jaeger, Erik; Dagher, Alain; Hakyemez, Helene; Rabiner, Eugenii A; Bushnell, M Catherine; Chizh, Boris A

    2007-06-01

    Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

  18. Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum.

    PubMed

    Bossong, Matthijs G; van Berckel, Bart N M; Boellaard, Ronald; Zuurman, Lineke; Schuit, Robert C; Windhorst, Albert D; van Gerven, Joop M A; Ramsey, Nick F; Lammertsma, Adriaan A; Kahn, René S

    2009-02-01

    The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

  19. The neurotransmitter dopamine modulates vascular permeability in the endothelium

    PubMed Central

    Bhattacharya, Resham; Sinha, Sutapa; Yang, Su-Ping; Patra, Chittaranjan; Dutta, Shamit; Wang, Enfeng; Mukhopadhyay, Debabrata

    2008-01-01

    Background Vascular permeability factor/Vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is a potent inducer of vascular permeability, an important early step in angiogenesis. It is known that the neurotransmitter dopamine can inhibit VPF/VEGF mediated angiogenesis, in particular microvascular permeability, but the effectors of this action remain unclear. Results Here, we define the signaling pathway modulated by dopamine that inhibits VPF/VEGF induced vascular permeability in endothelial cells. Signals from VPF/VEGF lead to changes in the phosphorylation of tight junction protein zonula occludens (ZO-1) and adherens junction proteins like VE-cadherin and associated catenins, thus weakening endothelial cell-cell adhesion and increasing vascular permeability. We found VEGF receptor-2 (VEGFR-2) to be part of a multi-protein complex involving ZO-1, VE-cadherin and β-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, β-catenin and ZO-1 were inhibited by dopamine treatment. Association of occludin with ZO-1 and ZO-1 with VE-cadherin were significantly inhibited by dopamine in VEGF treated cells. Furthermore, we identified Src as an important target for dopamine-mediated inhibition of VPF/VEGF induced permeability. Conclusion Taken together, our results provide molecular insights of dopamine function in the vascular endothelium and suggest a central role of Src in regulating key molecules that control vascular permeability. PMID:18662404

  20. Selective modulation of excitatory and inhibitory microcircuits by dopamine

    NASA Astrophysics Data System (ADS)

    Gao, Wen-Jun; Goldman-Rakic, Patricia S.

    2003-03-01

    Dopamine plays an important role in the working memory functions of the prefrontal cortex, functions that are impacted in age-related memory decline, drug abuse, and a wide variety of disorders, including schizophrenia and Parkinson's disease. We have previously reported that dopamine depresses excitatory transmission between pyramidal neurons in the prefrontal cortex. Here, using paired recordings, we have investigated dopaminergic modulation of excitatory transmission from pyramidal neurons to fast-spiking (FS) interneurons. In contrast to its effect on recurrent excitation, dopamine was without effect on excitatory transmission to FS interneurons. However, dopamine has directly enhanced the excitability of the FS interneurons to the extent that even a single excitatory postsynaptic potential could initiate spiking with great temporal precision in some of them. These results indicate that dopamine's effects on excitatory transmission are target-specific and that the axon terminals of pyramidal neurons can be selectively regulated at the level of individual synapses. Thus, dopamine's net inhibitory effect on cortical function is remarkably constrained by the nature of the microcircuit elements on which it acts.

  1. Differential effects of dopamine-directed treatments on cognition.

    PubMed

    Ashby, F Gregory; Valentin, Vivian V; von Meer, Stella S

    2015-01-01

    Dopamine, a prominent neuromodulator, is implicated in many neuropsychiatric disorders. It has wide-ranging effects on both cortical and subcortical brain regions and on many types of cognitive tasks that rely on a variety of different learning and memory systems. As neuroscience and behavioral evidence for the existence of multiple memory systems and their corresponding neural networks accumulated, so did the notion that dopamine's role is markedly different depending on which memory system is engaged. As a result, dopamine-directed treatments will have different effects on different types of cognitive behaviors. To predict what these effects will be, it is critical to understand: which memory system is mediating the behavior; the neural basis of the mediating memory system; the nature of the dopamine projections into that system; and the time course of dopamine after its release into the relevant brain regions. Consideration of these questions leads to different predictions for how changes in brain dopamine levels will affect automatic behaviors and behaviors mediated by declarative, procedural, and perceptual representation memory systems.

  2. Transient activation of midbrain dopamine neurons by reward risk.

    PubMed

    Fiorillo, C D

    2011-12-01

    Dopamine neurons of the ventral midbrain are activated transiently following stimuli that predict future reward. This response has been shown to signal the expected value of future reward, and there is strong evidence that it drives positive reinforcement of stimuli and actions associated with reward in accord with reinforcement learning models. Behavior is also influenced by reward uncertainty, or risk, but it is not known whether the transient response of dopamine neurons is sensitive to reward risk. To investigate this, monkeys were trained to associate distinct visual stimuli with certain or uncertain volumes of juice of nearly the same expected value. In a choice task, monkeys preferred the stimulus predicting an uncertain (risky) reward outcome. In a Pavlovian task, in which the neuronal responses to each stimulus could be measured in isolation, it was found that dopamine neurons were more strongly activated by the stimulus associated with reward risk. Given extensive evidence that dopamine drives reinforcement, these results strongly suggest that dopamine neurons can reinforce risk-seeking behavior (gambling), at least under certain conditions. Risk-seeking behavior has the virtue of promoting exploration and learning, and these results support the hypothesis that dopamine neurons represent the value of exploration.

  3. Photoaffinity ligand for dopamine D2 receptors: azidoclebopride

    SciTech Connect

    Niznik, H.B.; Guan, J.H.; Neumeyer, J.L.; Seeman, P.

    1985-02-01

    In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind (/sup 3/H)spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol.

  4. CXCL4 Downregulates the Atheroprotective Hemoglobin Receptor CD163 in Human Macrophages

    PubMed Central

    Gleissner, Christian A.; Shaked, Iftach; Erbel, Christian; Böckler, Dittmar; Katus, Hugo A.; Ley, Klaus

    2010-01-01

    Rationale CXCL4 is a platelet-derived chemokine that promotes macrophage differentiation from monocytes. Deletion of the PF4 gene that encodes CXCL4 reduces atherosclerotic lesions in ApoE−/− mice. Objective We sought to study effects of CXCL4 on macrophage differentiation with possible relevance for atherogenesis. Methods and Results Flow cytometry for expression of surface markers in macrophage colony–stimulating factor (M-CSF)– and CXCL4-induced macrophages demonstrated virtually complete absence of the hemoglobin scavenger receptor CD163 in CXCL4-induced macrophages. mRNA for CD163 was downregulated as early as 2 hours after CXCL4. CD163 protein reached a minimum after 3 days, which was not reversed by treatment of cells with M-CSF. The CXCL4 effect was entirely neutralized by heparin, which bound CXCL4 and prevented CXCL4 surface binding to monocytes. Pretreatment of cells with chlorate, which inhibits glycosaminoglycan synthesis, strongly inhibited CXCL4-dependent downregulation of CD163. Similar to recombinant CXCL4, releasate from human platelets also reduced CD163 expression. CXCL4-differentiated macrophages were unable to upregulate the atheroprotective enzyme heme oxygenase-1 at the RNA and protein level in response to hemoglobin–haptoglobin complexes. Immunofluorescence of human atherosclerotic plaques demonstrated presence of both CD68+CD163+ and CD68+CD163− macrophages. PF4 and CD163 gene expression within human atherosclerotic lesions were inversely correlated, supporting the in vivo relevance of CXCL4-induced downregulation of CD163. Conclusions CXCL4 may promote atherogenesis by suppressing CD163 in macrophages, which are then unable to upregulate the atheroprotective enzyme heme oxygenase-1 in response to hemoglobin. PMID:19910578

  5. Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

    PubMed Central

    Gantois, Ilse; Fang, Ke; Jiang, Luning; Babovic, Daniela; Lawrence, Andrew J.; Ferreri, Vincenzo; Teper, Yaroslav; Jupp, Bianca; Ziebell, Jenna; Morganti-Kossmann, Cristina M.; O'Brien, Terence J.; Nally, Rachel; Schütz, Günter; Waddington, John; Egan, Gary F.; Drago, John

    2007-01-01

    Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons. PMID:17360497

  6. Revision of the classical dopamine D2 agonist pharmacophore based on an integrated medicinal chemistry, homology modelling and computational docking approach.

    PubMed

    Krogsgaard-Larsen, N; Harpsøe, K; Kehler, J; Christoffersen, C T; Brøsen, P; Balle, T

    2014-10-01

    The scientific advances during the 1970ies and 1980ies within the field of dopaminergic neurotransmission enabled the development of a pharmacophore that became the template for design and synthesis of dopamine D2 agonists during the following four decades. A major drawback, however, is that this model fails to accommodate certain classes of restrained dopamine D2 agonists including ergoline structures. To accommodate these, a revision of the original model was required. The present study has addressed this by an extension of the original model without compromising its obvious qualities. The revised pharmacophore contains an additional hydrogen bond donor feature, which is required for it to accommodate ergoline structures in a low energy conformation and in accordance with the steric restrictions dictated by the original model. The additional pharmacophore feature suggests ambiguity in the binding mode for certain compounds, including a series of ergoline analogues, which was reported recently. The ambiguity was confirmed by docking to a homology model of the D2 receptor as well as by pharmacological characterization of individual enantiomers of one of the analogues. The present research also addresses the potential of designing ligands that interact with the receptor in a large, distal cavity of the dopamine D2 receptor that has not previously been studied systematically. The pharmacological data indicate that this area may be a major determinant for both the dopamine D2 affinity and efficacy, which remains to be explored in future studies.

  7. Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway

    PubMed Central

    Donato, Verónica; Ayala, Facundo Rodríguez; Cogliati, Sebastián; Bauman, Carlos; Costa, Juan Gabriel; Leñini, Cecilia; Grau, Roberto

    2017-01-01

    Beneficial bacteria have been shown to affect host longevity, but the molecular mechanisms mediating such effects remain largely unclear. Here we show that formation of Bacillus subtilis biofilms increases Caenorhabditis elegans lifespan. Biofilm-proficient B. subtilis colonizes the C. elegans gut and extends worm lifespan more than biofilm-deficient isogenic strains. Two molecules produced by B. subtilis — the quorum-sensing pentapeptide CSF and nitric oxide (NO) — are sufficient to extend C. elegans longevity. When B. subtilis is cultured under biofilm-supporting conditions, the synthesis of NO and CSF is increased in comparison with their production under planktonic growth conditions. We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway. PMID:28134244

  8. Zidovudine induces downregulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs.

    PubMed

    Sun, Ren; Eriksson, Staffan; Wang, Liya

    2014-11-01

    Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs.

  9. Acidosis-induced downregulation of hepatocyte mitochondrial aquaporin-8 and ureagenesis from ammonia.

    PubMed

    Molinas, Sara M; Soria, Leandro R; Marrone, Julieta; Danielli, Mauro; Trumper, Laura; Marinelli, Raúl A

    2015-08-01

    It has been proposed that, during metabolic acidosis, the liver downregulates mitochondrial ammonia detoxification via ureagenesis, a bicarbonate-consuming process. Since we previously demonstrated that hepatocyte mitochondrial aquaporin-8 channels (mtAQP8) facilitate the uptake of ammonia and its metabolism into urea, we studied whether mtAQP8 is involved in the liver adaptive response to acidosis. Primary cultured rat hepatocytes were adapted to acidosis by exposing them to culture medium at pH 7.0 for 40 h. Control cells were exposed to pH 7.4. Hepatocytes exposed to acid medium showed a decrease in mtAQP8 protein expression (-30%, p < 0.05). Ureagenesis from ammonia was assessed by incubating the cells with (15)N-labeled ammonia and measuring (15)N-labeled urea synthesis by nuclear magnetic resonance. Reduced ureagenesis was found in acidified hepatocytes (-31%, p < 0.05). In vivo studies in rats subjected to 7 days acidosis also showed decreased protein expression of hepatic mtAQP8 (-50%, p < 0.05) and reduced liver urea content (-35%; p < 0.05). In conclusion, our in vitro and in vivo data suggest that hepatic mtAQP8 expression is downregulated in acidosis, a mechanism that may contribute to decreased ureagenesis from ammonia in response to acidosis.

  10. Mimicking maternal smoking and pharmacotherapy of preterm labor: interactions of fetal nicotine and dexamethasone on serotonin and dopamine synaptic function in adolescence and adulthood.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2010-04-29

    Fetal coexposure to nicotine and dexamethasone is common: maternal smoking increases the incidence of preterm delivery and glucocorticoids are the consensus treatment for prematurity. We gave pregnant rats 3mg/kg/day of nicotine throughout gestation, a regimen that reproduces smokers' plasma levels, and then on gestational days 17, 18 and 19, we administered 0.2mg/kg of dexamethasone. We evaluated developmental indices for serotonin (5HT) and dopamine synaptic function throughout adolescence, young adulthood and later adulthood, assessing the brain regions possessing major 5HT and dopamine projections and cell bodies. Males displayed persistent upregulation of 5HT(1A) and 5HT(2) receptors and the 5HT transporter, with a distinct hierarchy of effects: nicotinedownregulation of the 5HT(1A) receptor with the same rank order; both sexes displayed presynaptic hyperactivity of 5HT and dopamine pathways as evidenced by increased neurotransmitter turnover. Superimposed on these overall effects, there were significant differences in temporal and regional relationships among the different treatments, often involving effects that emerged later in life, after a period of apparent normality. This indicates that nicotine and dexamethasone do not simply produce an initial neuronal injury that persists throughout the lifespan but rather, they alter the developmental trajectory of synaptic function. The fact that the combined treatment produced greater effects for many parameters points to potentially worse neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.

  11. Cardiovascular and adenylate cyclase stimulating effects of colforsin daropate, a water-soluble forskolin derivative, compared with those of isoproterenol, dopamine and dobutamine.

    PubMed

    Yoneyama, Masahiko; Sugiyama, Atsushi; Satoh, Yoshioki; Takahara, Akira; Nakamura, Yuji; Hashimoto, Keitaro

    2002-12-01

    Colforsin daropate is a recently developed water-soluble derivative of forskolin that directly stimulates adenylate cyclase, unlike the catecholamines. The chronotropic, inotropic and coronary vasodilator actions of colforsin daropate were compared with those of isoproterenol, dopamine and dobutamine, using canine isolated, blood-perfused heart preparations. The stimulating effect of each drug on adenylate cyclase activity was also assessed. Colforsin daropate, as well as each of the catecholamines, exerted positive chronotropic, inotropic and coronary vasodilator actions. The order of selectivity for the cardiovascular variables of colforsin daropate was coronary vasodilation > positive inotropy > positive chronotropy; whereas that of isoproterenol, dopamine and dobutamine was positive inotropy > coronary vasodilation > positive chronotropy. Thus, a marked characteristic of colforsin daropate is its potent coronary vasodilator action. On the other hand, each drug significantly increased the adenylate cyclase activity in a dose-related manner: colforsin daropate > isoproterenol > dopamine = dobutamine. These results suggest that colforsin daropate may be preferable in the treatment of severe heart failure where the coronary blood flow is reduced and beta-adrenoceptor-dependent signal transduction pathway is down-regulated.

  12. Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels.

    PubMed

    Evans, Rebekah C; Zhu, Manhua; Khaliq, Zayd M

    2017-03-29

    While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition.SIGNIFICANCE STATEMENT Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential

  13. Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

    PubMed

    Moreau, Caroline; Meguig, Sayah; Corvol, Jean-Christophe; Labreuche, Julien; Vasseur, Francis; Duhamel, Alain; Delval, Arnaud; Bardyn, Thomas; Devedjian, Jean-Christophe; Rouaix, Nathalie; Petyt, Gregory; Brefel-Courbon, Christine; Ory-Magne, Fabienne; Guehl, Dominique; Eusebio, Alexandre; Fraix, Valérie; Saulnier, Pierre-Jean; Lagha-Boukbiza, Ouhaid; Durif, Frank; Faighel, Mirela; Giordana, Caroline; Drapier, Sophie; Maltête, David; Tranchant, Christine; Houeto, Jean-Luc; Debû, Bettina; Azulay, Jean-Philippe; Tison, François; Destée, Alain; Vidailhet, Marie; Rascol, Olivier; Dujardin, Kathy; Defebvre, Luc; Bordet, Régis; Sablonnière, Bernard; Devos, David

    2015-05-01

    After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3

  14. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    PubMed

    Levite, M

    2016-01-01

    Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs

  15. Dopamine Signaling in the Dorsal Striatum Is Essential for Motivated Behaviors: Lessons from Dopamine-deficient Mice

    PubMed Central

    Palmiter, Richard D.

    2009-01-01

    Genetically engineered mice that lack tyrosine hydroxylase in all dopaminergic neurons become hypoactive and aphagic and they starve by 4 weeks of age. However, they can be rescued by daily treatment with L-dopa, which restores activity and feeding for about 10 hours. Thus, these mice can be examined in both dopamine-depleted and dopamine replete states. A series of behavioral experiments lead to the primary conclusion that in the dopamine-depleted state these mice are not motivated to engage in goal-directed behaviors. Nevertheless, they still have a preference for sucrose, they can learn the location of food rewards, and they can form a conditioned-place preference for drugs. Dopamine signaling can be restored to the striatum by several different viral gene therapy procedures. Restoring dopamine signaling selectively to the dorsal striatum is sufficient to allow feeding, locomotion, and reward-based learning. The rescued mice appear to have normal motivation to engage in all goal-directed behaviors that have been tested. The results suggest that dopamine facilitates the output from dorsal striatum, which provides a permissive signal allowing feeding and other goal-directed behaviors. PMID:18591467

  16. β-phenylethylamine Requires the Dopamine Transporter to Increase Extracellular Dopamine in C. elegans Dopaminergic Neurons

    PubMed Central

    Hossain, Murad; Wickramasekara, Rochelle N.; Carvelli, Lucia

    2013-01-01

    β-phenylethylamine (βPEA) is an endogenous amine that has been shown to increase the synaptic levels of dopamine (DA). A number of in vitro and behavioral studies suggest the dopamine transporter (DAT) plays a role in the effects generated by βPEA, however the mechanism through which βPEA affects DAT has not yet been elucidated. Here, we used Caenorhabditis (C.) elegans DAT (DAT-1) expressing LLC-pk1 cells and neuronal cultures to investigate whether the βPEA-induced increase of extracellular DA required DAT-1. Our data show that βPEA increases extracellular dopamine both in DAT-1 transfected cells and cultures of differentiated neurons. RTI-55, a cocaine homologue and DAT inhibitor, completely blocked the βPEA-induced effect in transfected cells. However in neuronal cultures, RTI-55 only partly inhibited the increase of extracellular DA generated by βPEA. These results suggest that βPEA requires DAT-1 and other, not yet identified proteins, to increase extracellular DA when tested in a native system. Furthermore, our results suggest that βPEA-induced increase of extracellular DA does not require functional monoamine vesicles as genetic ablation of the C. elegans homologue vesicular monoamine transporter, cat-1, did not compromise the ability of βPEA to increase extracellular DA. Finally, our electrophysiology data show that βPEA caused fast-rising and self-inactivating amperometric currents in a subset of wild-type DA neurons but not in neurons isolated from dat-1 knockout animals. Taken together, these data demonstrate that in both DA neurons and heterogeneous cultures of differentiated C. elegans neurons, βPEA releases cytoplasmic DA through DAT-1 to ultimately increase the extracellular concentration of DA. PMID:24161617

  17. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

    PubMed

    Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

    2016-05-01

    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

  18. Anterior cingulate dopamine turnover and behavior change in Parkinson's disease.

    PubMed

    Gallagher, Catherine L; Bell, Brian; Palotti, Matthew; Oh, Jen; Christian, Bradley T; Okonkwo, Ozioma; Sojkova, Jitka; Buyan-Dent, Laura; Nickles, Robert J; Harding, Sandra J; Stone, Charles K; Johnson, Sterling C; Holden, James E

    2015-12-01

    Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[(18) F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson's patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. Fifteen non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor, and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function-Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson's disease.

  19. The role of dopamine signaling in epileptogenesis

    PubMed Central

    Bozzi, Yuri; Borrelli, Emiliana

    2013-01-01

    Clinical and experimental studies implicate most neuromodulatory systems in epileptogenesis. The dopaminergic system has a seizure-modulating effect that crucially depends on the different subtypes of dopamine (DA) receptors involved and the brain regions in which they are activated. Specifically, DA plays a major role in the control of seizures arising in the limbic system. Studies performed in a wide variety of animal models contributed to illustrate the opposite actions of D1-like and D2-like receptor signaling in limbic epileptogenesis. Indeed, signaling from D1-like receptors is generally pro-epileptogenic, whereas D2-like receptor signaling exerts an anti-epileptogenic effect. However, this view might appear quite simplistic as the complex neuromodulatory action of DA in the control of epileptogenesis likely requires a physiological balance in the activation of circuits modulated by these two major DA receptor subtypes, which determines the response to seizure-promoting stimuli. Here we will review recent evidences on the identification of molecules activated by DA transduction pathways in the generation and spread of seizures in the limbic system. We will discuss the intracellular signaling pathways triggered by activation of different DA receptors in relation to their role in limbic epileptogenesis, which lead to the activation of neuronal death/survival cascades. A deep understanding of the signaling pathways involved in epileptogenesis is crucial for the identification of novel targets for the treatment of epilepsy. PMID:24062645

  20. Oxytocin, Motivation and the Role of Dopamine

    PubMed Central

    Love, Tiffany M.

    2013-01-01

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

  1. Modulation for emergent networks: serotonin and dopamine.

    PubMed

    Weng, Juyang; Paslaski, Stephen; Daly, James; VanDam, Courtland; Brown, Jacob

    2013-05-01

    In autonomous learning, value-sensitive experiences can improve the efficiency of learning. A learning network needs be motivated so that the limited computational resources and the limited lifetime are devoted to events that are of high value for the agent to compete in its environment. The neuromodulatory system of the brain is mainly responsible for developing such a motivation system. Although reinforcement learning has been extensively studied, many existing models are symbolic whose internal nodes or modules have preset meanings. Neural networks have been used to automatically generate internal emergent representations. However, modeling an emergent motivational system for neural networks is still a great challenge. By emergent, we mean that the internal representations emerge autonomously through interactions with the external environments. This work proposes a generic emergent modulatory system for emergent networks, which includes two subsystems - the serotonin system and the dopamine system. The former signals a large class of stimuli that are intrinsically aversive (e.g., stress or pain). The latter signals a large class of stimuli that are intrinsically appetitive (e.g., pleasure or sweet). We experimented with this motivational system for two settings. The first is a visual recognition setting to investigate how such a system can learn through interactions with a teacher, who does not directly give answers, but only punishments and rewards. The second is a setting for wandering in the presence of a friend and a foe.

  2. Biophysically realistic minimal model of dopamine neuron

    NASA Astrophysics Data System (ADS)

    Oprisan, Sorinel

    2008-03-01

    We proposed and studied a new biophysically relevant computational model of dopaminergic neurons. Midbrain dopamine neurons are involved in motivation and the control of movement, and have been implicated in various pathologies such as Parkinson's disease, schizophrenia, and drug abuse. The model we developed is a single-compartment Hodgkin-Huxley (HH)-type parallel conductance membrane model. The model captures the essential mechanisms underlying the slow oscillatory potentials and plateau potential oscillations. The main currents involved are: 1) a voltage-dependent fast calcium current, 2) a small conductance potassium current that is modulated by the cytosolic concentration of calcium, and 3) a slow voltage-activated potassium current. We developed multidimensional bifurcation diagrams and extracted the effective domains of sustained oscillations. The model includes a calcium balance due to the fundamental importance of calcium influx as proved by simultaneous electrophysiological and calcium imaging procedure. Although there are significant evidences to suggest a partially electrogenic calcium pump, all previous models considered only elecrtogenic pumps. We investigated the effect of the electrogenic calcium pump on the bifurcation diagram of the model and compared our findings against the experimental results.

  3. Prefrontal dopamine in associative learning and memory.

    PubMed

    Puig, M V; Antzoulatos, E G; Miller, E K

    2014-12-12

    Learning to associate specific objects or actions with rewards and remembering the associations are everyday tasks crucial for our flexible adaptation to the environment. These higher-order cognitive processes depend on the prefrontal cortex (PFC) and frontostriatal circuits that connect areas in the frontal lobe with the striatum in the basal ganglia. Both structures are densely innervated by dopamine (DA) afferents that originate in the midbrain. Although the activity of DA neurons is thought to be important for learning, the exact role of DA transmission in frontostriatal circuits during learning-related tasks is still unresolved. Moreover, the neural substrates of this modulation are poorly understood. Here, we review our recent work in monkeys utilizing local pharmacology of DA agents in the PFC to investigate the cellular mechanisms of DA modulation of associative learning and memory. We show that blocking both D1 and D2 receptors in the lateral PFC impairs learning of new stimulus-response associations and cognitive flexibility, but not the memory of highly familiar associations. In addition, D2 receptors may also contribute to motivation. The learning deficits correlated with reductions of neural information about the associations in PFC neurons, alterations in global excitability and spike synchronization, and exaggerated alpha and beta neural oscillations. Our findings provide new insights into how DA transmission modulates associative learning and memory processes in frontostriatal systems.

  4. Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson's disease and congenital dopamine beta-hydroxylase deficiency.

    PubMed

    O'Connor, D T; Cervenka, J H; Stone, R A; Levine, G L; Parmer, R J; Franco-Bourland, R E; Madrazo, I; Langlais, P J; Robertson, D; Biaggioni, I

    1994-02-01

    1. Dopamine beta-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine beta-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine beta-hydroxylase, we applied a homologous human dopamine beta-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine beta-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine beta-hydroxylase deficiency. 2. Authentic, physically stable dopamine beta-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 +/- 1.4 ng/ml (range: 18.5-52.5 ng/ml), but at a 283 +/- 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine beta-hydroxylase concentrations were correlated (r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine beta-hydroxylase was suggested by incomplete correlation with plasma dopamine beta-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine beta-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine beta-hydroxylase was not changed by the central alpha 2-agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine beta-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine beta-hydroxylase concentration was not closely

  5. Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys.

    PubMed

    Kimmel, Heather L; Nye, Jonathon A; Voll, Ronald; Mun, Jiyoung; Stehouwer, Jeffrey; Goodman, Mark M; Votaw, John R; Carroll, F I; Howell, Leonard L

    2012-06-01

    Several classes of drugs bind to the dopamine transporter (DAT) with high affinity, but some are weaker positive reinforcers than cocaine, suggesting that affinity for and occupancy of the DAT is not the only determinant of a drug's reinforcing effectiveness. Other factors such as the rate of onset have been positively and strongly correlated with the reinforcing effects of DAT inhibitors in nonhuman primates. In the current studies, we examined the effects of acute systemic administration of cocaine and three cocaine analogs (RTI-150, RTI-177, and RTI-366) on binding to DAT in squirrel monkey brain using positron emission tomography (PET) neuroimaging. During the PET scan, we also measured drug effects on dopamine (DA) levels in the caudate using in vivo microdialysis. In general, our results suggest a lack of concordance between drug occupancy at DAT and changes in DA levels. These studies also indicate that acute cocaine administration decreases the availability of plasma membrane DAT for binding, even after cocaine is no longer blocking DA uptake as evidence by a return to basal DA levels.

  6. SKF-83566, a D1-dopamine receptor antagonist, inhibits the dopamine transporter.

    PubMed

    Stouffer, Melissa A; Ali, Solav; Reith, Maarten E A; Patel, Jyoti C; Sarti, Federica; Carr, Kenneth D; Rice, Margaret E

    2011-09-01

    Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1)-receptor activation in axonal DA release regulation in dorsal striatum using a D(1)-receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration, with a maximum increase of ∼ 65% in 5 μM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 μM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [(3)H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 μM. Binding studies with [(3)H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 μM). Thus, data obtained using SKF-83566 as a D(1) DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT.

  7. Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake.

    PubMed

    Castro-Hernández, Javier; Afonso-Oramas, Domingo; Cruz-Muros, Ignacio; Salas-Hernández, Josmar; Barroso-Chinea, Pedro; Moratalla, Rosario; Millan, Mark J; González-Hernández, Tomás

    2015-02-01

    The dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DA from extracellular space and is regulated by diverse presynaptic proteins like protein kinases, α-synuclein, D2 and D3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeutically treated by dopaminergic D2/D3 receptor (D2/D3R) agonists. It is, then, important to improve our understanding of interactions between D3R and DAT. We show that prolonged administration of pramipexole (0.1mg/kg/day, 6 to 21 days), a preferential D3R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reduction in DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect of pramipexole was absent in mice with genetically-deleted D3R (D3R(-/-)), yet unaffected in mice genetically deprived of D2R (D2R(-/-)). Pramipexole treatment induced a physical interaction between D3R and DAT, as assessed by co-immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DAT dimers and DAT association with both D2R and α-synuclein, effects that were abolished in D3R(-/-) mice, yet unaffected in D2R(-/-) mice, indicating dependence upon D3R. Collectively, these data suggest that prolonged treatment with dopaminergic D3 agonists provokes a reduction in DA reuptake by dopaminergic neurons related to a hitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists.

  8. Mutant PINK1 upregulates tyrosine hydroxylase and dopamine levels, leading to vulnerability of dopaminergic neurons.

    PubMed

    Zhou, Zhi Dong; Refai, Fathima Shaffra; Xie, Shao Ping; Ng, Shin Hui; Chan, Christine Hui Shan; Ho, Patrick Ghim Hoe; Zhang, Xiao Dong; Lim, Tit Meng; Tan, Eng King

    2014-03-01

    PINK1 mutations cause autosomal recessive forms of Parkinson disease (PD). Previous studies suggest that the neuroprotective function of wild-type (WT) PINK1 is related to mitochondrial homeostasis. PINK1 can also localize to the cytosol; however, the cytosolic function of PINK1 has not been fully elucidated. In this study we demonstrate that the extramitochondrial PINK1 can regulate tyrosine hydroxylase (TH) expression and dopamine (DA) content in dopaminergic neurons in a PINK1 kinase activity-dependent manner. We demonstrate that overexpression of full-length (FL) WT PINK1 can downregulate TH expression and DA content in dopaminergic neurons. In contrast, overexpression of PD-linked G309D, A339T, and E231G PINK1 mutations upregulates TH and DA levels in dopaminergic neurons and increases their vulnerability to oxidative stress. Furthermore transfection of FL WT PINK1 or PINK1 fragments with the PINK1 kinase domain can inhibit TH expression, whereas kinase-dead (KD) FL PINK1 or KD PINK1 fragments upregulate TH level. Our findings highlight a potential novel function of extramitochondrial PINK1 in dopaminergic neurons. Deregulation of these functions of PINK1 may contribute to PINK1 mutation-induced dopaminergic neuron degeneration. However, deleterious effects caused by PINK1 mutations may be alleviated by iron-chelating agents and antioxidant agents with DA quinone-conjugating capacity.

  9. Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

    PubMed Central

    Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai-Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki

    2017-01-01

    Dopaminergic signaling plays a critical role in the nervous system, but little is known about its potential role in breast cancer and bone metabolism. A screening of ~1,000 biologically active compounds revealed that a selective agonist of dopamine receptor D1 (DRD1), A77636, inhibited proliferation of 4T1.2 mammary tumor cells as well as MDA-MB-231 breast cancer cells. Herein, we examined the effect of A77636 on bone quality using a mouse model of bone metastasis from mammary tumor. A77636 inhibited migration of cancer cells in a DRD1-dependent fashion and suppressed development of bone-resorbing osteoclasts by downregulating NFATc1 through the elevation of phosphorylation of eIF2α. In the mouse model of bone metastasis, A77636 reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Collectively, we expect that dopaminergic signaling might provide a novel therapeutic target for breast cancer and bone metastasis. PMID:28374823

  10. Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

    PubMed Central

    Dai, Wen-Ling; Xiong, Feng; Yan, Bing; Cao, Zheng-Yu; Liu, Wen-Tao; Liu, Ji-Hua; Yu, Bo-Yang

    2016-01-01

    Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic. PMID:28004735

  11. Calcineurin/NFAT Signaling Represses Genes Vamp1 and Vamp2 via PMCA-Dependent Mechanism during Dopamine Secretion by Pheochromocytoma Cells

    PubMed Central

    Kosiorek, Michalina; Zylinska, Ludmila; Zablocki, Krzysztof; Pikula, Slawomir

    2014-01-01

    Background Plasma membrane Ca2+-ATPases (PMCA) extrude Ca2+ ions out of the cell and contribute to generation of calcium oscillations. Calcium signaling is crucial for transcriptional regulation of dopamine secretion by neuroendocrine PC12 cells. Low resting [Ca2+]c in PC12 cells is maintained mainly by two Ca2+-ATPases, PMCA2 and PMCA3. Recently, we found that Ca2+ dependent phosphatase calcineurin was excessively activated under conditions of experimental downregulation of PMCA2 or PMCA3. Thus, the aim of this study was to explain if, via modulation of the Ca2+/calcineurin-dependent nuclear factor of activated T cells (NFAT) pathway, PMCA2 and PMCA3 affect intracellular signaling in pheochromocytoma/neuronal cells/PC12 cells. Secondly, we tested whether this might influence dopamine secretion by PC12 cells. Results PMCA2- and PMCA3-deficient cells displayed profound decrease in dopamine secretion accompanied by a permanent increase in [Ca2+]c. Reduction in secretion might result from changes in NFAT signaling, following altered PMCA pattern. Consequently, activation of NFAT1 and NFAT3 transcription factors was observed in PMCA2- or PMCA3-deficient cells. Furthermore, chromatin immunoprecipitation assay indicated that NFATs could be involved in repression of Vamp genes encoding vesicle associated membrane proteins (VAMP). Conclusions PMCA2 and PMCA3 are crucial for dopamine secretion in PC12 cells. Reduction in PMCA2 or PMCA3 led to calcium-dependent activation of calcineurin/NFAT signaling and, in consequence, to repression of the Vamp gene and deterioration of the SNARE complex formation in PC12 cells. PMID:24667359

  12. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area.

    PubMed

    Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello; Whistler, Jennifer L

    2013-07-24

    Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.

  13. Dopamine depletion impairs precursor cell proliferation in Parkinson disease.

    PubMed

    Höglinger, Günter U; Rizk, Pamela; Muriel, Marie P; Duyckaerts, Charles; Oertel, Wolfgang H; Caille, Isabelle; Hirsch, Etienne C

    2004-07-01

    Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Experiments with neural precursors from the adult subependymal zone grown as neurosphere cultures confirm that activation of D2L receptors directly increases the proliferation of these precursors. Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation.

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

    PubMed

    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.

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

    PubMed

    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.

  16. Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network

    PubMed Central

    Stagkourakis, Stefanos; Kim, Hoseok; Lyons, David J.; Broberger, Christian

    2016-01-01

    Summary How autoreceptors contribute to maintaining a stable output of rhythmically active neuronal circuits is poorly understood. Here, we examine this issue in a dopamine population, spontaneously oscillating hypothalamic rat (TIDA) neurons, that underlie neuroendocrine control of reproduction and neuroleptic side e