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Sample records for prevent nigrostriatal dopamine

  1. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

    Science.gov (United States)

    Mor, Danielle E.; Tsika, Elpida; Mazzulli, Joseph R.; Gould, Neal S.; Kim, Hanna; Daniels, Malcolm J.; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L.; Tan, Victor X.; Kalb, Robert G.; Caldwell, Kim A.; Caldwell, Guy A.; Wolfe, John H.; Ischiropoulos, Harry

    2018-01-01

    Parkinson’s disease is defined by the loss of dopaminergic neurons in the substantia nigra and formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated dopamine levels in addition to α-synuclein expression. Nigra-targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine without damaging neurons in non-transgenic mice. In contrast, raising dopamine in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable C. elegans models expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. The data suggest a unique mechanism linking two cardinal features of Parkinson’s disease, dopaminergic cell death and α-synuclein aggregation. PMID:28920936

  2. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    Science.gov (United States)

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-11-01

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  3. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

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    Tertia D Purves-Tyson

    Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

  4. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitoxicity and Environmental, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2002-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S...

  5. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environmental, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2005-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is a widespread problem and drug of abuse throughout the U.S...

  6. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2000-01-01

    .... Similarly, the psycho stimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is rapidly becoming a widespread problem and drug of abuse throughout the U.S...

  7. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environment, Metabolic and Oxidative Stress

    National Research Council Canada - National Science Library

    Yamamoto, Bryan

    2001-01-01

    .... Similarly, the psychostimulant drug, methamphetamine also produces relatively selective damage to nigrostriatal dopamine neurons and is rapidly becoming a widespread problem and drug of abuse throughout the U.S...

  8. Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

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    Lijuan Hou

    2017-11-01

    Full Text Available Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD, and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise-induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients.

  9. The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism.

    Science.gov (United States)

    Sonsalla, Patricia K; Coleman, Christal; Wong, Lai-Yoong; Harris, Suzan L; Richardson, Jason R; Gadad, Bharathi S; Li, Wenhao; German, Dwight C

    2013-12-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4-phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD. © 2013.

  10. Association of body mass index and the depletion of nigrostriatal dopamine in Parkinson's disease.

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    Lee, Jae Jung; Oh, Jungsu S; Ham, Jee H; Lee, Dong H; Lee, Injoo; Sohn, Young H; Kim, Jae S; Lee, Phil Hyu

    2016-02-01

    Several antecedent studies had reported close relationship between low body weight and Parkinson's disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice

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    Richter, Franziska; Gabby, Lauryn; McDowell, Kimberly A.; Mulligan, Caitlyn K.; De La Rosa, Krystal; Sioshansi, Pedrom C.; Mortazavi, Farzad; Cely, Ingrid; Ackerson, Larry C.; Tsan, Linda; Murphy, Niall P.; Maidment, Nigel T.; Chesselet, Marie-Françoise

    2016-01-01

    How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson’s disease (PD) remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta (SNc) at 3–4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5 weeks old mice, the toxins decreased SNc dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing PD when multiple factors are combined. PMID:28038352

  12. Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

    DEFF Research Database (Denmark)

    Lillethorup, Thea Pinholt; Glud, Andreas Nørgaard; Alstrup, Aage Kristian Olsen

    2018-01-01

    Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We...... displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs....... In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies...

  13. GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain

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    Susanne Nikolaus

    2018-03-01

    Full Text Available Purpose: The present study assessed the effects of the GABAA receptor (R agonist muscimol (MUS, and the GABAAR antagonist bicuculline (BIC on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat.Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region.Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012. In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022 and thalamus (p = 0.047 relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time.Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.

  14. Dopamine

    International Nuclear Information System (INIS)

    Walters, L.

    1983-01-01

    Dopamine is an important neurotransmittor in the central nervous system. The physiological function of the peripheral dopamine receptors is unknown, but they are of therapeutic importance as dopamine is used to improve renal blood flow in shocked patients. There are 4 dopamine receptors. The classification of these dopamine receptors has been made possible by research with radiopharmaceuticals. Dopamine sensitive adenylate cyclase is an inherent part of the dopamine-1-receptor. Dopamine-1-receptors are stimulated by micromolar (physiological) concentrations of dopamine and inhibited by micromolar (supratherapeutic) concentrations of the antipsychotic drugs. The vascular effect of dopamine is mediated through the dopamine-1-receptors. Dopamine-2-receptors are responsible for the effect of dopamine at the mesolimbic, nigrostriatal and chemoreceptortrigger areas. It is activated by micromolar concentrations of dopamine and blocked by nanomolar (therapeutic) concentrations of the anti-psychotic drugs. Dopamine-3-receptors are activated by nanomolar concentrations of dopamine and inhibited by micromolar concentrations of the antipsychotic drugs. They occur on presynaptic nerve terminals and have a negative feedback effect on the liberation of dopamine, noradrenaline and serotonin. The dopamine-4-receptors are activated by nanomolar concentrations of dopamine. These are the only dopamine receptors that could be responsible for effects in the hypophysis as only nanomolar concentrations of dopamine occur there. These receptors are blocked by nanomolar concentrations of the antipsychotic drugs

  15. Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion

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    Lisette Blanco-Lezcano

    2018-02-01

    Full Text Available Background: The degeneration of the pedunculopontine nucleus (PPN precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson’s disease (PD. Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. Methods: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH, vesicular monoamine transporter 2 (VMAT2 and dopamine transporter (DAT mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. Results: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05; in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01. DAT mRNA expression showed a significant decrease (p < 0.001 in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. Conclusions: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.

  16. Serotonin agonists reduce dopamine synthesis in the striatum only when the impulse flow of nigro-striatal neurons is intact.

    Science.gov (United States)

    Spampinato, U; Esposito, E; Samanin, R

    1985-09-01

    The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and m-chlorophenylpiperazine (CPP), two 5-hydroxytryptamine (5-HT, serotonin) agonists, on the accumulation of 3,4-dihydroxyphenylalanine (DOPA] were studied in the striatum of rats treated with gamma-butyrolactone (GBL). Unlike 2 mg/kg i.p. apomorphine, neither 5 mg/kg i.p. 5-MeO-DMT nor 2.5 mg/kg i.p. CPP significantly reduced the GBL-induced increase in DOPA accumulation in the striatum. 5-MeO-DMT and CPP significantly reduced DOPA accumulation in animals that had received the aromatic amino acid decarboxylase inhibitor Ro 4-4602 but not GBL. 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum. The data indicate that 5-HT agonists can reduce 3,4-dihydroxyphenylethylamine (DA, dopamine) synthesis in the striatum of rats only when the impulse flow of DA neurons is intact. An indirect effect through mechanisms controlling DA synthesis in the striatum, for instance cholinergic and GABA-ergic neurons, is suggested.

  17. Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism [v1; ref status: indexed, http://f1000r.es/5a9

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    Yasuko Kitao

    2015-05-01

    Full Text Available Background Dopamine (DA neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson’s disease (PD. This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT male littermates (3‒4 months old were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH, glial fibrillary acidic protein (GFAP, and nuclear DNA. In the substantia nigra pars compacta (SNpc of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

  18. Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease.

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    Zhang, Yu; Wu, I-Wei; Buckley, Shannon; Coffey, Christopher S; Foster, Eric; Mendick, Susan; Seibyl, John; Schuff, Norbert

    2015-08-01

    Parkinson's disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios. Diffusion tensor tractography was performed on 50 drug-naïve PD patients and 27 healthy control subjects from the international multicenter Parkinson's Progression Marker Initiative. Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients. Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD. © 2015 International Parkinson and Movement Disorder Society.

  19. Preventing or attenuating amphotericin B nephrotoxicity with dopamine receptor agonists: a literature review

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    Iman Karimzadeh

    2016-09-01

    Full Text Available Nephrotoxicity is generally considered as the most clinically significant and dose-limiting adverse reaction of amphotericin B. Currently, only the clinical effectiveness of salt loading and administering lipid formulations of amphotericin B have been clearly demonstrated to prevent its nephrotoxicity. In this review, we collected the published data related to dopamine receptor agonists in preventing amphotericin B nephrotoxicity. A literature search was conducted by the relevant keywords like ‘‘amphotericin B”, “nephrotoxicity’’, and ‘‘dopamine’’in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. Four relevant articles were considered. Results of all the 3 experimental studies demonstrated that co-administration of dopamine (0.5-10 μg/kg/min as continuous intravenous infusion, SK&F R-105058, a prodrug of fenoldopam (10 mg/kg twice daily, orally or fenoldopam, a relatively selective dopamine receptor type 1 agonist, (0.5 or 1 μg/kg/min as continuous intravenous infusion can at least significantly mitigate the decrease in creatinine clearance caused by amphotericin B. Furthermore, fenoldopam and SK&F R-105058 can also protect against or delay amphotericin B-induced tubular damage. In contrast, the only clinical trial published until now found that simultaneous continuous intravenous infusion of low dose dopamine (3 μg/kg/min had no beneficial effect on the incidence, severity and time onset of developing amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Considering the lack of beneficial effects in different settings such as acute kidney injury of any cause, negative results of the only clinical trial, and risk of significant adverse reactions, continuous intravenous infusion of low dose dopamine (1-3 μg/kg/min or selective dopamine receptor type 1 agonists (e.g., fenoldopam currently appears to have no promising clinical role in preventing or attenuating

  20. Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing*

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    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D.; Lin, Landon M.; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-01-01

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na+ or Cl− ion. Although isosmotic substitution of extracellular Na+ ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl− ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons. PMID:24962577

  1. Dopamine release in organotypic cultures of foetal mouse mesencephalon: effects of depolarizing agents, pargyline, nomifensine, tetrodotoxin and calcium

    DEFF Research Database (Denmark)

    Larsen, Trine R; Rossen, Sine; Gramsbergen, Jan B

    2008-01-01

    Organotypic mesencephalic cultures provide an attractive in vitro alternative to study development of the nigrostriatal system and pathophysiological mechanisms related to Parkinson's disease. However, dopamine (DA) release mechanisms have been poorly characterized in such cultures. We report here...

  2. Characterization of Fetal Antigen 1/Delta-Like 1 Homologue Expressing Cells in the Rat Nigrostriatal System

    DEFF Research Database (Denmark)

    Liechti, Rémy; Ducray, Angélique D; Jensen, Pia

    2015-01-01

    adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co...... suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian......-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata...

  3. Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum

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    Noël F.

    2000-01-01

    Full Text Available Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

  4. Clinical usefulness of dopamine transporter imaging

    International Nuclear Information System (INIS)

    Kim, Jong Min; Kim, Yu Kyeong; Kim, Sang Eun; Jeon, Beom S.

    2007-01-01

    Imaging of the dopamine transporter (DAT) provides a marker for the integrity of presynaptic nigrostriatal dopaminergic system. DAT density is reduced in Parkinson disease, multiple system atrophy, and progressive supranuclear palsy. In patients with suspicious parkinsonism, normal DAT imaging suggests an alternative diagnosis such as essential tremor, vascular parkinsonism, or drug-induced parkinsonism. DAT imaging is a useful tool to aid clinician's differential diagnosis in parkinsonism

  5. The nigrostriatal pathway: axonal collateralization and compartmental specificity.

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    Prensa, L; Giménez-Amaya, J M; Parent, A; Bernácer, J; Cebrián, C

    2009-01-01

    This paper reviews two of the major features of the nigrostriatal pathway, its axonal collateralization, and compartmental specificity, as revealed by single-axon labeling experiments in rodents and immunocytological analysis of human postmortem tissue. The dorsal and ventral tiers of the substantia nigra pars compacta harbor various types of neurons the axons of which branch not only within the striatum but also in other major components of the basal ganglia. Furthermore, some nigrostriatal axons send collaterals both to thalamus and to brainstem pedunculopontine tegmental nucleus. In humans, the compartmental specificity of the nigrostriatal pathway is revealed by the fact that the matrix compartment is densely innervated by dopaminergic fibers, whereas the striosomes display different densities of dopaminergic terminals depending on their location within the striatum. The nigral neurons most severely affected in Parkinson's disease are the ventral tier cells that project to the matrix and form deep clusters in the substantia nigra pars reticulata.

  6. Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei

    International Nuclear Information System (INIS)

    Chesselet, M.F.; Reisine, T.D.

    1983-01-01

    The effects of somatostatin on the release of tritiated dopamine (DA) formed continuously from tritiated tyrosine were studied in vitro in superfused striatal slices and in vivo in both caudate nuclei and both substantiae nigrae of halothane-anesthetized cats using a push-pull cannula technique. Somatostatin (3 X 10(-10) to 3 X 10(-7) M) increased the spontaneous tritiated dopamine release from rat striatal slices. This effect was dose dependent and was completely prevented by tetrodotoxin (5 X 10(-7) M). When applied for 30 min in one cat caudate nucleus, somatostatin (10(-7) M) immediately increased the local release of tritiated DA, while a gradual inhibition of the tritiated amine's efflux was observed in the contralateral caudate nucleus. No changes in tritiated dopamine were seen in either substantia nigra during or after the peptide's application in the caudate nucleus. These results suggest that somatostatin in the striatum may play a role in the local and the distal control of dopamine release from the terminals of dopaminergic nigrostriatal neurons

  7. N-acetylcysteine versus Dopamine to Prevent Acute Kidney Injury after Cardiac Surgery in Patients with Preexisting Moderate Renal Insufficiency.

    Science.gov (United States)

    Savluk, Omer Faruk; Guzelmeric, Fusun; Yavuz, Yasemin; Cevirme, Deniz; Gurcu, Emre; Ogus, Halide; Orki, Tulay; Kocak, Tuncer

    2017-01-01

    Acute kidney injury after cardiac surgery is associated with mortality and morbidity. Therefore, strategies to prevent acute kidney injury are very important. The aim of this placebo-controlled randomized double-blind study was to compare the prophylactic efficacy of N-Acetylcysteine and dopamine administration in patients with pre-existing moderate renal insufficiency who were undergoing cardiopulmonary bypass. This study included 135 patients with pre-existing moderate renal insufficiency who were scheduled for coronary artery bypass grafting surgery. Serum creatinine and GFR were recorded preoperatively and on the first and second postoperative days. On the first and second postoperative days, the drugs used showed statistically significant differences among the creatinine groups (Prenal function, whereas the application of renal dose dopamine did not have a protective effect in patients with pre-existing moderate renal failure.

  8. Evaluation of nigrostriatal damage and its change over weeks in a rat model of Parkinson's disease: small animal positron emission tomography studies with [11C]β-CFT

    International Nuclear Information System (INIS)

    Liu Limin; Wang Yong; Li Bo; Jia Jun; Sun Zuoli; Zhang Jinming; Tian Jiahe; Wang Xiaomin

    2009-01-01

    Introduction: The cardinal pathological feature of Parkinson's disease (PD) is progressive loss of dopaminergic neurons. Since dopamine transporter (DAT) is a protein located presynaptically on dopaminergic nerve terminals, radioligands that bind to these sites are promising radiopharmaceuticals for evaluation of the integrity of the dopamine system. This study using positron emission tomography (PET) tracers, [ 11 C]-2β-carbomethoxy-3β-(4-fluorophenyl)-tropane ([ 11 C]β-CFT, radioligand for DAT), was aimed at evaluating the degree of nigrostriatal damage and its change over weeks in a rat model of PD. Methods: The brains of these rats were unilaterally lesioned by mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB). Behavioral studies were carried out by apomorphine (APO) challenge prior to and 1, 2 and 4 weeks after MFB axotomy. Small animal PET scans were performed 2 days after the behavioral test. Immunohistochemistry was conducted 4 days after the last PET scan. Results: Compared with the contralateral intact side, a progressively decreased [ 11 C]β-CFT binding was observed on the lesioned side which correlated inversely with the APO-induced rotations. Postmortem immunohistochemical studies confirmed the loss of both striatal dopamine fibers and nigral neurons on the lesioned side. Conclusion: These findings not only demonstrate that the neuronal degeneration in this model is relatively slow, but also suggest [ 11 C]β-CFT is a sensitive marker to monitor the degree of nigrostriatal damage and its change over weeks. This marker can be used prospectively to study the progression of the disease, thereby making detection of early phases of PD possible.

  9. Malfunctioning DNA damage response (DDR) leads to the degeneration of nigro-striatal pathway in mouse brain.

    Science.gov (United States)

    Kirshner, Michal; Galron, Ronit; Frenkel, Dan; Mandelbaum, Gil; Shiloh, Yosef; Wang, Zhao-Qi; Barzilai, Ari

    2012-03-01

    Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm-/- mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm-/- and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm-/- and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

  10. Effect of prenatal lead exposure on nigrostriatal neurotransmission and hydroxyl radical formation in rat neostriatum: Dopaminergic-nitrergic interaction

    International Nuclear Information System (INIS)

    Nowak, Przemyslaw; Szczerbak, Grazyna; Nitka, Dariusz; Kostrzewa, Richard M.; Sitkiewicz, Tomasz; Brus, Ryszard

    2008-01-01

    The present study was designed to explore the role of ontogenetic lead (Pb 2+ ) exposure on a putative dopaminergic-nitrergic interaction in the nigrostriatal pathway. Pregnant Wistar rats were given tap water containing 250-ppm lead acetate, for the duration of pregnancy, with regular tap water (without Pb 2+ ) being substituted at birth. Control rats were derived from dams that consumed tap water throughout pregnancy, and had no exposure to Pb 2+ afterwards. At 12 weeks after birth in vivo microdialysis of the neostriatum was employed to demonstrate that maternal Pb 2+ exposure was without effect on the baseline dopamine (DA) microdialysate concentration as well as amphetamine (AMPH, 1.0 mg/kg i.p.)-evoked release of striatal DA. Also, prenatal Pb 2+ exposure did not enhance AMPH- and 7-nitroindazole (neuronal nitric oxide synthase inhibitor) (7-NI, 20 mg/kg i.p.)-induced hydroxyl radical (HO·) formation in the striatum, as indicated by analysis of the salicylate spin-trap product 2,5-dihydroxybenzoic acid. However, in rats exposed prenatally to Pb 2+ , the facilitatory effect of 7-NI on DA exocytosis was attenuated. On the basis of the current study we conclude that maternal Pb 2+ exposure distorts the dopaminergic-nitrergic interaction in the nigrostriatal pathway, but without involvement of reactive oxygen species (ROS)

  11. Nigrostriatal interaction in the aging brain: new therapeutic target for Parkinson's disease.

    Science.gov (United States)

    Błaszczyk, Janusz W

    2017-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder of unclear etiology and pathogenesis. Research results gathered to date support the hypothesis that the motor symptoms of the disease result from the gradual loss of midbrain dopamine neurons residing in the substantia nigra pars compacta (SNpc). Recent discoveries, however, significantly expand this knowledge indicating that the primary source of the PD pathogenesis may be located both in the SNpc as well as in the GABAergic striatum. Newly discovered striatal neurogenesis - normally a lifelong process - determines the efficiency of nigrostriatal interaction. Deficient neurogenesis within the striatum followed by a decline in the GABAergic/dopaminergic interaction results in progressive disconnection of the dopaminergic input, which initiates a 'vicious circle' cascade of neuronal damage. Effects of both deficient striatal neurogenesis and age-related neurodegeneration within the striatum accumulate, resulting in a progressive decline in the control functions of the basal ganglia, loss of dopaminergic neurons, and occurrence of PD clinical symptoms. Functional and pharmacological control of these dynamic relationships may result in treatments that are more effective with fewer side-effects.

  12. Predictive value of the smell identification test for nigrostriatal dopaminergic depletion in Korean tremor patients.

    Science.gov (United States)

    Hong, Jin Yong; Chung, Seok Jong; Lee, Ji E; Sunwoo, Mun Kyung; Lee, Phil Hyu; Sohn, Young H

    2013-11-01

    The predictive value of Cross-Cultural Smell Identification Test for nigrostriatal dopaminergic depletion in Korean tremor patients has yet to be assessed. Three hundred nineteen drug-naive patients who visited our clinic for the diagnosis of their tremor, and took both Cross-Cultural Smell Identification Test and dopamine transporter PET were included in the data analysis. Visual grading of each PET image was performed by two independent neurologists. Smell test scores were significantly correlated to the striatal dopaminergic activity (Kendall's τb = -0.291, p smell test score alone appeared to have relatively weak power for predicting dopaminergic depletion (area under the curve = 0.693). Multivariate logistic regression model with inclusion of the patient's age and symptom duration as independent variables enhanced predictive power for dopaminergic depletion (area under the curve = 0.812). These results demonstrated that Cross-Cultural Smell Identification Test measurements alone may be insufficient to predict striatal dopaminergic depletion in Korean tremor patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

    International Nuclear Information System (INIS)

    Gallagher, G.; Brown, A.; Szabo, S.

    1987-01-01

    Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer

  14. Ibuprofen abates cypermethrin-induced expression of pro-inflammatory mediators and mitogen-activated protein kinases and averts the nigrostriatal dopaminergic neurodegeneration.

    Science.gov (United States)

    Singh, Ashish; Tripathi, Pratibha; Prakash, Om; Singh, Mahendra Pratap

    2016-12-01

    Cypermethrin induces oxidative stress, microglial activation, inflammation and apoptosis leading to Parkinsonism in rats. While ibuprofen, a non-steroidal anti-inflammatory drug, relieves from inflammation, its efficacy against cypermethrin-induced Parkinsonism has not yet been investigated. The study aimed to explore the protective role of ibuprofen in cypermethrin-induced Parkinsonism, an environmentally relevant model of Parkinson's disease (PD), along with its underlying mechanism. Animals were treated with/without cypermethrin in the presence/absence of ibuprofen. Behavioural, immunohistochemical and biochemical parameters of Parkinsonism and expression of pro-inflammatory and pro-apoptotic proteins along with mitogen-activated protein kinases (MAPKs) were determined. Ibuprofen resisted cypermethrin-induced behavioural impairments, striatal dopamine depletion, oxidative stress in the nigrostriatal tissues and loss of the nigral dopamine producing cells and increase in microglial activation along with atypical expression of pro-inflammatory and apoptotic proteins that include cyclooxygenase-2, tumour necrosis factor-α, MAPKs (c-Jun N-terminal kinase, p38 and extracellular signal-regulated kinase), B cell lymphoma 2-associated protein X, tumour suppressor protein p53, cytochrome c and caspase-3 in the nigrostriatal tissue. The results obtained thus demonstrate that ibuprofen lessens inflammation and regulates MAPKs expression thereby averts cypermethrin-induced Parkinsonism.

  15. Assessing the Role of Dopamine in Limb and Cranial-Oromotor Control in a Rat Model of Parkinson's Disease

    Science.gov (United States)

    Kane, Jacqueline R.; Ciucci, Michelle R.; Jacobs, Amber N.; Tews, Nathan; Russell, John A.; Ahrens, Allison M.; Ma, Sean T.; Britt, Joshua M.; Cormack, Lawrence K.; Schallert, Timothy

    2011-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by sensorimotor dysfunction. The neuropathology of PD includes a loss of dopamine (DA) neurons of the nigrostriatal pathway. Classic signs of the disease include rigidity, bradykinesia, and postural instability. However, as many as 90% of patients also experience…

  16. Selegiline prevents long-term changes in dopamine efflux and stress immobility during the second and third weeks of abstinence following opiate withdrawal.

    Science.gov (United States)

    Grasing, K; Ghosh, S

    1998-08-01

    Selegiline is an irreversible inhibitor of monoamine oxidase B with trophic and neuroprotective effects. Because of evidence for decreased dopaminergic function during the withdrawal syndromes associated with opiates and other medications with potential for abuse, we investigated effects of treatment with selegiline on in vitro measures of dopamine efflux following opiate withdrawal. Treatment with 2.0 mg/kg/day of selegiline did not modify the severity of opiate withdrawal, as assessed by weight loss over the first 3 days of abstinence. Opiate withdrawal increased immobility in response to a forced warm water swim test performed during the second and third weeks of abstinence following the onset of withdrawal. Brain slices obtained from the nucleus accumbens of opiate-withdrawn animals immediately following swim stress testing displayed diminished efflux of tritiated dopamine after two in vitro exposures to cocaine or amphetamine. Cocaine increases neurotransmitter efflux through blockade of dopamine reuptake, while amphetamine augments efflux by stimulating release of dopamine from intracellular storage vesicles. Although slices from opiate withdrawal subjects showed decreases in efflux after in vitro treatment with these agents, no differences were observed after exposure to 4-aminopyridine, which increases neurotransmitter release by prolonging action potential duration. These findings indicate mechanisms of action that are specific for catecholamine neurotransmitter systems are important for demonstrating long-term changes in dopaminergic function following opiate withdrawal. Selegiline prevented decreases in the efflux of tritiated dopamine in slices obtained from opiate-withdrawn subjects. In addition, selegiline decreased withdrawal-induced immobility during warm water swim testing. In conclusion, treatment with selegiline can prevent long-term changes in stress-induced immobility and deficits in presynaptic dopaminergic function that occur following the

  17. Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration.

    Science.gov (United States)

    Madhavan, Lalitha; Daley, Brian F; Davidson, Beverly L; Boudreau, Ryan L; Lipton, Jack W; Cole-Strauss, Allyson; Steece-Collier, Kathy; Collier, Timothy J

    2015-01-01

    The expression of soluble growth and survival promoting factors by neural precursor cells (NPCs) is suggested to be a prominent mechanism underlying the protective and regenerative effects of these cells after transplantation. Nevertheless, how and to what extent specific NPC-expressed factors contribute to therapeutic effects is not well understood. Using RNA silencing, the current study investigated the roles of two donor NPC molecules, namely glial cell-line derived neurotrophic factor (GDNF) and sonic hedgehog (SHH), in the protection of substantia nigra dopamine neurons in rats treated with 6-hydroxydopamine (6-OHDA). Analyses indicate that as opposed to the knock-down of GDNF, SHH inhibition caused a profound decline in nigrostriatal neuroprotection. Further, SHH silencing also curbed endogenous neurogenesis and the migration of host brdU+/dcx+ neural precursors into the striatum, which was present in the animals receiving control or GDNF silenced NPCs. A change in graft phenotype, mainly reflected by a reduced proportion of undifferentiated nestin+ cells, as well as a significantly greater host microglial activity, suggested an important role for these processes in the attenuation of neuroprotection and neurogenesis upon SHH silencing. Overall these studies reveal core mechanisms fundamental to grafted NPC-based therapeutic effects, and delineate the particular contributions of two graft-expressed molecules, SHH and GDNF, in mediating midbrain dopamine neuron protection, and host plasticity after NPC transplantation.

  18. Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Lalitha Madhavan

    Full Text Available The expression of soluble growth and survival promoting factors by neural precursor cells (NPCs is suggested to be a prominent mechanism underlying the protective and regenerative effects of these cells after transplantation. Nevertheless, how and to what extent specific NPC-expressed factors contribute to therapeutic effects is not well understood. Using RNA silencing, the current study investigated the roles of two donor NPC molecules, namely glial cell-line derived neurotrophic factor (GDNF and sonic hedgehog (SHH, in the protection of substantia nigra dopamine neurons in rats treated with 6-hydroxydopamine (6-OHDA. Analyses indicate that as opposed to the knock-down of GDNF, SHH inhibition caused a profound decline in nigrostriatal neuroprotection. Further, SHH silencing also curbed endogenous neurogenesis and the migration of host brdU+/dcx+ neural precursors into the striatum, which was present in the animals receiving control or GDNF silenced NPCs. A change in graft phenotype, mainly reflected by a reduced proportion of undifferentiated nestin+ cells, as well as a significantly greater host microglial activity, suggested an important role for these processes in the attenuation of neuroprotection and neurogenesis upon SHH silencing. Overall these studies reveal core mechanisms fundamental to grafted NPC-based therapeutic effects, and delineate the particular contributions of two graft-expressed molecules, SHH and GDNF, in mediating midbrain dopamine neuron protection, and host plasticity after NPC transplantation.

  19. Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia.

    Science.gov (United States)

    Du, Yijuan; Grace, Anthony A

    2013-09-01

    Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period.

  20. Peripubertal Diazepam Administration Prevents the Emergence of Dopamine System Hyperresponsivity in the MAM Developmental Disruption Model of Schizophrenia

    Science.gov (United States)

    Du, Yijuan; Grace, Anthony A

    2013-01-01

    Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period. PMID:23612434

  1. The Nigrostriatal Dopamine System and Methamphetamine: Roles for Excitotoxicity and Environmental, Metabolic and Oxidative Stress

    Science.gov (United States)

    2005-07-01

    nucleus of the thalamus (VM) (Somogyi et al., 1979;Bevan et al., 1994). GABA tonically inhibits GABAergic neurons in the SNr via GABA-A receptors ( Rick ...PK, Riordan DE, Heikkila RE (1991) Competitive and non- macology 110:110-114. competitive antagonists at N-methyl-D-aspartate receptors protect...receptors ( Rick and Lacey, 3) and the long-term depletions of striatal DA tissue content 1994). Additionally, intranigral activation of GABA-A receptors

  2. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Leenders, K.L.; Salmon, E.P.; Tyrrell, P.; Perani, D.; Brooks, D.J.; Sager, H.; Jones, T.; Marsden, C.D.; Frackowiak, R.S. (Hammersmith Hospital, London (England))

    1990-12-01

    A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.

  3. Angiotensin II type 2 receptor signaling affects dopamine levels in the brain and prevents binge eating disorder.

    Science.gov (United States)

    Nakaoka, Hirotomo; Mogi, Masaki; Kan-No, Harumi; Tsukuda, Kana; Ohshima, Kousei; Wang, Xiao-Li; Chisaka, Toshiyuki; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-12-01

    Binge eating disorder (BED) is associated with dopaminergic activation as food reward, resulting in metabolism-related disorders. Stimulation of angiotensin type 2 (AT2) receptor is reported to inhibit dopamine synthesis. We investigated the possible roles of AT2 receptor-mediated dopamine regulation in the pathogenesis of BED. Male C57BL/6 mice, type 2 diabetic (KKAy) mice and AT2 receptor-null (AT2KO) mice at eight weeks old were treated with AT2 receptor agonist, compound 21 (C21) or saline for two weeks. Mice were subjected to fasting for two days followed by re-feeding for seven days. Treatment with C21 attenuated the rebound proportion of body weight, food intake and water intake in KKAy mice, but not in C57BL/6 and AT2KO mice. Dopamine concentration in the striatum was further increased by fasting in KKAy and AT2KO mice. Administration of C21 significantly attenuated this fasting-induced increase in dopamine level only in KKAy mice. Dopamine receptor D1, D2 expression in the substantia nigra were markedly lower in KKAy mice compared with C57BL/6 mice, while administration of C21 increased their expression in KKAy mice. Our study suggests that AT2 receptor stimulation may be a new therapeutic approach to improve eating disorder associated with dopamine resistance. © The Author(s) 2015.

  4. Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

    Science.gov (United States)

    Laloux, C; Gouel, F; Lachaud, C; Timmerman, K; Do Van, B; Jonneaux, A; Petrault, M; Garcon, G; Rouaix, N; Moreau, C; Bordet, R; Duce, J A; Devedjian, J C; Devos, D

    2017-07-01

    In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using (123I)FP-CIT (DaTSCAN) and SPECT

    DEFF Research Database (Denmark)

    Thomsen, G; Knudsen, Gitte Moos; Jensen, PS

    2013-01-01

    BACKGROUND: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like re...

  6. Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behaviour Disorder and Parkinson Disease

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Nikolic, Miki; Biernat, Heidi

    2016-01-01

    STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown...... that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated...... in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD....

  7. Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease

    DEFF Research Database (Denmark)

    Zoetmulder, Marielle; Nikolic, Miki; Biernat, Heidi B

    2016-01-01

    STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown...... that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated......-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD....

  8. Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of ?-synuclein aggregation and programmed cell death

    OpenAIRE

    Wang, Yi-Ting; Lin, Hui-Ching; Zhao, Wei-Zhong; Huang, Hui-Ju; Lo, Yu-Li; Wang, Hsiang-Tsui; Maan-Yuh Lin, Anya

    2017-01-01

    Clinical studies report significant increases in acrolein (an ?,?-unsaturated aldehyde) in the substantia nigra (SN) of patients with Parkinson?s disease (PD). In the present study, acrolein-induced neurotoxicity in the nigrostriatal dopaminergic system was investigated by local infusion of acrolein (15, 50, 150?nmoles/0.5??l) in the SN of Sprague-Dawley rats. Acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was delineated by reductions in tyrosine hydroxylase (TH) leve...

  9. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

  10. 123-I ioflupane (Datscan) presynaptic nigrostriatal imaging in patients with movement disorders

    International Nuclear Information System (INIS)

    Soriano Castrejon, Angel; Garcia Vicente, Ana Maria; Cortes Romera, Montserrat; Rodado Marina, Sonia; Poblete Garcia, Victor Manuel; Ruiz Solis, Sebastian Ruiz; Talavera Rubio, Maria del Prado; Vaamonde Cano, Julia

    2005-01-01

    123-I Ioflupane (Datscan) presynaptic imaging has been shown to have a significant utility in the assessment of patients with movement disorders 123 I Ioflupane SPECT is able to distinguish between Parkinson's disease (PD) and other forms of parkinsonism without degeneration of the nigrostriatal pathway, including a common movement disorder such as essential tremor, and to assess disease progression in PD and other neuro degenerative disorders involving the substantia nigra. (author)

  11. Dopamine and the management of attentional resources: genetic markers of striatal D2 dopamine predict individual differences in the attentional blink.

    Science.gov (United States)

    Colzato, Lorenza S; Slagter, Heleen A; de Rover, Mischa; Hommel, Bernhard

    2011-11-01

    The attentional blink (AB)--a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters--has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested whether individual differences in the size of the AB can be predicted by differences in genetic predisposition related to the efficiency of dopaminergic pathways. Polymorphisms related to mesocortical and nigrostriatal dopaminergic pathways were considered, as well as polymorphisms related to norepinephrine (NE), a transmitter system that has also been suspected to play a role in the AB. In a sample of 157 healthy adults, we studied the dependency of the individual magnitude of the AB and the C957T polymorphism at the DRD2 gene (associated with striatal DA/D2 receptors), the DARPP32 polymorphism (associated with striatal DA/D1), the COMT Val(158)Met polymorphism (associated with frontal DA), DBH444 g/a and DBH5'-ins/del polymorphisms (polymorphisms strongly correlated with DA beta hydroxylase, the enzyme catalyzing the DA-NE conversion) and NET T-182C (a polymorphism related to the NE transporter). DRD2 C957T T/T homozygotes showed a significantly smaller AB, whereas polymorphisms associated with frontal DA and NE were unrelated to performance. This outcome pattern suggests a crucial role of the nigrostriatal dopaminergic pathway and of nigrostriatal D2 receptors, in particular, in the management of attentional resources.

  12. Effect of superficial radial nerve stimulation on the activity of nigro-striatal dopaminergic neurons in the cat: role of cutaneous sensory input

    International Nuclear Information System (INIS)

    Nieoullon, A.; Dusticier, N.

    1982-01-01

    The release of 3 H-dopamine (DA) continuously synthesized from 3 H-thyrosine was measured in the caudate nucleus (CN) and in the substantia nigra (SN) in both sides of the brain during electrical stimulation of the superficial radial nerve in cats lightly anaesthetized with halothane. Use of appropriate electrophysiologically controlled stimulation led to selective activation of low threshold afferent fibers whereas high stimulation activated all cutaneous afferents. Results showed that low threshold fiber activation induced a decreased dopaminergic activity in CN contralateral to nerve stimulation and a concomitant increase in dopaminergic activity on the ipsilateral side. Stimulation of group I and threshold stimulation of group II afferent fibers induced changes in the release of 3 H-DA mainly on the contralateral CN and SN and in the ipsilateral CN. High stimulation was followed by a general increase of the neurotransmitter release in the four structures. This shows that the nigro-striatal dopaminergic neurons are mainly-if not exclusively-controlled by cutaneous sensory inputs. This control, non-specific when high threshold cutaneous fibers are also activated. Such activations could contribute to restablish sufficient release of DA when the dopaminergic function is impaired as in Parkinson's disease. (Author)

  13. Pyrethroid pesticide-induced alterations in dopamine transporter function

    International Nuclear Information System (INIS)

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W.

    2006-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD

  14. Response of colonic motility to dopaminergic stimulation is subverted in rats with nigrostriatal lesion: relevance to gastrointestinal dysfunctions in Parkinson's disease.

    Science.gov (United States)

    Levandis, G; Balestra, B; Siani, F; Rizzo, V; Ghezzi, C; Ambrosi, G; Cerri, S; Bonizzi, A; Vicini, R; Vairetti, M; Ferrigno, A; Pastoris, O; Blandini, F

    2015-12-01

    Constipation is extremely common in patients with Parkinson's disease (PD) and has been described in PD animal models. In this study, we investigated whether a PD-like degeneration of dopaminergic neurons of the substantia nigra can influence peristalsis in colonic segments of rats by impacting on enteric dopaminergic transmission. Male, Sprague-Dawley rats received a unilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA), or saline, into the medial-forebrain-bundle. Peristaltic activity was recorded in isolated colonic segments, in baseline conditions and following exposure to combinations of D2 receptor (DRD2) agonist sumanirole and antagonist L-741626. Dopamine levels and DRD2 expression were assessed in the ileum and colon of animals. We also investigated the involvement of the dorsal motor nucleus of the vagus (DMV) - a potential relay station between central dopaminergic denervation and gastrointestinal (GI) dysfunction - by analyzing cytochrome c oxidase activity and FosB/DeltaFosB expression in DMV neurons. We observed profound alterations in the response of colonic segments of 6-OHDA lesioned animals to DRD2 stimulation. In fact, the inhibition of colonic peristalsis elicited by sumanirole in control rats was absent in 6-OHDA-lesioned animals. These animals also showed reduced DRD2 expression in the colon, along with elevation of dopamine levels. No significant changes were detected within the DMV. Our results demonstrate that selective lesion of the nigrostriatal dopaminergic pathway subverts the physiological response of the colon to dopaminergic stimulation, opening new perspectives in the comprehension and treatment of GI dysfunctions associated with PD. © 2015 John Wiley & Sons Ltd.

  15. Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.

    Science.gov (United States)

    Rodríguez-Ruiz, Mar; Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Mallol, Josefa; Cortés, Antonio; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Franco, Rafael

    2017-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D 1 , histamine H 3 , and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H 3 receptor agonists, via negative cross-talk, and H 3 receptor antagonists, via cross-antagonism, decreased D 1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D 1 receptor-mediated excitotoxic cell death. Both D 1 and H 3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D 1 -H 3 receptor heteromer function. Likely due to heteromerization, H 3 receptors act as allosteric regulator for D 1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D 1 or H 3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D 1 -H 3 -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H 3 receptor antagonists reduced NMDA or D 1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H 3 receptor antagonists reverted the toxicity induced by ß 1-42 -amyloid peptide. Thus, histamine H 3 receptors in D 1 -H 3 -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

  16. Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice.

    Science.gov (United States)

    de Theije, Caroline G M; van den Elsen, Lieke W J; Willemsen, Linette E M; Milosevic, Vanja; Korte-Bouws, Gerdien A H; Lopes da Silva, Sofia; Broersen, Laus M; Korte, S Mechiel; Olivier, Berend; Garssen, Johan; Kraneveld, Aletta D

    2015-03-01

    Allergy is suggested to exacerbate impaired behaviour in children with neurodevelopmental disorders. We have previously shown that food allergy impaired social behaviour in mice. Dietary fatty acid composition may affect both the immune and nervous system. The aim of this study was to assess the effect of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) on food allergy-induced impaired social behaviour and associated deficits in prefrontal dopamine (DA) in mice. Mice were fed either control or n-3 LCPUFA-enriched diet before and during sensitization with whey. Social behaviour, acute allergic skin response and serum immunoglobulins were assessed. Monoamine levels were measured in brain and intestine and fatty acid content in brain. N-3 LCPUFA prevented impaired social behaviour of allergic mice. Moreover, n-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation into the brain and restored reduced levels of prefrontal DA and its metabolites 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine and homovanillic acid in allergic mice. In addition to these brain effects, n-3 LCPUFA supplementation reduced the allergic skin response and restored decreased intestinal levels of serotonin metabolite 5-hydroxyindoleacetic acid in allergic mice. N-3 LCPUFA may have beneficial effects on food allergy-induced deficits in social behaviour, either indirectly by reducing the allergic response and restoring intestinal 5-HT signalling, or directly by DHA incorporation into neuronal membranes, affecting the DA system. Therefore, it is of interest to further investigate the relevance of food allergy-enhanced impairments in social behaviour in humans and the potential benefits of dietary n-3 LCPUFA supplementation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Endocannabinoid-dopamine interactions in striatal synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Brian Neil Mathur

    2012-04-01

    Full Text Available The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson’s disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder.

  18. Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

    Science.gov (United States)

    Moratalla, R; Quinn, B; DeLanney, L E; Irwin, I; Langston, J W; Graybiel, A M

    1992-01-01

    The meperidine analogue derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model of Parkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide clues to the mechanisms underlying neurodegeneration in Parkinson disease as well. Images PMID:1570304

  19. AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons: Implications for Gene Therapy and Disease Models

    Directory of Open Access Journals (Sweden)

    Katrina Albert

    2017-02-01

    Full Text Available Gene delivery using adeno-associated virus (AAV vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson′s disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson′s disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson′s disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson′s disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV-a-synuclein (a-syn to target substantia nigra dopamine neurons to produce an α-syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP, which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in

  20. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  1. Apparent opposite effects of tetrabenazine and reserpine on the toxic effects of 1-methyl-4-phenylpyridinium or 6-hydroxydopamine on nigro-striatal dopaminergic neurons.

    Science.gov (United States)

    Cleren, Carine; Naudin, Bertrand; Costentin, Jean

    2003-11-07

    It is well documented that VMAT2 protects nigrostriatal DA neurons against MPP(+) by sequestering it inside vesicles away from its mitochondrial site of neurotoxic action. However, the implication of the VMAT2 in the mechanism of action exerted by 6-OHDA has received little attention. Therefore, the aim of the present study was to determine whether the vesicular sequestration of 6-OHDA would protect dopaminergic neurons from its toxicity similarly to what is observed with MPP(+). We injected mice with 6-OHDA 90 min after TBZ treatment. Since, unexpectedly, TBZ pretreatment prevented 6-OHDA neurotoxicity, we performed a similar experience replacing 6-OHDA with MPP(+) in order to check our experimental protocol. TBZ pretreatment similarly prevented MPP(+) neurotoxicity. This discrepancy with what is commonly describe in the literature, led us to use reserpine. Indeed, the long lasting VMAT2 inhibition induced by reserpine allowed us to inject neurotoxins while mice no longer presented hypothermia. Contrary to TBZ pretreatment, reserpine pretreatment potentiated both 6-OHDA and MPP(+) toxicity on dopaminergic neurons. Hypothermia elicited by TBZ appeared to be responsible, at least in part, for the neuroprotective effect observed. To verify this hypothesis, we investigated the influence of hypothermia on the toxic activity of both neurotoxins. A hypothermia similar to that induced by TBZ was obtained by a forced swimming test of putting mice into cool water (23 degrees C). The hypothermia prevented both 6-OHDA and MPP(+)-induced neurotoxicity. We finally reported that VMAT2 inhibition potentiates both MPP(+) and 6-OHDA neurotoxicity.

  2. Glutathione S-Transferase Alpha 4 Prevents Dopamine Neurodegeneration in a Rat Alpha-Synuclein Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Michael Jewett

    2018-04-01

    SNpc compared to DA. Immunofluorescent stainings showed co-expression of Gsta4 with Gfap at 8 weeks suggesting that astrocytic expression of Gsta4 underlies Vra1-mediated neuroprotection to α-syn induced pathology. This is the second PD model in which Vra1 is linked to protection of the nigrostriatal pathway, solidifying Gsta4 as a potential therapeutic target in PD.

  3. The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism

    International Nuclear Information System (INIS)

    Booij, J.; Speelman, J.DE.; Horstink, M. W.I.M.; Wolters, E.C.

    2001-01-01

    [ 123 I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several ''presynaptic parkinsonian'' syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [ 123 I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with ''presynaptic parkinsonism'' from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [ 123 I]FP-CIT SPET. Using [ 123 I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [ 123 I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases

  4. Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.

    Directory of Open Access Journals (Sweden)

    Nicole Speed

    Full Text Available The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt involved in insulin signaling induced by exposure to a high-fat (HF diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT. Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food

  5. Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

    Science.gov (United States)

    Hutson, Che Brown; Lazo, Carlos R.; Mortazavi, Farzad; Giza, Christopher C.; Hovda, David

    2011-01-01

    Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk. PMID:21644813

  6. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    is frequently employed in cases of acute oliguric renal failure but the results available concerning the therapeutic effect are frequently retrospective and uncontrolled. The results suggest that early treatment with 1-3 micrograms/kg/min dopamine combined with furosemide can postpone or possibly render...... are possible not exclusively secondary to alterations in the renal haemodynamics but may also be due to specific tubular effects. Recent investigations have revealed that dopamine does not increase RBF and GFR in patients with chronic renal failure if GFR is less than 60 ml/minute. Dopamine in low doses......Dopamine is an endogenic catecholamine which, in addition to being the direct precursor of noradrenaline, has also an effect on peripheral dopaminergic receptors. These are localized mainly in the heart, splanchnic nerves and the kidneys. Dopamine is produced in the kidneys and the renal metabolism...

  7. Dopamine Does Not Appear to Affect Mental Rotation in Parkinson’s Disease

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    Gregory P. Crucian

    2014-10-01

    Full Text Available ObjectivePatients with Parkinson’s disease (PD often have deficits with mental rotation (MR. The neuropathological factors underlying these deficits, however, remain to be elucidated. One hypothesis suggests that dopamine depletion in nigro-striatal systems adversely influences MR. Another hypothesis suggests that deterioration of cortical (fronto-temporo-parietal basal ganglia networks that mediate this function are responsible for this deficit. The goal of this study was to test the dopamine hypothesis by determining if dopamine abstinence negatively influences MR performance. MethodsThirty three non-demented right-handed individuals with PD were assess for their ability to perform a pencil and paper MR test while “on” and “off” dopaminergic medications. Dopamine abstinence followed the typical overnight withdrawal procedures. ResultsNo differences in mental rotation abilities were found between “on” and “off” dopaminergic medications. ConclusionsThese results suggest that other neuropathological factors, such as cortical-basal ganglia neurodegeneration, or dysfunction of other neurotransmitters systems, might account for these cognitive deficits and future research will have to test these alternative hypotheses.

  8. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

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    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  9. Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ss-CIT and high-resolution SPET

    International Nuclear Information System (INIS)

    Barthel, H.; Sorger, D.; Kluge, R.; Kuehn, H.-J.; Wagner, A.; Hermann, W.

    2001-01-01

    Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ss-carbomethoxy-3ss-(4[ 123 I]iodophenyl)tropane ([ 123 I]ss-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [ 123 I]ss-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [ 123 I]ss-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [ 123 I]ss-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4±3.0 vs 11.7±2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [ 123 I]ss-CIT binding ratios from pseudo-sclerosis CD (9.4±2.3), through pseudo-parkinsonian CD (9.1±2.1) to arrhythmic-hyperkinetic CD (8.5±1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30±0.19 vs 1.11±0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [ 123 I]ss-CIT binding ratios (r=-0.49 to -0

  10. 123-I ioflupane (Datscan® presynaptic nigrostriatal imaging in patients with movement disorders

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    Angel Soriano Castrejón

    2005-10-01

    Full Text Available 123-I Ioflupane (Datscan® presynaptic imaging has been shown to have a significant utility in the assessment of patients with movement disorders 123-I Ioflupane SPECT is able to distinguish between Parkinson’s disease (PD and other forms of parkinsonism without degeneration of the nigrostriatal pathway, including a common movement disorder such as essential tremor, and to assess disease progression in PD and other neurodegenerative disorders involving the substantia nigra.A imagem pré-sináptica através de 123-I Ioflupane (Datscan® tem mostrado um papel significante na avaliação de pacientes com distúrbios do movimento. 123-I Ioflupane SPECT é capaz de distinguir entre Mal de Parkinson (MP e outras formas de parkinsonismo sem degenerações da via nigroestriatal incluindo um distúrbio comum de movimento parecido com o tremor essencial e para medir a evolução da doença no Mal de Parkinson e outros distúrbios neurodegenerativos envolvendo a substantia nigra.

  11. Dopamine in heart failure and critical care

    NARCIS (Netherlands)

    Smit, AJ

    Dopamine is widely used in critical care to prevent renal function loss. Nevertheless sufficient evidence is still lacking of reduction in end points like mortality or renal replacement therapy. Dopaminergic treatment in chronic heart failure (CHF) has provided an example of unexpected adverse

  12. Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Rajib Paul

    Full Text Available Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

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

    Science.gov (United States)

    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. Copyright © 2014 the authors 0270-6474/14/3414769-08$15.00/0.

  14. Dopamine, psychosis and schizophrenia

    DEFF Research Database (Denmark)

    Kesby, J P; Eyles, D W; McGrath, J J

    2018-01-01

    The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic...... dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function...... in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve...

  15. Dopamine transporter imaging in the aged rat: a [123I]FP-CIT SPECT study

    International Nuclear Information System (INIS)

    Niñerola-Baizán, Aida; Rojas, Santiago; Roé-Vellvé, Núria; Lomeña, Francisco; Ros, Domènec

    2015-01-01

    Introduction: Rodent models are extensively used to assess the biochemical and physiological changes associated with aging. They play a major role in the development of therapies for age-related pathologies such as Parkinson's disease. To validate the usefulness of these animal models in aging or age-related disease research, the consistency of cerebral aging processes across species must be evaluated. The dopaminergic system seems particularly susceptible to the aging process. One of the results of this susceptibility is a decline in striatal dopamine transporter (DAT) availability. Methods: We sought to ascertain whether similar age changes could be detected in-vivo in rats, using molecular imaging techniques such as single photon emission computed tomography (SPECT) with [ 123 I]FP-CIT. Results: A significant decrease of 17.21% in the striatal specific uptake ratio was observed in the aged rats with respect to the young control group. Conclusions: Our findings suggest that age-related degeneration in the nigrostriatal track is similar in humans and rats, which supports the use of this animal in models to evaluate the effect of aging on the dopaminergic system. Advances in Knowledge and Implications for patient Care: Our findings indicate that age-related degeneration in the nigrostriatal track is similar in humans and rats and that these changes can be monitored in vivo using small animal SPECT with [ 123 I]FP-CIT, which could facilitate the translational research in rat models of age related disorders of dopaminergic system

  16. Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder.

    Science.gov (United States)

    Ellmore, Timothy M; Castriotta, Richard J; Hendley, Katie L; Aalbers, Brian M; Furr-Stimming, Erin; Hood, Ashley J; Suescun, Jessika; Beurlot, Michelle R; Hendley, Roy T; Schiess, Mya C

    2013-12-01

    Rapid eye movement sleep behavior disorder (RBD) is a condition closely associated with Parkinson disease (PD). RBD is a sleep disturbance that frequently manifests early in the development of PD, likely reflecting disruption in normal functioning of anatomical areas affected by neurodegenerative processes. Although specific neuropathological aspects shared by RBD and PD have yet to be fully documented, further characterization is critical to discovering reliable biomarkers that predict PD onset. In the current study, we tested the hypothesis of altered functional connections of the substantia nigra (SN) in patients in whom RBD was diagnosed. Between-groups, single time point imaging. UTHSC-H 3 telsa MRI center. Ten patients with RBD, 11 patients with PD, and 10 age-matched controls. NA. We measured correlations of SN time series using resting state blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in patients with idiopathic RBD who were at risk for developing PD, patients in whom PD was diagnosed, and age-matched controls. Using voxelwise analysis of variance, different correlations (P < 0.01, whole-brain corrected) between left SN and left putamen were found in patients with RBD compared with controls and patients with PD. SN correlations with right cuneus/precuneus and superior occipital gyrus were significantly different for patients with RBD compared with both controls and patients with PD. The results suggest that altered nigrostriatal and nigrocortical connectivity characterizes rapid eye movement sleep behavior disorder before onset of obvious motor impairment. The functional changes are discussed in the context of degeneration in dopaminergic and cognition-related networks.

  17. Metabolism of Dopamine in Nucleus Accumbens Astrocytes Is Preserved in Aged Mice Exposed to MPTP

    Directory of Open Access Journals (Sweden)

    Brittany M. Winner

    2017-12-01

    Full Text Available Parkinson disease (PD is prevalent in elderly individuals and is characterized by selective degeneration of nigrostriatal dopamine (NSDA neurons. Interestingly, not all dopamine (DA neurons are affected equally by PD and aging, particularly mesolimbic (ML DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA neurons and astrocyte DA metabolism. There were no differences in phenotypic markers of DA synthesis, reuptake or metabolism in NSDA or MLDA neurons in aged mice, but MLDA neurons displayed lower DA stores. Astrocyte metabolism of DA to 3-methoxytyramine (3-MT in the striatum was decreased in aged mice, but was maintained in the nucleus accumbens. Despite diminished DA vesicular storage capacity in MLDA neurons, susceptibility to acute neurotoxicant exposure was similar in young and aged mice. These results reveal an age- and neurotoxicant-induced impairment of DA metabolic activity in astrocytes surrounding susceptible NSDA neurons as opposed to maintenance of DA metabolism in astrocytes surrounding resistant MLDA neurons, and suggest a possible therapeutic target for PD.

  18. Ectopic pregnancy-derived human trophoblastic stem cells regenerate dopaminergic nigrostriatal pathway to treat parkinsonian rats.

    Directory of Open Access Journals (Sweden)

    Tony Tung-Yin Lee

    Full Text Available BACKGROUND: Stem cell therapy is a potential strategy to treat patients with Parkinson's disease (PD; however, several practical limitations remain. As such, finding the appropriate stem cell remains the primary issue in regenerative medicine today. We isolated a pre-placental pluripotent stem cell from the chorionic villi of women with early tubal ectopic pregnancies. Our objectives in this study were (i to identify the characteristics of hTS cells as a potential cell source for therapy; and (ii to test if hTS cells can be used as a potential therapeutic strategy for PD. METHODS AND FINDINGS: hTS cells expressed gene markers of both the trophectoderm (TE and the inner cell mass (ICM. hTS cells exhibited genetic and biological characteristics similar to that of hES cells, yet genetically distinct from placenta-derived mesenchymal stem cells. All-trans retinoic acid (RA efficiently induced hTS cells into trophoblast neural stem cells (tNSCs in 1-day. Overexpression of transcription factor Nanog was possibly achieved through a RA-induced non-genomic c-Src/Stat3/Nanog signaling pathway mediated by the subcellular c-Src mRNA localization for the maintenance of pluripotency in tNSCs. tNSC transplantation into the lesioned striatum of acute and chronic PD rats not only improved behavioral deficits but also regenerated dopaminergic neurons in the nigrostriatal pathway, evidenced by immunofluorescent and immunohistological analyses at 18-weeks. Furthermore, tNSCs showed immunological advantages for the application in regenerative medicine. CONCLUSIONS: We successfully isolated and characterized the unique ectopic pregnancy-derived hTS cells. hTS cells are pluripotent stem cells that can be efficiently induced to tNSCs with positive results in PD rat models. Our data suggest that the hTS cell is a dynamic stem cell platform that is potentially suitable for use in disease models, drug discovery, and cell therapy such as PD.

  19. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson's disease

    DEFF Research Database (Denmark)

    Winge, K; Friberg, L; Werdelin, L

    2005-01-01

    Patients with Parkinson's disease (PD) often have lower urinary tract symptoms (LUTS). Studies have indicated a correlation between dopaminergic degeneration and LUTS and presence of overactive bladder. We evaluated 18 patients with Parkinson's disease using single-photon emission computerized....... The effects of medication on bladder control, as evaluated by urodynamics are believed to involve structures outside the basal ganglia....... tomography (SPECT) imaging of the dopamine transporter with [(123)I]-FP-CIT, and bladder symptoms were assessed using questionnaires and full urodynamic evaluation both in medicated state and after cessation. Bladder symptoms correlated with age, stage and severity of disease but not with uptake...

  20. Dopamine Modulates Serotonin Innervation in the Drosophila Brain

    Directory of Open Access Journals (Sweden)

    Janna Niens

    2017-10-01

    Full Text Available Parkinson’s disease (PD results from a progressive degeneration of the dopaminergic nigrostriatal system leading to a decline in movement control, with resting tremor, rigidity and postural instability. Several aspects of PD can be modeled in the fruit fly, Drosophila melanogaster, including α-synuclein-induced degeneration of dopaminergic neurons, or dopamine (DA loss by genetic elimination of neural DA synthesis. Defective behaviors in this latter model can be ameliorated by feeding the DA precursor L-DOPA, analogous to the treatment paradigm for PD. Secondary complication from L-DOPA treatment in PD patients are associated with ectopic synthesis of DA in serotonin (5-HT-releasing neurons, leading to DA/5-HT imbalance. Here we examined the neuro-anatomical adaptations resulting from imbalanced DA/5-HT signaling in Drosophila mutants lacking neural DA. We find that, similar to rodent models of PD, lack of DA leads to increased 5-HT levels and arborizations in specific brain regions. Conversely, increased DA levels by L-DOPA feeding leads to reduced connectivity of 5-HT neurons to their target neurons in the mushroom body (MB. The observed alterations of 5-HT neuron plasticity indicate that loss of DA signaling is not solely responsible for the behavioral disorders observed in Drosophila models of PD, but rather a combination of the latter with alterations of 5-HT circuitry.

  1. Dopamine transporter imaging in rapid eye movement sleep behavior disorder

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease.

  2. Dopamine transporter imaging in rapid eye movement sleep behavior disorder

    International Nuclear Information System (INIS)

    Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun

    2007-01-01

    The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease

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

    Science.gov (United States)

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

    2013-01-01

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

  4. Dopamine and anorexia nervosa.

    Science.gov (United States)

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

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    is frequently employed in cases of acute oliguric renal failure but the results available concerning the therapeutic effect are frequently retrospective and uncontrolled. The results suggest that early treatment with 1-3 micrograms/kg/min dopamine combined with furosemide can postpone or possibly render...

  6. Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence

    OpenAIRE

    Lohoff, Falk W.; Bloch, Paul J.; Ferraro, Thomas N.; Berrettini, Wade H.; Pettinati, Helen M.; Dackis, Charles A.; O’Brien, Charles P.; Kampman, Kyle M.; Oslin, David W.

    2009-01-01

    Cocaine induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neu...

  7. Firing properties of dopamine neurons in freely moving dopamine-deficient mice: Effects of dopamine receptor activation and anesthesia

    OpenAIRE

    Robinson, Siobhan; Smith, David M.; Mizumori, Sheri J. Y.; Palmiter, Richard D.

    2004-01-01

    To examine the regulation of midbrain dopamine neurons, recordings were obtained from single neurons of freely moving, genetically engineered dopamine-deficient (DD) mice. DD mice were tested without dopamine signaling (basal state) and with endogenous dopamine signaling (after L-dopa administration). In the basal state, when dopamine concentration in DD mice is

  8. Effects of zoxazolamine and related centrally acting muscle relaxants on nigrostriatal dopaminergic neurons.

    Science.gov (United States)

    Matthews, R T; McMillen, B A; Speciale, S G; Jarrah, H; Shore, P A; Sanghera, M K; Shepard, P D; German, D C

    1984-05-01

    The effects of zoxazolamine (ZOX) and related centrally acting muscle relaxants on striatal dopamine (DA) metabolism and turnover, and substantia nigra zona compacta DA neuronal impulse flow were studied in rats. ZOX, chlorzoxazone and mephenesin, but not meprobamate, chloral hydrate, diazepam, pentobarbital, ethanol or dantrolene, decreased striatal DA metabolism without affecting striatal DA concentrations. More specifically, ZOX, as a representative muscle relaxant, was shown to decrease striatal DA turnover without directly affecting DA synthesis, catabolism, reuptake, or release. ZOX decreased nigral DA neuronal firing rates and dramatically decreased firing rate variability (normally many of the cells fire with bursting firing patterns but after ZOX the cells often fired with a very regular pacemaker-like firing pattern). ZOX and related centrally acting muscle relaxants appear to decrease striatal DA turnover by decreasing both neuronal firing rate and firing rate variability. The possible relationships between DA neuronal activity and muscle tone are discussed.

  9. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    Science.gov (United States)

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  10. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

    Science.gov (United States)

    Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

    2018-01-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  11. Widespread increases in malondialdehyde immunoreactivity in dopamine-rich and dopamine-poor regions of rat brain following multiple, high doses of methamphetamine.

    Directory of Open Access Journals (Sweden)

    Kristen Ashley eHorner

    2011-05-01

    Full Text Available Treatment with multiple high doses of methamphetamine (METH can induce oxidative damage, including dopamine (DA-mediated reactive oxygen species (ROS formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu and substantia nigra pars compacta (SNpc. Malondialdehyde (MDA, a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg every 2h for 6h, sacrificed one week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir in the CPu, SNpc, cortex and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area (VTA and nucleus accumbens (NAc. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system.

  12. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

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

  13. The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Walters, Jennifer L.; Lansdell, Theresa A.; Lookingland, Keith J.; Baker, Lisa E.

    2015-01-01

    This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. - Highlights: • Male rats received gestational and chronic exposure to ATZ (10 mg/kg and 100 μg/kg). • ATZ altered locomotor activity and impaired motor coordination. • ATZ lowered striatal DA and DOPAC concentrations. • ATZ produced a potential anxiogenic effect. • ATZ did not impair performance in learning and memory assessments.

  14. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

    Science.gov (United States)

    Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin A; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2012-07-04

    Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.

  15. Growth of dopamine crystals

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-05-06

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

  16. Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers

    DEFF Research Database (Denmark)

    Rademacher, Lena; Prinz, Susanne; Winz, Oliver

    2016-01-01

    putamen of consuming smokers. CONCLUSIONS: The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention...

  17. Genetics Home Reference: dopamine transporter deficiency syndrome

    Science.gov (United States)

    ... Twitter Home Health Conditions Dopamine transporter deficiency syndrome Dopamine transporter deficiency syndrome Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

  18. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  19. Fluorescent light induces neurodegeneration in the rodent nigrostriatal system but near infrared LED light does not.

    Science.gov (United States)

    Romeo, Stefania; Vitale, Flora; Viaggi, Cristina; di Marco, Stefano; Aloisi, Gabriella; Fasciani, Irene; Pardini, Carla; Pietrantoni, Ilaria; Di Paolo, Mattia; Riccitelli, Serena; Maccarone, Rita; Mattei, Claudia; Capannolo, Marta; Rossi, Mario; Capozzo, Annamaria; Corsini, Giovanni U; Scarnati, Eugenio; Lozzi, Luca; Vaglini, Francesca; Maggio, Roberto

    2017-05-01

    We investigated the effects of continuous artificial light exposure on the mouse substantia nigra (SN). A three month exposure of C57Bl/6J mice to white fluorescent light induced a 30% reduction in dopamine (DA) neurons in SN compared to controls, accompanied by a decrease of DA and its metabolites in the striatum. After six months of exposure, neurodegeneration progressed slightly, but the level of DA returned to the basal level, while the metabolites increased with respect to the control. Three month exposure to near infrared LED light (∼710nm) did not alter DA neurons in SN, nor did it decrease DA and its metabolites in the striatum. Furthermore mesencephalic cell viability, as tested by [ 3 H]DA uptake, did not change. Finally, we observed that 710nm LED light, locally conveyed in the rat SN, could modulate the firing activity of extracellular-recorded DA neurons. These data suggest that light can be detrimental or beneficial to DA neurons in SN, depending on the source and wavelength. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Molecular players in the development and maintenance of mesencephalic dopamine systems.

    Science.gov (United States)

    Burbach, J P; Cazorla, P; Smidt, M P

    1999-06-01

    Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies.

  1. In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

    Science.gov (United States)

    Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

    2012-12-16

    Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

  2. Photoaffinity ligand for dopamine D2 receptors: azidoclebopride

    International Nuclear Information System (INIS)

    Niznik, H.B.; Guan, J.H.; Neumeyer, J.L.; Seeman, P.

    1985-01-01

    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 [ 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

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

    Science.gov (United States)

    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

  4. Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine.

    Science.gov (United States)

    Zhang, K; Weiss, N T; Tarazi, F I; Kula, N S; Baldessarini, R J

    1999-11-13

    Dopamine D(3) receptors are structurally highly homologous to other D(2)-like dopamine receptors, but differ from them pharmacologically. D(3) receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D(2) receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D(2)-like receptor alkylating agent, for effects on D(3) and D(2) receptors in rat brain using autoradiographic analysis. Neither agent occluded D(3) receptors in vivo at doses that produced substantial blockade of D(2) receptors, even after catecholamine-depleting pretreatments. In vitro, however, D(3) receptors were readily alkylated by both NIPS (IC(50)=40 nM) and EEDQ (IC(50)=12 microM). These effects on D(3) sites were blocked by nM concentrations of dopamine, whereas microM concentrations were required to protect D(2) receptors from the alkylating agents. The findings are consistent with the view that alkylation of D(3) receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.

  5. SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

    Science.gov (United States)

    DeLorenzo, Christine; Lichenstein, Sarah; Schaefer, Karen; Dunn, Judith; Marshall, Randall; Organisak, Lisa; Kharidia, Jahnavi; Robertson, Brigitte; Mann, J John; Parsey, Ramin V

    2011-07-01

    SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about

  6. Dopamine and glucose, obesity and Reward Deficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Kenneth eBlum

    2014-09-01

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

  7. Brain perfusion correlates of cognitive and nigrostriatal functions in de novo Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Nobili, Flavio; Arnaldi, Dario; Campus, Claudio; Ferrara, Michela; Brugnolo, Andrea; Dessi, Barbara; Girtler, Nicola; Rodriguez, Guido [University of Genoa, Clinical Neurophysiology, Department of Neurosciences, Ophthalmology and Genetics, Genoa (Italy); De Carli, Fabrizio [National Research Council, Institute of Molecular Bioimaging and Physiology, Genoa (Italy); Morbelli, Silvia; Sambuceti, Gianmario [University of Genoa, Nuclear Medicine, Department of Internal Medicine, Genoa (Italy); Abruzzese, Giovanni [University Hospital San. Martino, Clinical Neurology, Department of Neurosciences, Ophthalmology and Genetics, Genoa (Italy)

    2011-12-15

    Subtle cognitive impairment is recognized in the first stages of Parkinson's disease (PD), including executive, memory and visuospatial dysfunction, but its pathophysiological basis is still debated. Twenty-six consecutive, drug-naive, de novo PD patients underwent an extended neuropsychological battery, dopamine transporter (DAT) and brain perfusion single photon emission computed tomography (SPECT). We previously reported that nigrocaudate impairment correlates with executive functions, and nigroputaminal impairment with visuospatial abilities. Here perfusion SPECT was first compared between the PD group and age-matched controls (CTR). Then, perfusion SPECT was correlated with both DAT SPECT and four neuropsychological factors by means of voxel-based analysis (SPM8) with a height threshold of p < 0.005 at peak level and p < 0.05 false discovery rate-corrected at cluster level. Both perfusion and DAT SPECT images were flipped in order to have the more affected hemisphere (MAH), defined clinically, on the same side. Significant hypoperfusion was found in an occipital area of the MAH in PD patients as compared to CTR. Executive functions directly correlated with brain perfusion in bilateral posterior cingulate cortex and precuneus in the less affected hemisphere (LAH), while verbal memory directly correlated with perfusion in the precuneus, inferior parietal lobule and superior temporal gyrus in the LAH. Furthermore, positive correlation was highlighted between nigrocaudate and nigroputaminal impairment and brain perfusion in the precuneus, posterior cingulate and parahippocampal gyri of the LAH. These data support the evidence showing an early involvement of the cholinergic system in the early cognitive dysfunction and point to a more relevant role of parietal lobes and posterior cingulate in executive functions in PD. (orig.)

  8. Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice

    Directory of Open Access Journals (Sweden)

    Wang Qingshan

    2012-06-01

    Full Text Available Abstract Background The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo. Methods 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and methamphetamine (MA, two commonly used neurotoxins in rodent models of Parkinson’s disease, were administered to wild-type (Dyn+/+ and prodynorphin-deficient mice (Dyn−/−. We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR. Results Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn-l- than in Dyn+/+. Dyn−/− showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn+/+. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn−/− than in Dyn+/+. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn−/− than in Dyn+/+. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP. Conclusions The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects.

  9. Brain perfusion correlates of cognitive and nigrostriatal functions in de novo Parkinson's disease

    International Nuclear Information System (INIS)

    Nobili, Flavio; Arnaldi, Dario; Campus, Claudio; Ferrara, Michela; Brugnolo, Andrea; Dessi, Barbara; Girtler, Nicola; Rodriguez, Guido; De Carli, Fabrizio; Morbelli, Silvia; Sambuceti, Gianmario; Abruzzese, Giovanni

    2011-01-01

    Subtle cognitive impairment is recognized in the first stages of Parkinson's disease (PD), including executive, memory and visuospatial dysfunction, but its pathophysiological basis is still debated. Twenty-six consecutive, drug-naive, de novo PD patients underwent an extended neuropsychological battery, dopamine transporter (DAT) and brain perfusion single photon emission computed tomography (SPECT). We previously reported that nigrocaudate impairment correlates with executive functions, and nigroputaminal impairment with visuospatial abilities. Here perfusion SPECT was first compared between the PD group and age-matched controls (CTR). Then, perfusion SPECT was correlated with both DAT SPECT and four neuropsychological factors by means of voxel-based analysis (SPM8) with a height threshold of p < 0.005 at peak level and p < 0.05 false discovery rate-corrected at cluster level. Both perfusion and DAT SPECT images were flipped in order to have the more affected hemisphere (MAH), defined clinically, on the same side. Significant hypoperfusion was found in an occipital area of the MAH in PD patients as compared to CTR. Executive functions directly correlated with brain perfusion in bilateral posterior cingulate cortex and precuneus in the less affected hemisphere (LAH), while verbal memory directly correlated with perfusion in the precuneus, inferior parietal lobule and superior temporal gyrus in the LAH. Furthermore, positive correlation was highlighted between nigrocaudate and nigroputaminal impairment and brain perfusion in the precuneus, posterior cingulate and parahippocampal gyri of the LAH. These data support the evidence showing an early involvement of the cholinergic system in the early cognitive dysfunction and point to a more relevant role of parietal lobes and posterior cingulate in executive functions in PD. (orig.)

  10. Prevention

    Science.gov (United States)

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  11. Dopamine Oxidation and Autophagy

    Directory of Open Access Journals (Sweden)

    Patricia Muñoz

    2012-01-01

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

  12. Nigrostriatal dynein changes in A53T alpha-synuclein transgenic mice [v1; ref status: indexed, http://f1000r.es/2wb

    Directory of Open Access Journals (Sweden)

    Yan Liu

    2014-03-01

    Full Text Available The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson’s disease (PD and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.

  13. Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT.

    Science.gov (United States)

    Zabelina, Darya L; Colzato, Lorenza; Beeman, Mark; Hommel, Bernhard

    2016-01-01

    The dopaminergic (DA) system may be involved in creativity, however results of past studies are mixed. We attempted to clarify this putative relation by considering the mediofrontal and the nigrostriatal DA pathways, uniquely and in combination, and their contribution to two different measures of creativity--an abbreviated version of the Torrance Test of Creative Thinking, assessing divergent thinking, and a real-world creative achievement index. We found that creativity can be predicted from interactions between genetic polymorphisms related to frontal (COMT) and striatal (DAT) DA pathways. Importantly, the Torrance test and the real-world creative achievement index related to different genetic patterns, suggesting that these two measures tap into different aspects of creativity, and depend on distinct, but interacting, DA sub-systems. Specifically, we report that successful performance on the Torrance test is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control, or with weak cognitive flexibility and strong top-down control. The latter is particularly true for the originality factor of divergent thinking. High real-world creative achievement, on the other hand, as assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control. Taken altogether, our findings support the idea that human creativity relies on dopamine, and on the interaction between frontal and striatal dopaminergic pathways in particular. This interaction may help clarify some apparent inconsistencies in the prior literature, especially if the genes and/or creativity measures were analyzed separately.

  14. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.

    Directory of Open Access Journals (Sweden)

    Pabla Aguirre

    Full Text Available Neuronal death in Parkinson's disease (PD is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.

  15. Electrophysiological and pharmacological evidence for the existence of distinct subpopulations of nigrostriatal dopaminergic neuron in the rat.

    Science.gov (United States)

    Shepard, P D; German, D C

    1988-11-01

    The electrophysiological and pharmacological properties of dopaminergic neurons were systematically examined throughout the anterior-posterior extent of the substantia nigra zona compacta in the rat. Cells were characterized in terms of their (1) firing pattern, (2) firing rate, (3) antidromic response properties, and (4) inhibition in firing rate following dopaminergic agonist administration. These properties were then related to the cell's position within one of four anterior-posterior segments of the nucleus. There were three types of neuronal discharge pattern encountered; irregular, burst and regular. Cells which exhibited different firing patterns exhibited different firing rates and anatomical locations within the substantia nigra zona compacta. All neurons were antidromically activated from the striatum, however, the burst- and regular-firing cells exhibited significantly faster estimated conduction velocities than irregular-firing cells. The irregular-firing cells were most sensitive to dopaminergic autoreceptor agonists whereas the burst-firing cells were most sensitive to an indirect-acting dopaminergic agonist. These experiments provide both electrophysiological and pharmacological evidence to indicate that nigrostriatal dopaminergic neurons are composed of distinct subpopulations which are characterized by their firing pattern.

  16. Dopamine signaling: target in glioblastoma

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  17. Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish.

    Directory of Open Access Journals (Sweden)

    Tianna Zhao

    Full Text Available Recessive mutations in the F-box only protein 7 gene (FBXO7 cause PARK15, a mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7 is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively, to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia, which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic

  18. Prevention

    Science.gov (United States)

    ... Contact Aging & Health A to Z Find a Geriatrics Healthcare Professional Medications & Older Adults Making Your Wishes ... Prevention Hearing Loss Heart Attack High Blood Pressure Nutrition Osteoporosis Shingles Skin Cancer Related News Quitting Smoking, ...

  19. Sleep attacks in patients taking dopamine agonists: review.

    Science.gov (United States)

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-06-22

    To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information.

  20. Prevention

    DEFF Research Database (Denmark)

    Halken, S; Høst, A

    2001-01-01

    , breastfeeding should be encouraged for 4-6 months. In high-risk infants a documented extensively hydrolysed formula is recommended if exclusive breastfeeding is not possible for the first 4 months of life. There is no evidence for preventive dietary intervention neither during pregnancy nor lactation...... populations. These theories remain to be documented in proper, controlled and prospective studies. Breastfeeding and the late introduction of solid foods (>4 months) is associated with a reduced risk of food allergy, atopic dermatitis, and recurrent wheezing and asthma in early childhood. In all infants....... Preventive dietary restrictions after the age of 4-6 months are not scientifically documented....

  1. A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935

    Directory of Open Access Journals (Sweden)

    Helga eHöifödt Lidö

    2011-03-01

    Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.

  2. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    Full Text Available Dopamine is one of the principal neurotransmitters in the central nervous system (CNC, and its neuronal pathways are involved in several key functions such as behavior (Hefco et al., 2003a,b, control of movement, endocrine regulation, immune response (Fiserova et al., 2002; Levite et al., 2001, Hritcu et al., 2006a,b,c, and cardiovascular function. Dopamine has at least five G-protein, coupled receptor subtypes, D1-D5, each arising from a different gene (Sibley et al., 1993. Traditionally, these receptors have been classified into D1-like (the D1 and D5 and D2-like (D2, D3 and D4 receptors subtypes, primarily according to their ability to stimulate or inhibit adenylate cyclase, respectively, and to their pharmacological characteristics (Seeman et al., 1993. Receptors for dopamine (particularly of D2 subclass are the primary therapeutic target in a number of neuropathological disorders including schizophrenia, Parkinson’s disease and Huntington’s chorea (Seeman et al., 1987. Neither dopamine by itself, nor dopaminergic agonists by themselves, has been shown to activate T cell function. Nevertheless, lymphocytes are most probably exposed to dopamine since the primary and secondary lymphoid organs of various mammals are markedly innervated, and contain nerve fibers which stain for tyrosine hydroxylase (Weihe et al., 1991, the enzyme responsible for dopamine synthesis. Moreover, cathecolamines and their metabolites are present in single lymphocytes and in extracts of T and B cell clones, and pharmacological inhibition of tyrosine hydroxylase reduces catecholamine levels, suggesting catecholamine synthesis by lymphocytes (Bergquist et al., 1994. The existence of putative dopamine receptors of D2, D3, D4 and D5 subtypes on immune cells has been proposed of several authors, primarily on the basis of dopaminergic ligand binding assays and specific mRNA expression as monitored by reverse transcription-PCR. Several experiments evoked the idea of a

  3. Dopamine agonists and Othello's syndrome

    Science.gov (United States)

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  4. Behavioural effects of chemogenetic dopamine neuron activation

    NARCIS (Netherlands)

    Boekhoudt, L

    2016-01-01

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

  5. Molecular Mechanisms of Dopamine Receptor Mediated Neuroprotection

    National Research Council Canada - National Science Library

    Sealfon, Stuart

    2000-01-01

    ... of the cellular changes characteristic of this process. Evidence from our laboratory and others suggest that activation of dopamine receptors can oppose the induction of apoptosis in dopamine neurons...

  6. Dopamine, reward learning, and active inference

    Directory of Open Access Journals (Sweden)

    Thomas eFitzgerald

    2015-11-01

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

  7. Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice.

    Directory of Open Access Journals (Sweden)

    Nicola J Platt

    Full Text Available Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn, cause familial Parkinson's disease (PD. Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction.

  8. Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine.

    Science.gov (United States)

    Gomez-A, Alexander; Fiorenza, Amanda M; Boschen, Suelen L; Sugi, Adam H; Beckman, Danielle; Ferreira, Sergio T; Lee, Kendall; Blaha, Charles D; Da Cunha, Claudio

    2017-02-15

    Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

  9. Dopamine agents for hepatic encephalopathy

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...

  10. Subsecond dopamine release promotes cocaine seeking.

    Science.gov (United States)

    Phillips, Paul E M; Stuber, Garret D; Heien, Michael L A V; Wightman, R Mark; Carelli, Regina M

    2003-04-10

    The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signalling, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.

  11. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

    Science.gov (United States)

    Murphy, B L; Arnsten, A F; Goldman-Rakic, P S; Roth, R H

    1996-01-01

    The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex. PMID:8577763

  12. Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.

    Science.gov (United States)

    Muralikrishnan, Dhanasekaran; Ebadi, Manuchair; Brown-Borg, Holly M

    2004-02-01

    We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

  15. Dopamine infusion for postresuscitation blood pressure support after profound asphyxia in near-term fetal sheep.

    Science.gov (United States)

    Drury, Paul P; Booth, Lindsea C; Bennet, Laura; Davidson, Joanne O; Wibbens, Bert; Gunn, Alistair Jan

    2013-03-01

    Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122-129 days of gestation; term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 μg kg(-1) min(-1) and titrated according to mean arterial blood pressure up to a maximum of 40 μg kg(-1) min(-1) (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96-280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240-715) versus 106 min (range 23-497) after the start of infusions, P < 0.05]. In conclusion, dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia.

  16. Increased brain dopamine and dopamine receptors in schizophrenia

    International Nuclear Information System (INIS)

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

    1982-01-01

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

  17. Peripheral Dopamine in Restless Legs Syndrome

    Directory of Open Access Journals (Sweden)

    Ulrike H. Mitchell

    2018-03-01

    Full Text Available Objective/BackgroundRestless Legs Syndrome (RLS is a dopamine-dependent disorder characterized by a strong urge to move. The objective of this study was to evalulate blood levels of dopamine and other catecholamines and blood D2-subtype dopamine receptors (D2Rs in RLS.Patients/MethodsDopamine levels in blood samples from age-matched unmedicated RLS subjects, medicated RLS subjects and Controls were evaluated with high performance liquid chromatography and dopamine D2R white blood cell (WBC expression levels were determined with fluorescence-activated cell sorting and immunocytochemistry.ResultsBlood plasma dopamine levels, but not norepinepherine or epinephrine levels, were significantly increased in medicated RLS subjects vs unmedicated RLS subjects and Controls. The percentage of lymphocytes and monocytes expressing D2Rs differed between Control, RLS medicated and RLS unmedicated subjects. Total D2R expression in lymphocytes, but not monocytes, differed between Control, RLS medicated and RLS unmedicated subjects. D2Rs in lymphocytes, but not monocytes, were sensitive to dopamine in Controls only.ConclusionDownregulation of WBCs D2Rs occurs in RLS. This downregulation is not reversed by medication, although commonly used RLS medications increase plasma dopamine levels. The insensitivity of monocytes to dopamine levels, but their downregulation in RLS, may reflect their utility as a biomarker for RLS and perhaps brain dopamine homeostasis.

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

    Science.gov (United States)

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

    2014-01-01

    of powerful dopamine D2 agonists have failed due to chronic down regulation of D2 receptors newer targets based on novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency.

  19. Enhanced nigrostriatal neuron-specific, long-term expression by using neural-specific promoters in combination with targeted gene transfer by modified helper virus-free HSV-1 vector particles

    Directory of Open Access Journals (Sweden)

    Kong Lingxin

    2008-04-01

    Full Text Available Abstract Background Direct gene transfer into neurons has potential for developing gene therapy treatments for specific neurological conditions, and for elucidating neuronal physiology. Due to the complex cellular composition of specific brain areas, neuronal type-specific recombinant gene expression is required for many potential applications of neuronal gene transfer. One approach is to target gene transfer to a specific type of neuron. We developed modified Herpes Simplex Virus (HSV-1 particles that contain chimeric glycoprotein C (gC – glial cell line-derived neurotrophic factor (GDNF or brain-derived neurotrophic factor (BDNF proteins. HSV-1 vector particles containing either gC – GDNF or gC – BDNF target gene transfer to nigrostriatal neurons, which contain specific receptors for GDNF or BDNF. A second approach to achieve neuronal type-specific expression is to use a cell type-specific promoter, and we have used the tyrosine hydroxylase (TH promoter to restrict expression to catecholaminergic neurons or a modified neurofilament heavy gene promoter to restrict expression to neurons, and both of these promoters support long-term expression from HSV-1 vectors. To both improve nigrostriatal-neuron specific expression, and to establish that targeted gene transfer can be followed by long-term expression, we performed targeted gene transfer with vectors that support long-term, neuronal-specific expression. Results Helper virus-free HSV-1 vector packaging was performed using either gC – GDNF or gC – BDNF and vectors that contain either the TH promoter or the modified neurofilament heavy gene promoter. Vector stocks were injected into the midbrain proximal to the substantia nigra, and the rats were sacrificed at either 4 days or 1 month after gene transfer. Immunofluorescent costaining was performed to detect both recombinant gene products and nigrostriatal neurons. The combination of targeted gene transfer with neuronal

  20. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

    Science.gov (United States)

    Fortin, Samantha M; Roitman, Mitchell F

    2017-07-01

    Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    Science.gov (United States)

    España, Rodrigo A.; Jones, Sara R.

    2013-01-01

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

  2. On-Chip Determination of Dopamine Exocytosis Using Mercaptopropionic Acid Modified Microelectrodes

    DEFF Research Database (Denmark)

    Spégel, C.; Heiskanen, Arto; Acklid, J.

    2007-01-01

    Gold and platinum, which often are used for thin film metallization, are not suitable for the measurement of dopamine (DA), since the oxidation product of DA forms a non-conducting polymer on the electrode surface. In this work several thiols were screened for their ability to prevent this polyme......Gold and platinum, which often are used for thin film metallization, are not suitable for the measurement of dopamine (DA), since the oxidation product of DA forms a non-conducting polymer on the electrode surface. In this work several thiols were screened for their ability to prevent...

  3. Genetics Home Reference: dopamine beta-hydroxylase deficiency

    Science.gov (United States)

    ... Twitter Home Health Conditions Dopamine beta-hydroxylase deficiency Dopamine beta-hydroxylase deficiency Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Dopamine beta (β)-hydroxylase deficiency is a condition that ...

  4. Computational systems analysis of dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Zhen Qi

    2008-06-01

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

  5. Dopamine genes and pathological gambling in discordant sib-pairs.

    Science.gov (United States)

    da Silva Lobo, Daniela Sabbatini; Vallada, Homero P; Knight, Joanne; Martins, Silvia S; Tavares, Hermano; Gentil, Valentim; Kennedy, James L

    2007-12-01

    Pathological gambling (PG) is an impulse control disorder that has been considered as a behavioral addiction. Recent studies have suggested the involvement of the dopaminergic system in addictions and impulse control disorders and associations of dopamine receptor genes (DRD1, DRD2, and DRD4) and PG have been reported. In the present study, 140 sib-pairs discordant for the diagnosis of PG (70 males and 70 females on each group) were recruited through the Gambling Outpatient Unit at the Institute of Psychiatry, University of Sao Paulo and were assessed by trained psychiatrists. A family-based association design was chosen to prevent population stratification. All subjects were genotyped for dopamine receptor genes (DRD1 -800 T/C, DRD2 TaqIA RFLP, DRD3 Ser9Gly, DRD4 48bp exon III VNTR, DRD5 (CA) repeat) and the dopamine transporter gene (SCL6A3 40 bp VNTR). Our results suggest the association of PG with DRD1 -800 T/C allele T (P = .03).

  6. Heterogeneity of Monosymptomatic Resting Tremor in a Prospective Study: Clinical Features, Electrophysiological Test, and Dopamine Transporter Positron Emission Tomography.

    Science.gov (United States)

    Zheng, Hua-Guang; Zhang, Rong; Li, Xin; Li, Fang-Fei; Wang, Ya-Chen; Wang, Xue-Mei; Lu, Ling-Long; Feng, Tao

    2015-07-05

    The relationship between monosymptomatic resting tremor (mRT) and Parkinson's disease (PD) remains controversial. In this study, we aimed to assess the function of presynaptic dopaminergic neurons in patients with mRT by dopamine transporter positron emission tomography (DAT-PET) and to evaluate the utility of clinical features or electrophysiological studies in differential diagnosis. Thirty-three consecutive patients with mRT were enrolled prospectively. The Unified Parkinson's Disease Rating Scale and electromyography were tested before DAT-PET. Striatal asymmetry index (SAI) was calculated, and a normal DAT-PET was defined as a SAI of hygiene score, walking in motor experiences of daily living (Part II) and motor examination (Part III) were significant different between two groups (P postural tremor tend to be higher in the SWEDDs group (P = 0.08 and P = 0.05, respectively). mRT is heterogeneous in presynaptic nigrostriatal dopaminergic degeneration, which can be determined by DAT-PET brain imaging. Clinical and electrophysiological features may provide clues to distinguish PD from SWEDDs.

  7. CNB-001 a Novel Curcumin Derivative, Guards Dopamine Neurons in MPTP Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Richard L. Jayaraj

    2014-01-01

    Full Text Available Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson’s disease (PD pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH, dopamine transporter, and vesicular monoamine transporter 2 (VMAT2 expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD.

  8. On the role of subsecond dopamine release in conditioned avoidance

    Directory of Open Access Journals (Sweden)

    Erik B Oleson

    2013-06-01

    Full Text Available Using shock avoidance procedures to study conditioned behavioral responses has a rich history within the field of experimental psychology. Such experiments led to the formulation of the general concept of negative reinforcement and specific theories attempting to explain escape and avoidance behavior, or why animals choose to either terminate or prevent the presentation of an aversive event. For example, the two-factor theory of avoidance holds that cues preceding an aversive event begin to evoke conditioned fear responses, and these conditioned fear responses reinforce the instrumental avoidance response. Current neuroscientific advances are providing new perspectives into this historical literature. Due to its well-established role in reinforcement processes and behavioral control, the mesolimbic dopamine system presented itself as a logical starting point in the search for neural correlates of avoidance and escape behavior. We recently demonstrated that phasic dopamine release events are inhibited by stimuli associated with aversive events but increased by stimuli preceding the successful avoidance of the aversive event. The latter observation is inconsistent with the second component of the two-factor theory of avoidance and; therefore, led us propose a new theoretical explanation of conditioned avoidance: 1 fear is initially conditioned to the warning signal and dopamine computes this fear association as a decrease in release, 2 the warning signal, now capable of producing a negative emotional state, suppresses dopamine release and behavior, 3 over repeated trials the warning signal becomes associated with safety rather than fear; dopaminergic neurons already compute safety as an increase in release and begin to encode the warning signal as the earliest predictor of safety 4 the warning signal now promotes conditioned avoidance via dopaminergic modulation of the brain’s incentive-motivational circuitry.

  9. Dopamine transporter imaging and the effects of deep brain stimulation in patients with Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Lokkegaard, A. [Bispebjerg University Hospital, Department of Clinical Physiology and Nuclear Medicine, Copenhagen (Denmark); Bispebjerg University Hospital, Department of Neurology, Copenhagen, NV (Denmark); Werdelin, L.M.; Regeur, L.; Karlsborg, M.; Jensen, S.R. [Bispebjerg University Hospital, Department of Neurology, Copenhagen, NV (Denmark); Broedsgaard, E.; Lonsdale, M.N.; Friberg, L. [Bispebjerg University Hospital, Department of Clinical Physiology and Nuclear Medicine, Copenhagen (Denmark); Madsen, F.F. [Rigshospitalet, Copenhagen University Hospitals, Department of Neurosurgery, Copenhagen (Denmark)

    2007-04-15

    Single-photon emission computed tomography (SPECT) with [{sup 123}I]FP-CIT is a marker for loss of presynaptic dopamine transporters in the striatum in Parkinson's disease (PD). We used [{sup 123}I]FP-CIT SPECT in order to evaluate binding to the dopamine transporter before and after neurosurgical treatment with bilateral stimulation in the subthalamic nucleus (STN). Thirty-five patients with levodopa-responsive PD were examined with [{sup 123}I]FP-CIT SPECT pre-operatively (baseline scan: mean 3 months before surgery), and 3 and 12 months after surgery. Pre-operatively, all patients already had substantial signs of severe nigrostriatal neuronal loss as determined from the [{sup 123}I]FP-CIT SPECT scans. One year after surgery the specific [{sup 123}I]FP-CIT binding to the striatum was significantly reduced by 10.3% compared with the pre-operative baseline scan. The mean time span from the baseline scan before surgery to the follow-up scan 1 year after surgery was 16.2 months. Hence, the rate of reduction equals a mean annual reduction of 7.7%. A comparable control group of patients with PD who did not undergo surgery was also examined longitudinally. In this group the specific binding of [{sup 123}I]FP-CIT was reduced by 6.7% per year. The specific binding of [{sup 123}I]FP-CIT was reduced equally in the STN-stimulated patients and a group of non-operated PD patients with advanced disease. Our study does not support the notion that electrode implantation and STN stimulation exert a neuroprotective effect by themselves. (orig.)

  10. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel

    2006-03-01

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

  11. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

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

  12. Dopamine-transporter SPECT and Dopamine-D2-receptor SPECT in basal ganglia diseases

    International Nuclear Information System (INIS)

    Hesse, S.; Barthel, H.; Seese, A.; Sabri, O.

    2007-01-01

    The basal ganglia comprise a group of subcortical nuclei, which are essential for motor control. Dysfunction of these areas, especially in dopaminergic transmission, results in disordered movement and neurological diseases such as Parkinson's disease, Wilson's disease, or Huntington disease. Positron emission tomography and single photon emission computed tomography (SPECT) have enhanced the understanding of the underlying pathophysiology, but they much more contribute to the early differential diagnosis of patients suffering from Parkinsonian syndrome in routine care. The present article provides dopamine transporter and D 2 receptor SPECT findings in selected movement disorders. (orig.)

  13. Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

    Energy Technology Data Exchange (ETDEWEB)

    Engber, T.M.; Susel, Z.; Kuo, S.; Chase, T.N. (National Institute of Neurological Disorders and Stroke, Bethesda, MD (USA))

    1990-12-01

    The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.

  14. D-2 dopamine receptor activation reduces free [3H]arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells

    International Nuclear Information System (INIS)

    Canonico, P.L.

    1989-01-01

    Dopamine reduces the stimulation of intracellular [ 3 H]arachidonate release produced by the two PRL-stimulating peptides angiotensin-II and TRH. This effect is concentration dependent and is mediated by stimulation of D-2 dopamine receptors. D-2 receptor agonists (bromocriptine, dihydroergocryptine, and dihydroergocristine) inhibit the release of fatty acid induced by angiotensin-II with a potency that parallels their ability to inhibit PRL release in vitro. Conversely, the selective D-2 receptor antagonist L-sulpiride completely prevents dopamine's effect, whereas SCH 23390 (a D-1 receptor antagonist) is ineffective. The inhibitory action of dopamine does not seem to be consequent to an action on the adenylate cyclase-cAMP system, as 8-bromo-cAMP (1 mM) does not affect either basal or dopamine-inhibited [ 3 H]arachidonate release. However, a 24-h pertussis toxin pretreatment significantly reduces the action of dopamine on fatty acid release. Collectively, these results suggest that D-2 dopamine receptor-mediated inhibition of intracellular [ 3 H]arachidonate release requires the action of a GTP-binding protein, but is not a consequence of an inhibitory action on cAMP levels

  15. Decreased prefrontal cortical dopamine transmission in alcoholism.

    Science.gov (United States)

    Narendran, Rajesh; Mason, Neale Scott; Paris, Jennifer; Himes, Michael L; Douaihy, Antoine B; Frankle, W Gordon

    2014-08-01

    Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as 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 of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (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. Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. 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.

  16. Stereoselectivity of presynaptic autoreceptors modulating dopamine release

    International Nuclear Information System (INIS)

    Arbilla, S.; Langer, S.Z.

    1981-01-01

    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 [ 3 H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01-1μM enhanced the electrically evoked release of [ 3 H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.1-1 μM) but not to (R)-butaclamol (0.1-10μM) enhanced the field-stimulated release of [ 3 H]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 (1μM) of the stimulated release of [ 3 H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [ 3 H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective. (Auth.)

  17. Human dopamine receptor and its uses

    Energy Technology Data Exchange (ETDEWEB)

    Civelli, Olivier (Portland, OR); Van Tol, Hubert Henri-Marie (Toronto, CA)

    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.

  18. Cellular regulation of the dopamine transporter

    DEFF Research Database (Denmark)

    Eriksen, Jacob

    2010-01-01

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

  19. Action of dopamine in radiation protection

    International Nuclear Information System (INIS)

    Gupta, G.S.

    1983-01-01

    Administration of dopamine prior to irradiation modified biochemical processes in testes and other radioresponsive tissues. Results suggested that dopamine exerts its radio-protection which may be direct or indirect at molecular level in the tissues. At molecular level it protects cell injury by inhibiting DNA replication and acting as a lipotropic agent. Coincidently it protects the activity of -SH group containing enzymes such as inorganic pyrophosphatase which is sensitive index of tissue injury. Moreover, dopamine modifies the levels of phosphorylase and glycogen in testes indicating that its action is similar to epinephrine

  20. Evaluation of the ratio method compared with graphical analyses for estimating nigrostriatal function in human [sup 18]F-dopa PET studies with or without carbidopa

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, M.; Ichiya, Y.; Kuwabara, Y.; Fukumura, T.; Sasaki, M.; Masuda, K. (Kyushu Univ., Fukuoka (Japan). Dept. of Radiology)

    1993-10-01

    The striatal to cerebellar (S/C) activity ratio for estimating nigrostriatal function was compared with the Patlak analyses in [sup 18]F-dopa (FD) positron emission tomography (PET) with pretreatment with 100 mg carbidopa (CD). Two different time-activity curves of plasma FD or cerebellar [sup 18]F were used for the Patlak analyses. The S/C ratio increased linearly with time for 120 min and the ratio at 120 min correlated closely with the uptake constants by the two Patlak analyses in six normal volunteers and six Parkinsons disease patients. The S/C ratio and the uptake constant by the cerebellar Patlak analysis without CD also showed a fairly good correlation. Then, the S/C ratios with and without CD were compared. Since CD increased both the striatal and the cerebellar radioactivities proportionally within each subject, CD did not change the S/C ratios. The S/C ratios both with and without CD were simple and comparable to the uptake constants in the FD PET studies. (author).

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

    Science.gov (United States)

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

    2015-01-01

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

  2. Modeling the dopamine system in vivo

    International Nuclear Information System (INIS)

    Gjedde, A.

    1991-01-01

    Positron Emission Tomography (PET) can be used to measure several steps in the synthesis, binding, and metabolism of dopamine in the normal or abnormal living human brain. Fluorodopa is a PET tracer of DOPA metabolism. Recent evidence suggests that only a fraction of striatal fluorodopamine accumulates in the large, static pool of dopamine. Hence, the accumulation of FDOPA-derived radioactivity in striatum reflects the dopamine turnover of this pool. Labeled L-deprenyl is a PET tracer of monoamine oxidase B. The accumulation in striatum and other regions of the human brain reflects the number of reactive sites on the enzyme. The densities of dopamine-binding neuroreceptors may be calculated from the accumulation of reversibly binding tracers by equilibrium kinetics or from the accumulation of irreversibly binding tracers by transient analysis. The reversible tracers include labeled SCH 23390 and raclopride. An irreversibly binding tracer is N- methylspiperone

  3. Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

    Directory of Open Access Journals (Sweden)

    Laurent Ladepeche

    Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

  4. Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus

    Directory of Open Access Journals (Sweden)

    John I. Broussard

    2016-03-01

    Full Text Available Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

  5. Dopamine versus noradrenaline in septic shock

    Directory of Open Access Journals (Sweden)

    Bo Xu

    2011-10-01

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

  6. Tonic dopamine modulates exploitation of reward learning

    Directory of Open Access Journals (Sweden)

    Jeff A Beeler

    2010-11-01

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

  7. Glycyrrhetinic acid and E.resveratroloside act as potential plant derived compounds against dopamine receptor D3 for Parkinson’s disease: a pharmacoinformatics study

    Directory of Open Access Journals (Sweden)

    Mirza MU

    2014-12-01

    Full Text Available Muhammad Usman Mirza,1 A Hammad Mirza,2 Noor-Ul-Huda Ghori,3 Saba Ferdous4 1Centre for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan; 2Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan; 3Atta-ur-Rehman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan; 4Institute of Structural and Molecular Biology, University College London, UK Abstract: Parkinson’s disease (PD is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Unfortunately, use of these pharmacological therapies such as bromocriptine, apomorphine, and ropinirole provides only temporary relief of the disease symptoms and is frequently linked with insomnia, anxiety, depression, and agitation. Thus, there is a need for an alternative treatment that not only hinders neurodegeneration, but also has few or no side effects. Since the past decade, much attention has been given to exploitation of phytochemicals and their use in alternative medicine research. This is because plants are a cheap, indispensable, and never ending resource of active compounds that are beneficial against various diseases. In the current study, 40 active phytochemicals against PD were selected through literature survey. These ligands were docked with dopamine receptor D3 using AutoDock and AutoDockVina. Binding energies were compared to docking results of drugs approved by the US Food and Drug Administration against PD. The compounds were further analyzed for their absorption, distribution

  8. Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

    Science.gov (United States)

    Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

    2017-12-01

    Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  10. Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity

    NARCIS (Netherlands)

    van de Giessen, Elsmarieke; Celik, Funda; Schweitzer, Dave H.; van den Brink, Wim; Booij, Jan

    2014-01-01

    The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted

  11. Endocannabinoid modulation of dopamine neurotransmission.

    Science.gov (United States)

    Covey, Dan P; Mateo, Yolanda; Sulzer, David; Cheer, Joseph F; Lovinger, David M

    2017-09-15

    Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Immunomodulatory Effects Mediated by Dopamine

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2016-01-01

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

  13. Imaging dopamine transmission in schizophrenia

    International Nuclear Information System (INIS)

    Laruelle, M.

    1998-01-01

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D 2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D 2 receptor density parameters, under the assumption that all tracers labeled the same population of D 2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D 2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D 2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

  14. Dopamine, behavioral economics, and effort

    Directory of Open Access Journals (Sweden)

    John D Salamone

    2009-09-01

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

  15. Addiction: Beyond dopamine reward circuitry

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-09-13

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

  16. Addiction: Beyond dopamine reward circuitry

    International Nuclear Information System (INIS)

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

    2011-01-01

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

  17. Dopamine signaling and myopia development: What are the key challenges.

    Science.gov (United States)

    Zhou, Xiangtian; Pardue, Machelle T; Iuvone, P Michael; Qu, Jia

    2017-11-01

    In the face of an "epidemic" increase in myopia over the last decades and myopia prevalence predicted to reach 2.5 billion people by the end of this decade, there is an urgent need to develop effective and safe therapeutic interventions to slow down this "myopia booming" and prevent myopia-related complications and vision loss. Dopamine (DA) is an important neurotransmitter in the retina and mediates diverse functions including retina development, visual signaling, and refractive development. Inspired by the convergence of epidemiological and animal studies in support of the inverse relationship between outdoor activity and risk of developing myopia and by the close biological relationship between light exposure and dopamine release/signaling, we felt it is timely and important to critically review the role of DA in myopia development. This review will revisit several key points of evidence for and against DA mediating light control of myopia: 1) the causal role of extracellular retinal DA levels, 2) the mechanism and action of dopamine D1 and D2 receptors and 3) the roles of cellular/circuit retinal pathways. We examine the experiments that show causation by altering DA, DA receptors and visual pathways using pharmacological, transgenic, or visual environment approaches. Furthermore, we critically evaluate the safety issues of a DA-based treatment strategy and some approaches to address these issues. The review identifies the key questions and challenges in translating basic knowledge on DA signaling and myopia from animal studies into effective pharmacological treatments for myopia in children. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. The nigrostriatal pathway in the rat: A single-axon study of the relationship between dorsal and ventral tier nigral neurons and the striosome/matrix striatal compartments.

    Science.gov (United States)

    Prensa, L; Parent, A

    2001-09-15

    Axons from dorsal/ventral tiers of substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) were traced after injecting their cell body with biotinylated dextran amine. Fifty-three single axons were reconstructed from serial sagittal sections with a camera lucida, and mu-opiate receptor immunostaining served to differentiate the striosome/matrix striatal compartments. Most dorsal tier SNc axons terminate within the matrix of the dorsal striatum, but their patterns of arborization vary markedly; some axons innervate one specific matriceal area, whereas others arborize in multiple discontinuous loci. Some dorsal tier SNc axons also project to both striosomes and matrix. Other dorsal tier SNc axons, as well as VTA axons, innervate the ventral striatum and send collaterals to striosomes lying ventrally in the dorsal striatum or to the ventral sector of the subcallosal streak (SS). Ventral tier SNc axons arborize principally in striosomes, but some ramify in both compartments or in striosomes and the SS. Ventral tier neurons that form deep clusters in substantia nigra pars reticulata innervate principally the matrix and the SS. The amygdala and ventral pallidum receive secondary collaterals from striatal axons of dorsal/ventral tier neurons or RRF neurons. The subthalamic nucleus receives collaterals from striatal axons of SNc clustered neurons, whereas the globus pallidus gets collaterals from striatal axons of dorsal/ventral tier SNc neurons. These findings reveal that the nigrostriatal pathway is composed of several neuronal subsystems, each endowed with a widely distributed axonal arborization that allows them to exert a multifaceted influence on striatal and/or extrastriatal structures.

  19. Amphetamine and Dopamine-Induced Immediate Early Gene Expression in Striatal Neurons Depends on Postsynaptic NMDA Receptors and Calcium

    Science.gov (United States)

    Konradi, Christine; Leveque, Jean-Christophe; Hyman, Steven E.

    2014-01-01

    Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine- or forskolin-mediated IEG induction requires Ca2+ entry via NMDA receptors but not via L-type Ca2+ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons. PMID:8753884

  20. Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

    Science.gov (United States)

    Achterberg, E J Marijke; van Kerkhof, Linda W M; Servadio, Michela; van Swieten, Maaike M H; Houwing, Danielle J; Aalderink, Mandy; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-02-01

    Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

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

    International Nuclear Information System (INIS)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R.

    1996-01-01

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

  2. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    OpenAIRE

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

    1990-01-01

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

  3. Cerebral vascular effects of hypovolemia and dopamine infusions

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

    Volkow, N D; Fowler, J S; Gatley, S J; Logan, J; Wang, G J; Ding, Y S; Dewey, 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 changes 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 neurological 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. Through the parallel development of new radiotracers, kinetic models and better instruments, PET technology is enabling investigation of increasingly more complex aspects of the human brain dopamine system. This paper summarizes the different tracers and experimental

  5. Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia

    Directory of Open Access Journals (Sweden)

    Yasunori Oda

    2015-12-01

    Full Text Available Although the dopamine D2 receptor (DRD2 has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s, is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

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

    Science.gov (United States)

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-05-01

    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

  7. Mesolimbic dopamine in desire and dread: enabling motivation to be generated by localized glutamate disruptions in nucleus accumbens.

    Science.gov (United States)

    Faure, Alexis; Reynolds, Sheila M; Richard, Jocelyn M; Berridge, Kent C

    2008-07-09

    An important issue in affective neuroscience concerns the role of mesocorticolimbic dopamine systems in positive-valenced motivation (e.g., reward) versus negative-valenced motivation (e.g., fear). Here, we assessed whether endogenous dopamine receptor stimulation in nucleus accumbens contributes to both appetitive behavior and fearful behavior that is generated in keyboard manner by local glutamate disruptions at different sites in medial shell. 6,7-Dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) microinjections (450 ng) locally disrupt glutamate signals in <4 mm(3) of nucleus accumbens, and generate either desire or fear (or both) depending on precise rostrocaudal location in medial shell. At rostral shell sites, local AMPA/kainate blockade generates positive ingestive behavior, but the elicited motivated behavior becomes incrementally more fearful as the same microinjection is moved caudally. A dopamine-blocking mixture of D(1) and D(2) antagonists (raclopride and SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrochloride]) was combined here in the same microinjection with DNQX to assess the role of endogenous local dopamine in mediating the DNQX-motivated behaviors. We report that local dopamine blockade prevented DNQX microinjections from generating appetitive behavior (eating) in rostral shell, and equally prevented DNQX from generating fearful behavior (defensive treading) in caudal shell. We conclude that local dopamine is needed to enable disruptions of corticolimbic glutamate signals in shell to generate either positive incentive salience or negative fearful salience (valence depending on site and other conditions). Thus, dopamine interacts with localization of valence-biased glutamate circuits in medial shell to facilitate keyboard stimulation of both appetitive and fearful motivations.

  8. Progressive supranuclear palsy dopamine D2 receptor tomoscintigraphy to detect L-dopamine efficiency

    International Nuclear Information System (INIS)

    Tranquart, F.; Henry Le Bras, F.; Toffol, B. de; Autret, A.; Guilloteau, D.; Baulieu, J.L.

    1994-01-01

    Progressive supranuclear palsy (PSP) may sometimes be misdiagnosed as Parkinson's disease in its early stages, hence an early positive diagnosis of PSP based on dopamine D2 receptor density could be extremely valuable. In the present case report, the absence of dopamine D2 receptors was clearly demonstrated in the striatum using 123 I-iodobenzamide (IBZM) tomoscintigraphy. This illustrates the potential use of IBZM tomoscintigraphy to identify Parkinson-like's disease presenting with decreased dopamine D2 receptor density; and hence to predict L-Dopa effectiveness. Further studies are needed to evaluate the value of IBZM tomoscintigraphy in the different Parkinson's like diseases. (authors). 11 refs., 2 figs

  9. Sleep patterns in congenital dopamine beta-hydroxylase deficiency

    NARCIS (Netherlands)

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

    1990-01-01

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

  10. ORAL IBOPAMINE SUBSTITUTION IN PATIENTS WITH INTRAVENOUS DOPAMINE DEPENDENCE

    NARCIS (Netherlands)

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

    1995-01-01

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

  11. Clinically Combating Reward Deficiency Syndrome (RDS) with Dopamine Agonist Therapy as a Paradigm Shift: Dopamine for Dinner?

    Science.gov (United States)

    Blum, Kenneth; Febo, Marcelo; Thanos, Panayotis K; Baron, David; Fratantonio, James; Gold, Mark

    2015-12-01

    Everyday, there are several millions of people that are increasingly unable to combat their frustrating and even fatal romance with getting high and/or experiencing "normal" feelings of well-being. In the USA, the FDA has approved pharmaceuticals for drug and alcohol abuse: tobacco and nicotine replacement therapy. The National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) remarkably continue to provide an increasing understanding of the intricate functions of brain reward circuitry through sophisticated neuroimaging and molecular genetic applied technology. Similar work is intensely investigated on a worldwide basis with enhanced clarity and increased interaction between not only individual scientists but across many disciplines. However, while it is universally agreed that dopamine is a major neurotransmitter in terms of reward dependence, there remains controversy regarding how to modulate its role clinically to treat and prevent relapse for both substance and non-substance-related addictive behaviors. While the existing FDA-approved medications promote blocking dopamine, we argue that a more prudent paradigm shift should be biphasic-short-term blockade and long-term upregulation, enhancing functional connectivity of brain reward circuits.

  12. Dopamine uptake inhibitors but not dopamine releasers induce greater increases in motor behavior and extracellular dopamine in adolescent rats than in adult male rats.

    Science.gov (United States)

    Walker, Q David; Morris, Sarah E; Arrant, Andrew E; Nagel, Jacqueline M; Parylak, Sarah; Zhou, Guiying; Caster, Joseph M; Kuhn, Cynthia M

    2010-10-01

    Most life-long drug addiction begins during adolescence. Important structural and functional changes in brain occur during adolescence and developmental differences in forebrain dopamine systems could mediate a biologic vulnerability to drug addiction during adolescence. Studies investigating age differences in psychostimulant responses have yielded mixed results, possibly because of different mechanisms for increasing extracellular dopamine. Recent research from our laboratory suggests that adolescent dopamine systems may be most affected by selective dopamine uptake inhibitors. We investigated age-related behavioral responses to acute administration of several dopamine uptake inhibitors [methylphenidate, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR12909), and nomifensine] and releasing agents [amphetamine and methylenedioxymethamphetamine (MDMA)] in adolescent and adult male rats. Methylphenidate and amphetamine effects on stimulated dopamine efflux were determined using fast-scan cyclic voltammetry in vivo. Dopamine uptake inhibitors but not dopamine releasing agents induced more locomotion and/or stereotypy in adolescent relative to adult rats. MDMA effects were greater in adults at early time points after dosing. Methylphenidate but not amphetamine induced much greater dopamine efflux in periadolescent relative to adult rats. Periadolescent male rats are particularly sensitive to psychostimulants that are DAT inhibitors but are not internalized and do not release dopamine. Immaturity of DAT and/or DAT associated signaling systems in adolescence specifically enhances behavioral and dopaminergic responses in adolescence.

  13. Activation of dopamine receptors in the nucleus accumbens promotes sucrose-reinforced cued approach behavior

    Directory of Open Access Journals (Sweden)

    Saleem M. Nicola

    2016-07-01

    Full Text Available Dopamine receptor activation in the nucleus accumbens (NAc promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety.

  14. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of dexamphetamine.

    NARCIS (Netherlands)

    Watanabe, S.; Aono, Y.; Fusa, K.; Takada, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2005-01-01

    Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally

  15. Dopamine-based reward circuitry responsivity, genetics, and overeating.

    Science.gov (United States)

    Stice, Eric; Yokum, Sonja; Zald, David; Dagher, Alain

    2011-01-01

    Data suggest that low levels of dopamine D2 receptors and attenuated responsivity of dopamine-target regions to food intake is associated with increased eating and elevated weight. There is also growing (although mixed) evidence that genotypes that appear to lead to reduced dopamine signaling (e.g., DRD2, DRD4, and DAT) and certain appetite-related hormones and peptides (e.g., ghrelin, orexin A, leptin) moderate the relation between dopamine signaling, overeating, and obesity. This chapter reviews findings from studies that have investigated the relation between dopamine functioning and food intake and how certain genotypes and appetite-related hormones and peptides affect this relation.

  16. The binding sites for benztropines and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Jensen, Heidi Bisgaard; Larsen, M Andreas B; Mazier, Sonia

    2011-01-01

    Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational...... with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine....

  17. Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    BACKGROUND: For the normal resolution of an acute inflammatory response, neutrophil (PMN) apoptosis is essential to maintain immune homeostasis and to limit inappropriate host tissue damage. A delay in PMN apoptosis has been implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS). Dopamine, a biogenic amine with known cardiovascular and neurotransmitter properties, is used in patients with SIRS to maintain hemodynamic stability. We sought to determine whether dopamine may also have immunoregulatory properties capable of influencing PMN apoptosis, function, and activation state in patients with SIRS. METHODS: PMNs were isolated from healthy volunteers and patients with SIRS and treated with varying doses of dopamine and a dopamine D-1 receptor agonist, fenoldopam. PMN apoptosis was assessed every 6 hours with use of propidium iodide DNA staining and PMN function was assessed with use of respiratory burst activity, phagocytosis ability, and CD11a, CD11b, and CD18 receptor expression as functional markers. RESULTS: There was a significant delay in PMN apotosis in patients with SIRS compared with controls. Treatment of isolated PMNs from both healthy controls and patients with SIRS with 10 and 100 mumol\\/L dopamine induced apoptosis. PMN ingestive and cytocidal capacity were both decreased in patients with SIRS compared with controls. Treatment with dopamine significantly increased phagocytic function. Fenoldopam did not induce PMN apoptosis. CONCLUSION: Our data demonstrate for the first time that dopamine induces PMN apoptosis and modulates PMN function both in healthy controls and in patients with SIRS. These results indicate that dopamine may be beneficial during SIRS through a nonhemodynamic PMN-dependent proapoptotic mechanism.

  18. Quantification of L-Dopa and Dopamine in Squid Ink: Implications for Chemoreception.

    Science.gov (United States)

    Lucero, M T; Farrington, H; Gilly, W F

    1994-08-01

    Squid ink is an alarm substance that both confuses predators and alerts conspecifics to the presence of danger. Although the ejection of ink is a powerful visual stimulus, studies also indicate a chemical component to the signal. Squid ink is composed mainly of melanin pigments, but the nonpigmented portion of the ink contains the enzymes and precursors of melanin synthesis. Our previous behavioral studies showed that squid olfactory organs detect L-dopa, a key chemical in melanogenesis. Squid olfactory neurons also respond to dopamine, a biogenic amine not previously described in squid ink. We performed HPLC on ink taken from the ink sacs of adult Loligo opalescens. The ink was conjugated with orthophthaldialdehyde (OPA) and injected into the HPLC, and amine-containing compounds were detected fluorometrically. Standard curves constructed for L-dopa and dopamine allowed quantitation from individual ink sacs. We found that L-dopa was present in undiluted ink at a mean concentration of 1.15 mM and was significantly greater than the mean dopamine concentration of 0.19 mM. These values are greater than those at which both compounds are effective in behavioral and electrophysiological experiments. In addition we found that an unidentified antioxidant in the ink may prevent rapid oxidation of L-dopa and dopamine following dilution in seawater.

  19. Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice.

    Science.gov (United States)

    Runegaard, Annika H; Jensen, Kathrine L; Fitzpatrick, Ciarán M; Dencker, Ditte; Weikop, Pia; Gether, Ulrik; Rickhag, Mattias

    2017-01-01

    Cre-driver mouse lines have been extensively used as genetic tools to target and manipulate genetically defined neuronal populations by expression of Cre recombinase under selected gene promoters. This approach has greatly advanced neuroscience but interpretations are hampered by the fact that most Cre-driver lines have not been thoroughly characterized. Thus, a phenotypic characterization is of major importance to reveal potential aberrant phenotypes prior to implementation and usage to selectively inactivate or induce transgene expression. Here, we present a biochemical and behavioural assessment of the dopaminergic system in hemizygous tyrosine hydroxylase (TH)-Cre mice in comparison to wild-type (WT) controls. Our data show that TH-Cre mice display preserved dopaminergic homeostasis with unaltered levels of TH and dopamine as well as unaffected dopamine turnover in striatum. TH-Cre mice also show preserved dopamine transporter expression and function supporting sustained dopaminergic transmission. In addition, TH-Cre mice demonstrate normal responses in basic behavioural paradigms related to dopaminergic signalling including locomotor activity, reward preference and anxiolytic behaviour. Our results suggest that TH-Cre mice represent a valid tool to study the dopamine system, though careful characterization must always be performed to prevent false interpretations following Cre-dependent transgene expression and manipulation of selected neuronal pathways. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  20. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

    Directory of Open Access Journals (Sweden)

    Alexander Kurz

    2010-07-01

    Full Text Available Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice.Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

  1. Effects of Estrogen, Nitric Oxide, and Dopamine on Behavioral Locomotor Activities in the Embryonic Zebrafish: A Pharmacological Study

    Directory of Open Access Journals (Sweden)

    Vania Murcia

    2016-09-01

    Full Text Available Nitric oxide (NO has been shown to affect motor function. Specifically, NO has been shown to act through regulation of dopamine (DA release, transporter function, and the elicitation of neuroprotection/neurodegeneration of neurons. Recently, zebrafish have been proposed to be a new model for the study of various types of motor dysfunctions, since neurotoxin damage to their nigrostriatal-like neurons exhibit motor anomalies similar to those of mammalian models and human patients. Results from this study demonstrate that when NO synthesis is inhibited in zebrafish, using a neuronal NO synthase inhibitor (nNOSI, a condition called ‘listless’ occurs, where the fish lack swimming abilities, are rigid, and have difficulty maintaining balance. Additionally, co-treatment with either NO or estrogen (E2, an upstream regulator of NO synthase, can rescue fish from the ‘listless’ phenotype caused by exposure to the neurotoxin 6-hydroxydopamine (6 OHDA. In turn, NO deprived zebrafish were rescued from the ‘listless’ phenotype when co-treated with L-DOPA, a precursor to DA. Interestingly, the longer fish are exposed to a 6 OHDA + nNOSI co-treatment, the slower the recovery after washout, compared to a single treatment of each. Most significantly, NO involvement in the motor homeostasis of the embryonic zebrafish was shown to be expressed through the NO-cGMP-dependent pathway, and response to nNOSI treatments is developmentally regulated. In conclusion, these results indicate that there is a link between E2, NO, and DA systems that regulate motor functions in the embryonic zebrafish.

  2. Early Paradoxical Increase of Dopamine: A Neurochemical Study of Olfactory Bulb in Asymptomatic and Symptomatic MPTP Treated Monkeys

    Directory of Open Access Journals (Sweden)

    Christian Pifl

    2017-05-01

    Full Text Available Parkinson’s disease (PD is a neurodegenerative disease with both motor and non-motor manifestations. Hyposmia is one of the early non-motor symptoms, which can precede motor symptoms by several years. The relationship between hyposmia and PD remains elusive. Olfactory bulb (OB pathology shows an increased number of olfactory dopaminergic cells, protein aggregates and dysfunction of neurotransmitter systems. In this study we examined tissue levels of dopamine (DA and serotonin (5-hydroxytryptamine, 5-HT and their metabolites, of noradrenaline (NA and of the amino acid neurotransmitters aspartate, glutamate, taurine and γ-aminobutyric acid in OBs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP treated Macaca fascicularis in different stages, including monkeys who were always asymptomatic, monkeys who recovered from mild parkinsonian signs, and monkeys with stable moderate or severe parkinsonism. DA was increased compared to controls, while neither NA and 5-HT nor the amino acid neurotransmitters were significantly changed. Furthermore, DA increased before stable motor deficits appear with +51% in asymptomatic and +96% in recovered monkeys. Unchanged DA metabolites suggest a special metabolic profile of the newly formed DA neurons. Significant correlation of homovanillic acid (HVA with taurine single values within the four MPTP groups and of aspartate with taurine within the asymptomatic and recovered MPTP groups, but not within the controls suggest interactions in the OB between taurine and the DA system and taurine and the excitatory neurotransmitter triggered by MPTP. This first investigation of OB in various stages after MPTP administration suggests that the DA increase seems to be an early phenomenon, not requiring profound nigrostriatal neurodegeneration or PD symptoms.

  3. Dopamine 3 or 4 phosphate: pharmacologic properties

    International Nuclear Information System (INIS)

    Byington, K.H.

    1986-01-01

    The 3 or 4 phosphate ester of dopamine (PD) is being used to test the hypothesis that PD, as well as phosphate esters of other catecholamines, occur and function physiologically. In 1.00 mM PD-20 mM NaHEPES, pH 7.15 - 5.00 mM MgCl 2 (PDase conditions) the order of the rates at which homogenates of rat tissues catalyzed the hydrolysis of PD to give Pi at 37 0 were: kidney > brain > liver > heart > blood. Recoveries of dopamine and PD showed that dopamine and Pi are the main products generated when PD was incubated with 1% homogenates of brain, heart, kidney and liver. Purine nucleotides inhibited the hydrolysis of 32 PD to give 32 Pi with the following order of activity: ATP 32 PD could be recovered as dopamine and 32 PD after incubation with kidney homogenate under PDase conditions with 5 mM ATP. Incubation of 1% tissue homogenates with 32 PD under PDase conditions resulted in accumulation of acid precipitable label as follows: kidney 19, heart 11, liver 10, brain 6 nmole label/g tissue. The results suggest that specific enzymes exist to metabolize PD and support the hypothesis that PD and related phosphate esters are physiologic. In addition, the results indicate that PD may be useful as a prodrug for catecholamines

  4. Oscillating from Neurosecretion to Multitasking Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    David R. Grattan

    2016-04-01

    Full Text Available In this issue of Cell Reports, Stagkourakis et al. (2016 report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits.

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

    Science.gov (United States)

    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. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

    Directory of Open Access Journals (Sweden)

    N. L. Rukavina Mikusic

    2016-01-01

    Full Text Available Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP and Ang-(1-7 may regulate renal dopamine availability in tubular cells, contributing to Na+, K+-ATPase inhibition. Present results show that CNP did not affect either 3H-dopamine uptake in renal tissue or Na+, K+-ATPase activity; meanwhile, Ang-(1-7 was able to increase 3H-dopamine uptake and decreased Na+, K+-ATPase activity in renal cortex. Ang-(1-7 and dopamine together decreased further Na+, K+-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7 stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide did not modify CNP effects on 3H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7 on 3H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7 was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7 on AT1 receptors on 3H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7 enhances Na+, K+-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  7. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and L-DOPA reversible motor deficits

    OpenAIRE

    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

    2014-01-01

    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 wheth...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    International Nuclear Information System (INIS)

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

    1987-01-01

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 μM 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 μM 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 μM respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D 2 -dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 μM. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, 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 1 - and D 2 -dopamine receptors. 33 references, 3 figures, 2 tables

  10. The Effect of Subchronic Dosing of Ciproxifan and Clobenpropit on Dopamine and Histamine Levels in Rats

    Directory of Open Access Journals (Sweden)

    D. Mahmood

    2015-01-01

    Full Text Available The present study was designed to investigate the effect of once daily for 7-day (subchronic treatment dosing of histamine H 3 receptor antagonists, ciproxifan (CPX (3 mg/kg, i.p., and clobenpropit (CBP (15 mg/kg, i.p, including clozapine (CLZ (3.0 mg/kg, i.p. and chlorpromazine (CPZ (3.0 mg/kg, i.p., the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.-induced locomotor activity, and dopamine and histamine levels in rats. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. Atypical and typical antipsychotics were used to serve as clinically relevant reference agents to compare the effects of the H 3 receptor antagonists. MK-801-induced increase of horizontal activity was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised dopamine levels in the striatum, which was reduced in rats pretreated with CPX and CBP. CPZ also lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increase in histamine levels in the hypothalamus compared to the MK-801 treatment alone. Histamine H 3 receptor agonist, R-OC methylhistamine (10 mg/kg, i.p. counteracted the effects of CPX and CBP. In conclusion, the subchronic dosing of CPX/CBP suggests some antipsychotic-like activities as CPX/CBP counteracts the modulatory effects of MK-801 on dopamine and histamine levels and prevents MK-801-induced hyperlocomotor behaviors.

  11. Optical suppression of drug-evoked phasic dopamine release

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2014-09-01

    Full Text Available Brief fluctuations in dopamine concentration (dopamine transients play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc of urethane-anesthetized rats. We targeted halorhodopsin (NpHR specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats. Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Peter J Gaskill

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

  14. Heterogeneity of Monosymptomatic Resting Tremor in a Prospective Study: Clinical Features, Electrophysiological Test, and Dopamine Transporter Positron Emission Tomography

    Directory of Open Access Journals (Sweden)

    Hua-Guang Zheng

    2015-01-01

    Conclusions: mRT is heterogeneous in presynaptic nigrostriatal dopaminergic degeneration, which can be determined by DAT-PET brain imaging. Clinical and electrophysiological features may provide clues to distinguish PD from SWEDDs.

  15. Effects of irradiation on neuronal dopamine uptake

    International Nuclear Information System (INIS)

    Martin, C.; Pham, H.T.; Becker, C.; Fatome, M.

    1996-01-01

    The aim of this study was to better understand the mechanism of action of gamma and neutron radiation on the central nervous system, particularly the dopaminergic system. The influence of the two irradiation modalities on the 3 H-DA uptake by synaptosomes prepared from striatum was studied in mice. Four hours after increase of neuronal dopamine uptake is observed. (Authors). 6 refs., 2 figs

  16. The multiplicity of the D-1 dopamine receptor

    International Nuclear Information System (INIS)

    Mailman, R.B.; Klits, C.D.; Lewis, M.H.; Rollema, H.; Schulz, D.W.; Wyrick, S.

    1986-01-01

    The authors have sought to address two questions of some neuropharmacological importance in this chapter. First, they examine the nature of mechanisms by which dopamine initiates many psychopharmacological effects and, second, they study the possibility of designing highly specific drugs targeted only at a selected subpopulation of dopamine receptors. Effects of SCH23390 and haloperidol on concentrations of dopamine, DOPAC, and HVA in various rat brain regions are shown. In addition, the effects of SCH23390 on the in vivo binding of dipropyl-5, 6-ADTN are shown. Differential distribution of a dopamine sensitive adenylate cyclase and ( 3 H)-SCH23390 binding sites are examined. A model is presented of D 1 dopamine receptors in membrane, illustrating the lack of identity of some of the ( 3 H)-SCH23390 binding sites with the dopamine receptor linked to stimulation of cAMP synthesis

  17. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  18. Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

    Science.gov (United States)

    Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana; Karam, Caline S; Farino, Zachary J; Sonders, Mark S; Choi, Se Joon; Grygoruk, Anna; Zhang, Yuchao; Cela, Carolina; Choi, Ben Jiwon; Flores, Jorge; Freyberg, Robin J; McCabe, Brian D; Mosharov, Eugene V; Krantz, David E; Javitch, Jonathan A; Sulzer, David; Sames, Dalibor; Rayport, Stephen; Freyberg, Zachary

    2017-08-30

    The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Dopamine and light: effects on facial emotion recognition.

    Science.gov (United States)

    Cawley, Elizabeth; Tippler, Maria; Coupland, Nicholas J; Benkelfat, Chawki; Boivin, Diane B; Aan Het Rot, Marije; Leyton, Marco

    2017-09-01

    Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light × mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect.

  20. Dopamine supports sentence comprehension in Parkinson's Disease.

    Science.gov (United States)

    Grossman, M; Glosser, G; Kalmanson, J; Morris, J; Stern, M B; Hurtig, H I

    2001-03-01

    To determine the role of dopamine in the executive resource component of sentence comprehension. We studied sentence-picture matching in 20 right-handed, non-demented, native English speakers with mild Parkinson's disease (PD) when 'on' and 'off' their levodopa, taking into account disease duration to control for endogenous dopamine metabolism. We also administered a verbal working memory measure that does not involve specific grammatical manipulations. PD patients 'off' levodopa demonstrated a significant discrepancy in their comprehension of grammatically complex sentences compared to grammatically simpler sentences that was not evident when PD patients were 'on' levodopa. An error analysis demonstrated that impaired comprehension of grammatically complex sentences when 'off' levodopa was associated with poorer performance on foils requiring working memory resources. Performance on an independent measure of verbal working memory correlated only with comprehension of grammatically complex sentences during levodopa supplementation, but working memory according to this measure did not differ during 'on' and 'off' states. Dopamine supports the executive resources contributing to sentence comprehension in PD.

  1. Dopamine ups and downs in vulnerability to addictions: a neurodevelopmental model.

    Science.gov (United States)

    Leyton, Marco; Vezina, Paul

    2014-06-01

    Addictions are commonly presaged by problems in childhood and adolescence. For many individuals this starts with the early expression of impulsive risk-taking, social gregariousness, and oppositional behaviors. Here we propose that these early diverse manifestations reflect a heightened ability of emotionally salient stimuli to activate dopamine pathways that foster behavioral approach. If substance use is initiated, these at-risk youth can also develop heightened responses to drug-paired cues. Through conditioning and drug-induced sensitization, these effects strengthen and accumulate, leading to responses that exceed those elicited by other rewards. At the same time, cues not paired with drug become associated with comparatively lower dopamine release, accentuating further the difference between drug and non-drug rewards. Together, these enhancing and inhibiting processes steer a pre-existing vulnerability toward a disproportionate concern for drugs and drug-related stimuli. Implications for prevention and treatment are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  3. Practical Approach for the Clinical Use of Dopamine Transporter Imaging

    International Nuclear Information System (INIS)

    Kim, Jae Seung

    2008-01-01

    Dopamine transporter imaging is useful in the diagnosis of Parkinson's disease and the most successful technique in the clinical use of neuroreceptor imaging. Recently, several radiopharmaceuticals including I-123 FP-CIT, Tc-99m TRODAT, and F-18 FP-CIT for dopamine transporter imaging have been approved for the routine clinical use in several European countries, Taiwan and Korea, respectively. This review summarized the practical issue for the routine clinical examination of dopamine transporter imaging

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

    International Nuclear Information System (INIS)

    Bannon, Michael J.

    2005-01-01

    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)

  5. Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

    Directory of Open Access Journals (Sweden)

    Hsu Chih W

    2010-01-01

    Full Text Available Abstract Background Caffeine, a nonselective adenosine A1 and A2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD. Evidence also indicates that low doses of caffeine and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum. Methods In this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC and homovanilic acid (HVA, and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor, we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine. Results Chronic treatments with low dose caffeine (10 mg/kg or SCH58261 (2 mg/kg increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced

  6. Cross-hemispheric dopamine projections have functional significance

    Science.gov (United States)

    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

  7. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

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

    Directory of Open Access Journals (Sweden)

    Nijhout H Frederik

    2009-09-01

    Full Text Available Abstract 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

  9. Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Directory of Open Access Journals (Sweden)

    Javier A Urra

    Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  10. Responses of in vivo renal microvessels to dopamine.

    Science.gov (United States)

    Steinhausen, M; Weis, S; Fleming, J; Dussel, R; Parekh, N

    1986-09-01

    The split hydronephrotic kidney preparation was used to directly observe the effects of locally applied dopamine on the in vivo diameters of renal vessels. Dopamine (1 X 10(-6) to 3 X 10(-5) M) produced a concentration-dependent dilation of the arcuate and interlobular arteries and afferent arterioles. Efferent arterioles near the glomeruli also dilated to dopamine but the dilation was less than that of the preglomerular vessels. Higher dopamine concentrations (3 X 10(-4) and 1 X 10(-3) M) produced more variable effects, with a tendency for the arcuate and interlobular arteries and the afferent and efferent arterioles away from the glomeruli to decrease in diameter. After pretreatment with haloperidol, dopamine (1 X 10(-6) to 1 X 10(-4) M) did not dilate any pre- or postglomerular vascular segment, but the tendency for pre- and postglomerular constrictions with higher dopamine concentrations were not abolished. Pretreatment with phentolamine and propranolol enhanced the dilator response of the pre- and postglomerular vessels (except the afferent arterioles near glomeruli and efferent arterioles near welling points) to dopamine (3 X 10(-5) and 1 X 10(-4) M), and abolished the reductions in diameter produced by the high dopamine levels. These data indicate that the dilator effect of dopamine is mediated by interactions with specific dopaminergic receptors, while alpha and beta adrenergic receptors appear to mediate a constrictor influence observed with high dopamine concentrations. The overall effect of dopamine on the renal vessel diameters thus appears to depend on the balance of dilator and constrictor stimuli mediated by multiple receptors.

  11. Central actions of a novel and selective dopamine antagonist

    International Nuclear Information System (INIS)

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D 1 class, which is linked to the stimulation of adenylate cyclase-activity, and the D 2 class which is not. There is much evidence suggesting that it is the D 2 class which is not. There is much evidence suggesting that it is the D 2 dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D 1 class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of [ 3 H]-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D 1 receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for [ 3 H]-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D 1 receptors and [ 3 H]-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D 1 dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...

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

    International Nuclear Information System (INIS)

    Brann, M.R.

    1985-01-01

    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

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

    DEFF Research Database (Denmark)

    Binda, Francesca; Dipace, Concetta; Bowton, Erica

    2008-01-01

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

  15. Increased dopamine tone during meditation-induced change of consciousness

    DEFF Research Database (Denmark)

    Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola

    2002-01-01

    -raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7...

  16. Modafinil-Induced Increases in Brain Dopamine Levels

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-04-01

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

  17. Dopamine D2 receptors in the pathophysiology of insulin resistance

    NARCIS (Netherlands)

    Leeuw van Weenen, Judith Elisabeth de

    2011-01-01

    Extensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we focused on unraveling the characteristics of the interplay between dopamine D2 receptors and glucose

  18. CRYSTAL STRUCTURE OF HUMAN DOPAMINE BETA-HYDROXYLASE

    DEFF Research Database (Denmark)

    2017-01-01

    A crystalline form of dopamine β-hydroxylase is provided. X-ray crystallography reveals the space group and cell dimensions, as well as the atomic coordinates. The information can be used for identifying one or more modulators of dopamine β-hydroxylase, which can then be chemically synthesised...

  19. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

    NARCIS (Netherlands)

    Osinga, Thamara E; Links, Thera P; Dullaart, Robin P F; Pacak, Karel; Horst-Schrivers, van der Anouk; Kerstens, Michiel N.; Kema, Ido P

    Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets.

  20. Free and conjugated dopamine in human ventricular fluid

    International Nuclear Information System (INIS)

    Sharpless, N.S.; Thal, L.J.; Wolfson, L.I.; Tabaddor, K.; Tyce, G.M.; Waltz, J.M.

    1981-01-01

    Free dopamine and an acid hydrolyzable conjugate of dopamine were measured in human ventricular fluid specimens with a radioenzymatic assay and by high performance liquid chromatography (HPLC) with electrochemical detection. Only trace amounts of free norepinephrine and dopamine were detected in ventricular fluid from patients with movement disorders. When the ventricular fluid was hydrolyzed by heating in HClO 4 or by lyophilization in dilute HClO 4 , however, a substantial amount of free dopamine was released. Values for free plus conjugated dopamine in ventricular fluid from patients who had never taken L-DOPA ranged from 139 to 340 pg/ml when determined by HPLC and from 223 to 428 pg/ml when measured radioenzymatically. The correlation coefficient for values obtained by the two methods in the same sample of CSF was 0.94 (P<0.001). Patients who had been treated with L-DOPA had higher levels of conjugated dopamine in their ventricular CSF which correlated inversely with the time between the last dose of L-DOPA and withdrawal of the ventricular fluid. Additionally, one patient with acute cerebral trauma had elevated levels of free norepinephrine and both free and conjugated dopamine in his ventricular fluid. Conjugation may be an important inactivation pathway for released dopamine in man. (Auth.)

  1. Modelling the active site properties of dopamine b-hydroxylase

    Indian Academy of Sciences (India)

    Administrator

    Dopamine b-hydroxylase (DbH) is a copper-containing glycoprotein that hydroxylates dopamine to norepinephrine 1,2. Based on spectroscopic studies the active site of the metalloenzyme is proposed to have two copper centres. The enzyme in the oxidized dicopper(II) form gets reduced to the dicopper(I) unit by ascorbate ...

  2. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

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

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

  4. Current treatments in Parkinson's including the proposal of an innovative dopamine microimplant

    Directory of Open Access Journals (Sweden)

    M. Velázquez-Paniagua

    2016-04-01

    Full Text Available Parkinson's disease is a chronic, debilitating, progressive neurological disorder of multifactorial origin. It affects between 0.3% and 2% of the over-65 population worldwide, with a predilection for men, and is characterised by bradykinesia, muscular rigidity, resting tremor and postural instability. Parkinson's is caused by decreased dopamine levels due to the loss of dopaminergic neurons in the substantia nigra. Because dopamine is a highly oxidisable molecule, precursors such as levodopa, together with catechol-O-methyltransferase and monoamine oxidase inhibitors to prevent degradation, are used in the treatment of this disease. These therapies, however, are not without their adverse effects. Surgical treatments for Parkinson's include pallidotomy, therapy deep brain stimulation, and stem cells. A more recent development involves a titanium dioxide micro-implant containing nanopores that stabilise the dopamine for continuous release. When inserted into the caudate nucleus, this micro-implant was found to counteract 85% of symptoms in hemiparkinsonian rats, and is a promising therapy for patients with Parkinson's disease.

  5. Dopamine D1 receptors are responsible for stress-induced emotional memory deficit in mice.

    Science.gov (United States)

    Wang, Yongfu; Wu, Jing; Zhu, Bi; Li, Chaocui; Cai, Jing-Xia

    2012-03-01

    It is established that stress impairs spatial learning and memory via the hypothalamus-pituitary-adrenal axis response. Dopamine D1 receptors were also shown to be responsible for a stress-induced deficit of working memory. However, whether stress affects the subsequent emotional learning and memory is not elucidated yet. Here, we employed the well-established one-trial step-through task to study the effect of an acute psychological stress (induced by tail hanging for 5, 10, or 20 min) on emotional learning and memory, and the possible mechanisms as well. We demonstrated that tail hanging induced an obvious stress response. Either an acute tail-hanging stress or a single dose of intraperitoneally injected dopamine D1 receptor antagonist (SCH23390) significantly decreased the step-through latency in the one-trial step-through task. However, SCH23390 prevented the acute tail-hanging stress-induced decrease in the step-through latency. In addition, the effects of tail-hanging stress and/or SCH23390 on the changes in step-through latency were not through non-memory factors such as nociceptive perception and motor function. Our data indicate that the hyperactivation of dopamine D1 receptors mediated the stress-induced deficit of emotional learning and memory. This study may have clinical significance given that psychological stress is considered to play a role in susceptibility to some mental diseases such as depression and post-traumatic stress disorder.

  6. Guanine nucleotide regulatory protein co-purifies with the D2-dopamine receptor

    International Nuclear Information System (INIS)

    Senogles, S.E.; Caron, M.G.

    1986-01-01

    The D 2 -dopamine receptor from bovine anterior pituitary was purified ∼1000 fold by affinity chromatography on CMOS-Sepharose. Reconstitution of the affinity-purified receptor into phospholipid vesicles revealed the presence of high and low affinity agonist sites as detected by N-n-propylnorapomorphine (NPA) competition experiments with 3 H-spiperone. High affinity agonist binding could be converted to the low affinity form by guanine nucleotides, indicating the presence of an endogenous guanine nucleotide binding protein (N protein) in the affinity-purified D 2 receptor preparations. Furthermore, this preparation contained an agonist-sensitive GTPase activity which was stimulated 2-3 fold over basal by 10 μM NPA. 35 S-GTPγS binding to these preparations revealed a stoichiometry of 0.4-0.7 mole N protein/mole receptor, suggesting the N protein may be specifically coupled with the purified D 2 -dopamine receptor and not present as a contaminant. Pertussis toxin treatment of the affinity purified receptor preparations prevented high affinity agonist binding, as well as agonist stimulation of the GTPase activity, presumably by inactivating the associated N protein. Pertussis toxin lead to the ADP-ribosylation of a protein of 39-40K on SDS-PAGE. These findings indicate that an endogenous N protein, N/sub i/ or N/sub o/, co-purifies with the D 2 -dopamine receptor which may reflect a precoupling of this receptor with an N protein within the membranes

  7. The effects of Δ9-tetrahydrocannabinol on the dopamine system.

    Science.gov (United States)

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

    2016-11-17

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

  8. Dopamine release in ventral striatum of pathological gamblers losing money

    DEFF Research Database (Denmark)

    Linnet, J; Peterson, E; Doudet, D J

    2010-01-01

    Linnet J, Peterson E, Doudet DJ, Gjedde A, Møller A. Dopamine release in ventral striatum of pathological gamblers losing money. Objective: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue...... gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). Method: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure...... dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). Results: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. Conclusion: Our findings...

  9. Surface functionalization of polyamide fiber via dopamine polymerization

    Science.gov (United States)

    Kuang, Xiao-Hui; Guan, Jin-Ping; Tang, Ren-Cheng; Chen, Guo-Qiang

    2017-09-01

    The oxidative polymerization of dopamine for the functional surface modification of textile fibers has drawn great attention. In this work, the functionalization of polyamide fiber via dopamine polymerization was studied with the aim of the fabrication of hydrophilic and antistatic surface. The conditions of dopamine application were first discussed in the absence of specific oxidants in terms of the apparent color depth of polyamide fiber. Dopamine concentration, pH and time were found to exert great impact on color depth. The highest color depth was achieved at pH 8.5. In the process of modification, polydopamine was deposited onto the surface of polyamide fiber. The modified polyamide fiber displayed a yellowish brown color with excellent wash and light color fastness, and exhibited good hydrophilic, UV protection and antistatic effects. A disadvantage of the present approach was the slow rate of dopamine polymerization and functionalization.

  10. ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

    Science.gov (United States)

    Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

    2014-01-01

    Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. PMID:24656971

  11. A causal link between prediction errors, dopamine neurons and learning.

    Science.gov (United States)

    Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2013-07-01

    Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.

  12. Temporal Profiles Dissociate Regional Extracellular Ethanol versus Dopamine Concentrations

    Science.gov (United States)

    2015-01-01

    In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25–30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these “response ratios” differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research. PMID:25537116

  13. Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish

    NARCIS (Netherlands)

    T. Zhao (Tianna); H. Zondervan-van der Linde (Herma); E.A.W.F.M. Severijnen (Lies-Anne); B.A. Oostra (Ben); R. Willemsen (Rob); V. Bonifati (Vincenzo)

    2012-01-01

    textabstractRecessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15

  14. Bilateral nigral 6-hydroxydopamine lesions increase the amount of extracellular dopamine in the nucleus accumbens.

    NARCIS (Netherlands)

    Oosten, R.V. van; Verheij, M.M.M.; Cools, A.R.

    2005-01-01

    The goal of the present study was to provide neurochemical evidence for a shift in the functional balance between the nigrostriatal and mesolimbic pathway in favour of the mesolimbic pathway by investigating the effects of a partial, nigral, bilateral 6-hydroxydopamine lesion on basal and

  15. Male/female differences in neuroprotection and neuromodulation of brain dopamine.

    Directory of Open Access Journals (Sweden)

    Mélanie eBourque

    2011-09-01

    Full Text Available The existence of a sex difference in Parkinson’s disease is observed in several variables, including susceptibility of the disease, age at onset and symptoms. These differences between men and women represent a significant characteristic of Parkinson’s disease which suggests that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effect of 17β-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mice model of Parkinson’s disease and methamphetamine toxicity faithfully reproduce the sex differences of Parkinson’s disease in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the nigrostriatal dopaminergic system. Exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against nigrostriatal dopaminergic toxins while androgens fail to induce beneficial effect. Sex steroids treatments show males and females difference in their neuroprotective action against methamphetamine toxicity. Nigrostriatal dopaminergic structure and function, as well as the distribution of estrogen receptors, show sex difference and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17β-estradiol converge to promote survival factors and the presence of both estrogen receptors α and β are critical to 17β-estradiol neuroprotective action against MPTP toxicity.

  16. Essential Oils from the Medicinal Herbs Upregulate Dopamine Transporter in Rat Pheochromocytoma Cells.

    Science.gov (United States)

    Choi, Min Sun; Choi, Bang-sub; Kim, Sang Heon; Pak, Sok Cheon; Jang, Chul Ho; Chin, Young-Won; Kim, Young-Mi; Kim, Dong-il; Jeon, Songhee; Koo, Byung-Soo

    2015-10-01

    The dopamine transporter (DAT) protein, a component of the dopamine system, undergoes adaptive neurobiological changes from drug abuse. Prevention of relapse and reduction of withdrawal symptoms are still the major limitations in the current pharmacological treatments of drug addiction. The present study aimed to investigate the effects of essential oils extracted from Elsholtzia ciliata, Shinchim, Angelicae gigantis Radix, and Eugenia caryophyllata, well-known traditional Korean medicines for addiction, on the modulation of dopamine system in amphetamine-treated cells and to explore the possible mechanism underlying its therapeutic effect. The potential cytotoxic effect of essential oils was evaluated in PC12 rat pheochromocytoma cells using cell viability assays. Quantification of DAT, p-CREB, p-MAPK, and p-Akt was done by immunoblotting. DAT was significantly reduced in cells treated with 50 μM of amphetamine in a time-dependent manner. No significant toxicity of essential oils from Elsholtzia ciliata and Shinchim was observed at doses of 10, 25, and 50 μg/mL. However, essential oils from A. gigantis Radix at a dose of 100 μg/mL and E. caryophyllata at doses of 50 and 100 μg/mL showed cytotoxicity. Treatment with GBR 12909, a highly selective DAT inhibitor, significantly increased DAT expression compared with that of amphetamine only by enhancing phosphorylation of mitogen-activated protein kinases (MAPK) and Akt. In addition, essential oils effectively induced hyperphosphorylation of cyclic-AMP response element-binding protein (CREB), MAPK, and Akt, which resulted in DAT upregulation. Our study implies that the essential oils may rehabilitate brain dopamine function through increased DAT availability in abstinent former drug users.

  17. Dopamine receptors in the Parkinsonian brain

    International Nuclear Information System (INIS)

    Rinne, U.K.; Loennberg, P.; Koskinen, V.

    1981-01-01

    Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using 3 H-spiroperidol. The specific binding of 3 H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of 3 H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3 H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy. (author)

  18. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

    Science.gov (United States)

    Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

    2018-03-18

    The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

  19. Alterations of emotion, cognition and firing activity of the basolateral nucleus of the amygdala after partial bilateral lesions of the nigrostriatal pathway in rats.

    Science.gov (United States)

    Chen, Li; Liu, Jian; Zhang, Qiao Jun; Feng, Jian Jun; Gui, Zhen Hua; Ali, Umar; Wang, Yong; Fan, Ling Ling; Hou, Chen; Wang, Tao

    2011-07-15

    Although increasing evidence indicates that psychiatric symptoms are crucial characteristic of the early stage of Parkinson's disease (PD) and precede motor impairments, the neuronal firing activity of the basolateral nucleus of the amygdala (BLA) in the psychiatric symptom of PD and the involved mechanism are still unclear. In the present study, we examined the changes in emotional and cognitive tests not focused on motor fluency and firing activity of projection neurons in the BLA rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum, and the effects of apomorphine and the medial prefrontal cortex (mPFC) on these changes. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 18-22% and 26-30% loss of tyrosine hydroxylase immunoreactive neurons in the ventral tegmental area and substantia nigra pars compacta of rats, respectively. The striatal lesions induced anxiety-like responses in the rats but did not result in depressive-like behavior or cognitive impairments. In the lesioned rats, the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and the firing pattern of BLA projection neurons was not changed. No significant differences were observed either in behaviors or firing activity of BLA projection neurons by further ibotenic acid lesions of the mPFC in the lesioned rats. Systemic administration of cumulative apomorphine (10-160 μg/kg) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA-lesioned and combined 6-OHDA- and mPFC-lesioned rats, but the latter needed more apomorphine stimulation. These data suggest that the anxiety in early stage of PD is possibly related to the decrease in firing activity of BLA projection neurons, which may be regulated by the activation of dopamine receptor in the mPFC. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Decreased striatal dopamine transporter binding assessed with [123I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism.

    Science.gov (United States)

    Mateos, Jose J; Lomeña, Francisco; Parellada, Eduardo; Font, Mireia; Fernandez, Emili; Pavia, Javier; Prats, Alberto; Pons, Francisca; Bernardo, Miquel

    2005-09-01

    Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance of DIP. The goal of the study is to determine the striatal DAT binding assessed with [(123)I] FP-CIT SPECT in first-episode neuroleptic-naive schizophrenic in-patients with DIP after short-term antipsychotic treatment. The [(123)I] FP-CIT binding ratios of ten schizophrenic in-patients who developed DIP during the first 4-week period of risperidone treatment (6+/-2 mg/day) were compared with ten schizophrenic in-patients treated with the same doses of risperidone and who do not developed DIP and with ten age-matched healthy subjects. Quantitative analyses of SPECTs were performed using regions of interest located in caudate, putamen and occipital cortex. Parkinsonism was assessed by the Simpson-Angus Scale and the psychopathological status by the Clinical General Impression and Positive and Negative Syndrome Scales. Whole striatal [(123)I] FP-CIT binding ratios were significantly lower in patients with and without DIP than in healthy subjects (p<0.001). This was also observed in whole putamen (p<0.001) and caudate nucleus (p<0.001). Females showed higher whole striatal [(123)I] FP-CIT binding ratios than males (p<0.05). No differences in psychopathological scales were observed between patients with and without DIP. Our first-episode schizophrenic patients with and without DIP after short-term risperidone treatment have a decreased striatal DAT binding assessed with [(123)I] FP-CIT. This alteration could be related to the schizophrenic disease or may be secondary to the antipsychotic treatment.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    , Alzheimer’s disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600...... into the numerous devastating disorders of both physiological and neurological origins associated with the dopamine system....

  2. Dopamine modulates metabolic rate and temperature sensitivity in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Taro Ueno

    Full Text Available Homeothermal animals, such as mammals, maintain their body temperature by heat generation and heat dissipation, while poikilothermal animals, such as insects, accomplish it by relocating to an environment of their favored temperature. Catecholamines are known to regulate thermogenesis and metabolic rate in mammals, but their roles in other animals are poorly understood. The fruit fly, Drosophila melanogaster, has been used as a model system for the genetic studies of temperature preference behavior. Here, we demonstrate that metabolic rate and temperature sensitivity of some temperature sensitive behaviors are regulated by dopamine in Drosophila. Temperature-sensitive molecules like dTrpA1 and shi(ts induce temperature-dependent behavioral changes, and the temperature at which the changes are induced were lowered in the dopamine transporter-defective mutant, fumin. The mutant also displays a preference for lower temperatures. This thermophobic phenotype was rescued by the genetic recovery of the dopamine transporter in dopamine neurons. Flies fed with a dopamine biosynthesis inhibitor (3-iodo-L-tyrosine, which diminishes dopamine signaling, exhibited preference for a higher temperature. Furthermore, we found that the metabolic rate is up-regulated in the fumin mutant. Taken together, dopamine has functions in the temperature sensitivity of behavioral changes and metabolic rate regulation in Drosophila, as well as its previously reported functions in arousal/sleep regulation.

  3. Dopamine-imprinted monolithic column for capillary electrochromatography.

    Science.gov (United States)

    Aşır, Süleyman; Sarı, Duygu; Derazshamshir, Ali; Yılmaz, Fatma; Şarkaya, Koray; Denizli, Adil

    2017-11-01

    A dopamine-imprinted monolithic column was prepared and used in capillary electrochromatography as stationary phase for the first time. Dopamine was selectively separated from aqueous solution containing the competitor molecule norepinephrine, which is similar in size and shape to the template molecule. Morphology of the dopamine-imprinted column was observed by scanning electron microscopy. The influence of the organic solvent content of mobile phase, applied pressure and pH of the mobile phase on the recognition of dopamine by the imprinted monolithic column has been evaluated, and the imprinting effect in the dopamine-imprinted monolithic polymer was verified. Developed dopamine-imprinted monolithic column resulted in excellent separation of dopamine from structurally related competitor molecule, norepinephrine. Separation was achieved in a short period of 10 min, with the electrophoretic mobility of 5.81 × 10 -5  m 2 V -1 s -1 at pH 5.0 and 500 mbar pressure. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Noncovalent Interactions between Dopamine and Regular and Defective Graphene.

    Science.gov (United States)

    Fernández, Ana C Rossi; Castellani, Norberto J

    2017-08-05

    The role of noncovalent interactions in the adsorption of biological molecules on graphene is a subject of fundamental interest regarding the use of graphene as a material for sensing and drug delivery. The adsorption of dopamine on regular graphene and graphene with monovacancies (GV) is theoretically studied within the framework of density functional theory. Several adsorption modes are considered, and notably those in which the dopamine molecule is oriented parallel or quasi-parallel to the surface are the more stable. The adsorption of dopamine on graphene implies an attractive interaction of a dispersive nature that competes with Pauli repulsion between the occupied π orbitals of the dopamine ring and the π orbitals of graphene. If dopamine adsorbs at the monovacancy in the A-B stacking mode, a hydrogen bond is produced between one of the dopamine hydroxy groups and one carbon atom around the vacancy. The electronic charge redistribution due to adsorption is consistent with an electronic drift from the graphene or GV surface to the dopamine molecule. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive...

  6. Regulation of bat echolocation pulse acoustics by striatal dopamine.

    Science.gov (United States)

    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.

  7. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper.

  8. Problematic gambling on dopamine agonists: Not such a rarity.

    Science.gov (United States)

    Grosset, Katherine A; Macphee, Graeme; Pal, Guru; Stewart, David; Watt, Andrew; Davie, Jim; Grosset, D G

    2006-12-01

    Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinson's disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti-Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect. Copyright 2006 Movement Disorder Society.

  9. Evidence that Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

    OpenAIRE

    Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Benveniste, Helene; Kim, Ron; Thanos, Panayotis K.; Ferré, Sergi

    2012-01-01

    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 [11C]raclopride in controls) in striatum, but could not determine if this reflected dopamine increases ([11C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases in...

  10. Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

    Science.gov (United States)

    Masellis, Mario; Collinson, Shannon; Freeman, Natalie; Tampakeras, Maria; Levy, Joseph; Tchelet, Amir; Eyal, Eli; Berkovich, Elijahu; Eliaz, Rom E; Abler, Victor; Grossman, Iris; Fitzer-Attas, Cheryl; Tiwari, Arun; Hayden, Michael R; Kennedy, James L; Lang, Anthony E; Knight, Jo

    2016-07-01

    The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in

  11. Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.

    Directory of Open Access Journals (Sweden)

    Jean Lud Cadet

    Full Text Available Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH (2.5 mg/kg known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT and 5-hydroxyindoleacetic acid (5-HIAA levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025 in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection

  12. Dopamine Signaling in reward-related behaviors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun eBaik

    2013-10-01

    Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  13. Role of Dopamine Signaling in Drug Addiction.

    Science.gov (United States)

    Chen, Wan; Nong, Zhihuan; Li, Yaoxuan; Huang, Jianping; Chen, Chunxia; Huang, Luying

    2017-01-01

    Addiction is a chronic, relapsing disease of the brain that includes drug-induced compulsive seeking behavior and consumption of drugs. Dopamine (DA) is considered to be critical in drug addiction due to reward mechanisms in the midbrain. In this article, we review the major animal models in addictive drug experiments in vivo and in vitro. We discuss the relevance of the structure and pharmacological function of DA receptors. To improve the understanding of the role of DA receptors in reward pathways, specific brain regions, including the Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, and Habenula, are highlighted. These factors contribute to the development of novel therapeutic targets that act at DA receptors. In addiction, the development of neuroimaging method will increase our understanding of the mechanisms underlying drug addiction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Prefrontal cortical dopamine from an evolutionary perspective.

    Science.gov (United States)

    Lee, Young-A; Goto, Yukiori

    2015-04-01

    In this article, we propose the hypothesis that the prefrontal cortex (PFC) acquired neotenic development as a consequence of mesocortical dopamine (DA) innervation, which in turn drove evolution of the PFC into becoming a complex functional system. Accordingly, from the evolutionary perspective, decreased DA signaling in the PFC associated with such adverse conditions as chronic stress may be considered as an environmental adaptation strategy. Psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder may also be understood as environmental adaptation or a by-product of such a process that has emerged through evolution in humans. To investigate the evolutionary perspective of DA signaling in the PFC, domestic animals such as dogs may be a useful model.

  15. Possible involvement of dopamine and dopamine2 receptors in the inhibitions of gastric emptying by escin Ib in mice.

    Science.gov (United States)

    Matsuda, H; Li, Y; Yoshikawa, M

    2000-11-03

    It was previously reported that escin Ib isolated from horse chestnut inhibited gastric emptying (GE) in mice, in which the capsaicin-sensitive sensory nerves (CPSN), the central nervous system and endogenous prostaglandins (PGs) were involved. In the present study, the possible involvement of dopamine and dopamine receptors in the inhibition of GE by escin Ib were investigated in mice. GE inhibition by escin Ib (25 mg/kg, p.o.) was attenuated after pretreatment with a single bolus of DL-alpha-methyl-p-tyrosine methyl ester (400 mg/kg, s.c., an inhibitor of tyrosine hydroxylase), reserpine (5 mg/kg, p.o., a catecholamine depletor), 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor). Furthermore, pretreatment with spiperone (0.5-5 mg/kg, s.c., a dopamine2 receptor antagonist), haloperidol (0.5-10 mg/kg, s.c.) and metoclopramide (1-10 mg/kg, s.c.) (centrally acting dopamine2 receptor antagonists) attenuated the effect of escin Ib. Domperidone (0.1-5 mg/kg, s.c., a peripheral-acting dopamine2 antagonist) showed a weak attenuation, but SCH 23390 (1-5 mg/kg, s.c., a dopamine, receptor antagonist) did not. It is postulated that escin Ib inhibits GE, at least in part, mediated by CPSN, to stimulate the synthesis and/or release of dopamine, to act through central dopamine2 receptor, which in turn causes the release of PGs.

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

    National Research Council Canada - National Science Library

    Schumacher, Paul

    2001-01-01

    The neuronal membrane transporter for dopamine (DAT) is a member of the Na+ and Cl dependent family of transporters and concentrates dopamine intracellularly up to 106 fold over extracellular levels...

  17. Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior.

    Science.gov (United States)

    Young, Emily A; Dreumont, Sarah E; Cunningham, Christopher L

    2014-02-01

    These studies examined the roles of dopamine D1- and D2-like receptors within the nucleus accumbens (Acb) in the acquisition and expression of ethanol-induced (2g/kg) conditioned place preference (CPP) in adult male DBA/2J mice. Bilateral intra-Acb infusions of the D1-like dopamine receptor antagonist SCH23390 (0.05, 0.5μg/side) or the D2-like dopamine receptor antagonist raclopride (0.5-5.0μg/side) were administered 30min before each ethanol conditioning trial (acquisition studies) or before preference tests (expression studies). CPP was conditioned to tactile cues using an unbiased apparatus and procedure. Intra-Acb infusion of SCH23390 prevented CPP acquisition, whereas intra-Acb infusion of raclopride did not. Intra-Acb infusion of both antagonists, however, dose-dependently reduced ethanol-stimulated locomotor activity during conditioning. In contrast, intra-Acb antagonist infusion had no effect on ethanol CPP expression, suggesting that dopamine's role in the Acb is limited to neurobiological processes engaged during the learning of the relationship between contextual cues and ethanol reward. Control experiments showed that intra-Acb injection of SCH23390 alone produced no place conditioning and did not interfere with the acquisition of conditioned place aversion induced by lithium chloride, suggesting that the antagonist's effect on ethanol CPP was not due to a more general detrimental effect on associative learning. Overall, these data suggest that D1-like (but not D2-like) dopamine Acb receptors play an important role in the learning of context-ethanol associations, either by modulating the magnitude of ethanol reward or the rate of learning about ethanol reward. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [11C]raclopride to measure...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand...

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

    Science.gov (United States)

    Waddell, Scott

    2013-06-01

    Reinforcement systems are believed to drive synaptic plasticity within neural circuits that store memories. Recent evidence from the fruit fly suggests that anatomically distinct dopaminergic neurons ultimately provide the key instructive signals for both appetitive and aversive learning. This dual role for dopamine overturns the previous model that octopamine signalled reward and dopamine punishment. More importantly, this anatomically segregated double role for dopamine in reward and aversion mirrors that emerging in mammals. Therefore, an antagonistic organization of distinct reinforcing dopaminegic neurons is a conserved feature of brains. It now seems crucial to understand how the dopaminergic neurons are controlled and what the released dopamine does to the underlying circuits to convey opposite valence. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. High content of dopamine, a strong antioxidant, in Cavendish banana.

    Science.gov (United States)

    Kanazawa, K; Sakakibara, H

    2000-03-01

    A strong water-soluble antioxidant was identified in the popular commercial banana Musa cavendishii. It is dopamine, one of the catecholamines. For suppressing the oxygen uptake of linoleic acid in an emulsion and scavenging a diphenylpicrylhydrazyl radical, dopamine had greater antioxidative potency than glutathione, food additives such as butylated hydroxyanisole and hydroxytoluene, flavone luteolin, flavonol quercetin, and catechin, and similar potency to the strongest antioxidants gallocatechin gallate and ascorbic acid. Banana contained dopamine at high levels in both the peel and pulp. Dopamine levels ranged from 80-560 mg per 100 g in peel and 2.5-10 mg in pulp, even in ripened bananas ready to eat. Banana is thus one of the antioxidative foods.

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

    DEFF Research Database (Denmark)

    Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa

    2014-01-01

    Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we......-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake...... experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine...

  2. The effects of Δ9-tetrahydrocannabinol on the dopamine system

    Science.gov (United States)

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

    2016-01-01

    Preface Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug. PMID:27853201

  3. Selective response of dopamine in the presence of ascorbic acid ...

    African Journals Online (AJOL)

    Selective response of dopamine in the presence of ascorbic acid and uric acid at gold nanoparticles and multi-walled carbon nanotubes grafted with ethylene diamine tetraacetic acid modified electrode.

  4. Pharmacological modifications of dopamine transmission do not influence the striatal in vivo binding of [3H]mazindol or [3H]cocaine in mice.

    Science.gov (United States)

    Thibaut, F; Bonnet, J J; Vaugeois, J M; Costentin, J

    1996-03-01

    We have considered the in vivo striatal binding of two ligands of the neuronal dopamine uptake complex: [3H]cocaine and [3H]mazindol. The [3H]cocaine tracer dose labelled the dopamine uptake complex in striatum but not the noradrenaline complex in cerebellum. On the contrary, the [3H]mazindol tracer dose induced a marked labelling of the noradrenaline uptake complex in cerebellum; its prevention by desipramine (5 mg/kg) increased simultaneously the cerebral bioavailability and thereby the striatal labelling of the dopamine transporter. In mice submitted to treatments modifying dopaminergic transmission either to decrease it (gammabutyrolactone, 750 mg/kg, i.p.) or to increase it (L-DOPA, 200 mg/kg, i.p., dexamphetamine, 4 mg/kg, s.c., or their combination), only dexamphetamine pretreatment significantly reduced [3H]cocaine and [3H]mazindol binding. Thus it appears that the level of dopamine transmission would not interfere with the in vivo quantification of striatal dopamine uptake sites assessed with either ligands.

  5. Dopamine Modulates Motor Control in a Specific Plane Related to Support.

    Science.gov (United States)

    Herbin, Marc; Simonis, Caroline; Revéret, Lionel; Hackert, Rémi; Libourel, Paul-Antoine; Eugène, Daniel; Diaz, Jorge; de Waele, Catherine; Vidal, Pierre-Paul

    2016-01-01

    At the acute stage following unilateral labyrinthectomy (UL), rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion) and rolling (utricular lesion). At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats) and systemic injection of apomorphine (APO rats). The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL-rats, exhibited

  6. Dopamine Modulates Motor Control in a Specific Plane Related to Support.

    Directory of Open Access Journals (Sweden)

    Marc Herbin

    Full Text Available At the acute stage following unilateral labyrinthectomy (UL, rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion and rolling (utricular lesion. At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats and systemic injection of apomorphine (APO rats. The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL

  7. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    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.

  8. The effects of Δ9-tetrahydrocannabinol on the dopamine system

    OpenAIRE

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

    2016-01-01

    The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid–dopamine interactions...

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

    Directory of Open Access Journals (Sweden)

    Rothmond Debora A

    2012-02-01

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

  10. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Science.gov (United States)

    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. PMID:25988121

  11. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available 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.

  12. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

    Science.gov (United States)

    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.

  13. Purity and Enrichment of Laser-Microdissected Midbrain Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Amanda L. Brown

    2013-01-01

    Full Text Available The ability to microdissect individual cells from the nervous system has enormous potential, as it can allow for the study of gene expression in phenotypically identified cells. However, if the resultant gene expression profiles are to be accurately ascribed, it is necessary to determine the extent of contamination by nontarget cells in the microdissected sample. Here, we show that midbrain dopamine neurons can be laser-microdissected to a high degree of enrichment and purity. The average enrichment for tyrosine hydroxylase (TH gene expression in the microdissected sample relative to midbrain sections was approximately 200-fold. For the dopamine transporter (DAT and the vesicular monoamine transporter type 2 (Vmat2, average enrichments were approximately 100- and 60-fold, respectively. Glutamic acid decarboxylase (Gad65 expression, a marker for GABAergic neurons, was several hundredfold lower than dopamine neuron-specific genes. Glial cell and glutamatergic neuron gene expression were not detected in microdissected samples. Additionally, SN and VTA dopamine neurons had significantly different expression levels of dopamine neuron-specific genes, which likely reflects functional differences between the two cell groups. This study demonstrates that it is possible to laser-microdissect dopamine neurons to a high degree of cell purity. Therefore gene expression profiles can be precisely attributed to the targeted microdissected cells.

  14. Demonstration of specific dopamine receptors on human pituitary adenomas

    International Nuclear Information System (INIS)

    Koga, Masafumi; Nakao, Haruyoshi; Arao, Masayo; Sato, Bunzo; Noma, Keizo; Morimoto, Yasuhiko; Kishimoto, Susumu; Mori, Shintaro; Uozumi, Toru

    1987-01-01

    Dopamine receptors on human pituitary adenoma membranes were characterized using [ 3 H]spiperone as the radioligand. The specific [ 3 H]spiperone binding sites on prolactin (PRL)-secreting adenoma membranes were recognized as a dopamine receptor, based upon the data showing high affinity binding, saturability, specificity, temperature dependence, and reversibility. All of 14 PRL-secreting adenomas had high affinity dopamine receptors, with a dissociation constant (Kd) of 0.85±0.11 nmol/l (mean±SEM) and a maximal binding capacity (Bmax) of 428±48.6 fmol/mg protein. Among 14 growth hormone (GH)-secreting adenomas examined, 8 (57%) had dopamine receptors with a Kd of 1.90±0.47 nmol/l and a Bmax of 131±36.9 fmol/mg protein. Furthermore, 15 of 24 (58%) nonsecreting pituitary adenomas also had dopamine receptors with a Kd of 1.86±0.37 nmol/l and a Bmax of 162±26.0 fmol/mg protein. These results indicate that some GH-secreting adenomas as well as some nonsecreting pituitary adenomas contain dopamine receptors. But their affinity and number of binding sites are significantly lower (P<0.05) and fewer (P<0.001) respectively, than those in PRL-secreting adenomas. (author)

  15. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  16. Genetics of dopamine and its contribution to cocaine addiction.

    Science.gov (United States)

    Haile, Colin N; Kosten, Thomas R; Kosten, Therese A

    2007-01-01

    Cocaine addiction is a major health and social problem for which there are presently no effective pharmacotherapies. Many of the most promising medications target dopamine based on the large literature that supports its role in addiction. Recent studies show that genetic factors are also important. Rodent models and gene knock-out technology have helped elucidate the involvement of specific genes in the function of the dopamine reward system and intracellular cascades that lead to neuronal changes in this system. Human epidemiological, linkage, and association studies have identified allelic variants (polymorphisms) that give rise to altered metabolism of dopamine and its functional consequences. Individuals with these polymorphisms respond differently to psychostimulants and possibly to pharmacotherapies. Here we review the literature on genetic variations that affect dopamine neurotransmission, responses to psychostimulants and potential treatments for cocaine addiction. Behavioral responses to psychostimulants in animals with different or modified genetics in dopamine signaling are discussed. We also review polymorphisms in humans that affect dopaminergic neurotransmission and alter the subjective effects of psychostimulants. Pharmacotherapies may have increased efficacy when targeted to individuals possessing specific genetic polymophisms in dopamine's metabolic and intracellular messenger systems.

  17. Dopamine D1receptor activation maintains motor coordination and balance in rats.

    Science.gov (United States)

    Avila-Luna, Alberto; Gálvez-Rosas, Arturo; Durand-Rivera, Alfredo; Ramos-Languren, Laura-Elisa; Ríos, Camilo; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

    2018-02-01

    Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D 1 receptors (D 1 Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D 1 Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D 1 R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D 1 R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D 1 R agonist to prevent and reverse the effect of the D 1 R antagonist in beam-walking scores is an indicator that the function of D 1 Rs is necessary to maintain motor coordination and balance in rats. Our results support that D 1 Rs mediate the SCH-23390-induced deficit in motor coordination.

  18. Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: a trigger for pathological gambling in Parkinson's disease?

    Science.gov (United States)

    van Eimeren, Thilo; Ballanger, Bénédicte; Pellecchia, Giovanna; Miyasaki, Janis M; Lang, Anthony E; Strafella, Antonio P

    2009-12-01

    The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson's disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.

  19. SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

    International Nuclear Information System (INIS)

    Jongen, Cynthia; Bruin, Kora de; Booij, Jan; Beekman, Freek

    2008-01-01

    The dopamine D 2 receptor (D2R) is important in the mediation of addiction. [ 123 I]iodobenzamide (IBZM), a SPECT ligand for the D2R, has been used for in vivo studies of D2R availability in humans, monkeys, and rats. Although mouse models are important in the study of addiction, [ 123 I]IBZM has not been used in mice SPECT studies. This study evaluates the use of [ 123 I]IBZM for measuring D2R availability in mice. Pharmacokinetics of [ 123 I]IBZM in mice were studied with pinhole SPECT imaging after intravenous (i.v.) injection of [ 123 I]IBZM (20, 40, and 70 MBq). In addition, the ability to measure the release of endogenous dopamine after amphetamine administration with [ 123 I]IBZM SPECT was investigated. Thirdly, i.v. administration, the standard route of administration, and intraperitoneal (i.p.) administration of [ 123 I]IBZM were compared. Specific binding of [ 123 I]IBZM within the mouse striatum could be clearly visualized with SPECT. Peak specific striatal binding ratios were reached around 90 min post-injection. After amphetamine administration, the specific binding ratios of [ 123 I]IBZM decreased significantly (-27.2%; n=6; p=0.046). Intravenous administration of [ 123 I]IBZM led to significantly higher specific binding than i.p. administration of the same dose. However, we found that i.v. administration of a dose of 70 MBq [ 123 I]IBZM might result in acute ethanol intoxication because ethanol is used as a preparative aid for the routine production of [ 123 I]IBZM. Imaging of D2R availability and endogenous dopamine release in mice is feasible using [ 123 I]IBZM single pinhole SPECT. Using commercially produced [ 123 I]IBZM, a dose of 40 MBq injected i.v. can be recommended. (orig.)

  20. Toward a molecular understanding of psychostimulant actions using genetically engineered dopamine receptor knockout mice as model systems.

    Science.gov (United States)

    Zhang, J; Xu, M

    2001-01-01

    A major focus in studying the progression and prevention of addictive diseases has been to understand the molecular and cellular mechanisms underlying drug addiction. The brain dopaminergic system plays a central role in reward and motivation and is thought to be the main neural substrate for the actions of abusive drugs. We have used the gene targeting technology to generate dopamine D1 and D3 receptor knockout mice and used these mice as model systems to gain a molecular understanding of acute effects of psychostimulants cocaine and amphetamine. The use of a combined approach involving behavioral, electrophysiological as well as molecular studies has allowed us to define initially the roles of dopamine D1 and D3 receptors in the acute effects of psychostimulants and will enable us to understand mechanisms underlying their chronic actions in the future.

  1. Dopamine, prolactin and treatment of psychoses

    Directory of Open Access Journals (Sweden)

    Marić-Bojović Nađa P.

    2015-01-01

    Full Text Available Prolactin (pro-lactis, lat. is a hormone discovered around eight decades ago, with a numerous functions in human body including the effects on growth and development, influences on behavior, metabolism, reproduction, etc. More than 60 years after antipsychotic drugs were introduced, these medications have been keeping prolactin in the spotlight of the psychiatric research community as practically all D2-antagonists change prolactin levels. Hyperprolactinemia has been evaluated in several aspects, either related to patient's characteristics (genetic and functional individual features or to some drug-related phenomena (penetrability across the blood-brain barrier; D2 receptor binding affinity; capacity to antagonize serotonin receptors, but a critical review of the current literature indicates many unknowns in the field. The present paper will discuss the mechanism and dynamics of changes in prolactin levels throughout treatment with dopamine antagonists on the molecular and clinical level, and the risk of certain acute vs. late adverse effects. Moreover, different techniques that could be applied in common psychiatric practice aiming to control prolactin levels will be considered, with a special emphasis on the possibilities following synthesis and increasing availability of a third generation antipsychotics.

  2. Prefrontal Dopamine in Associative Learning and Memory

    Science.gov (United States)

    Puig, M. Victoria; Antzoulatos, Evan G.; Miller, Earl K.

    2014-01-01

    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 modulate associative learning and memory processes in frontostriatal systems. PMID:25241063

  3. Decreased lymphocyte dopamine transporter in romantic lovers.

    Science.gov (United States)

    Marazziti, Donatella; Baroni, Stefano; Giannaccini, Gino; Piccinni, Armando; Mucci, Federico; Catena-Dell'Osso, Mario; Rutigliano, Grazia; Massimetti, Gabriele; Dell'Osso, Liliana

    2017-06-01

    The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

  4. Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

    Science.gov (United States)

    Rioult-Pedotti, Mengia-Seraina; Pekanovic, Ana; Atiemo, Clement Osei; Marshall, John; Luft, Andreas Rüdiger

    2015-01-01

    Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

  5. Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

    Directory of Open Access Journals (Sweden)

    Mengia-Seraina Rioult-Pedotti

    Full Text Available Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA, leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

  6. Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours.

    Science.gov (United States)

    O'Sullivan, Sean S; Wu, Kit; Politis, Marios; Lawrence, Andrew D; Evans, Andrew H; Bose, Subrata K; Djamshidian, Atbin; Lees, Andrew J; Piccini, Paola

    2011-04-01

    Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive

  7. Levodopa and pramipexole effects on presynaptic dopamine PET markers and estimated dopamine release

    Energy Technology Data Exchange (ETDEWEB)

    Sossi, Vesna; Fuente-Fernandez, Raul de la [University of British Columbia, Vancouver (Canada); Department of Physics and Astronomy, Vancouver, BC (Canada); Dinelle, Katherine; Doudet, Doris J. [University of British Columbia, Vancouver (Canada); Schulzer, Michael; Mak, Edwin [Department of Physics and Astronomy, Vancouver, BC (Canada)

    2010-12-15

    Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson's disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [{delta}(DA)]. Twenty-three unilaterally 6-OHDA lesioned rats underwent an {sup 11}C-dihydrotetrabenazine (DTBZ, VMAT2 marker), an {sup 11}C-methylphenidate (MP, DAT marker), and a double {sup 11}C-raclopride (RAC, D{sub 2}-type receptor marker) scan. They were assigned to three treatment groups: saline (N = 7), pramipexole (N = 8), and levodopa (N = 8). After 4 weeks of treatment, imaging was repeated. Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on {delta}(DA). These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level. (orig.)

  8. Dopamine D1 and D2 receptor immunoreactivities in the arcuate-median eminence complex and their link to the tubero-infundibular dopamine neurons

    Directory of Open Access Journals (Sweden)

    W. Romero-Fernandez

    2014-07-01

    Full Text Available Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tubero-infundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region.  Dopamine D1 and D2 receptors may therefore directly

  9. Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.

    Science.gov (United States)

    Adrover, Martín F; Shin, Jung Hoon; Alvarez, Veronica A

    2014-02-26

    Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals.

  10. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Zigmond, Michael J; Smith, Amanda; Liou, Anthony

    2006-01-01

    Parkinson's disease results in part from the loss of dopamine neurons. We hypothesize that exercise reduces the vulnerability of dopamine neurons to neurotoxin exposure, whereas stress increases vulnerability...

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

    Science.gov (United States)

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

    2016-01-01

    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

  12. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans

    OpenAIRE

    Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2012-01-01

    Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT2C) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT2C receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT2C receptor...

  13. Creating dynamic images of short-lived dopamine fluctuations with lp-ntPET: dopamine movies of cigarette smoking.

    Science.gov (United States)

    Morris, Evan D; Kim, Su Jin; Sullivan, Jenna M; Wang, Shuo; Normandin, Marc D; Constantinescu, Cristian C; Cosgrove, Kelly P

    2013-08-06

    We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis--yielding a dopamine movie--is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters. This aspect of the analysis--temporal-variation--is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of five main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique 'HYPR' spatial filter that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model to a conventional model. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented.

  14. Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

    Directory of Open Access Journals (Sweden)

    Dimitri Ryczko

    2017-05-01

    Full Text Available In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the substantia nigra pars compacta was recently discovered. It innervates the mesencephalic locomotor region (MLR from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the substantia nigra pars compacta elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.

  15. Plasma functionalized surface of commodity polymers for dopamine detection

    Energy Technology Data Exchange (ETDEWEB)

    Fabregat, Georgina [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); Osorio, Joaquin [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Castedo, Alejandra [Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); Institut de Tècniques Energètiques, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Armelin, Elaine [Departament d’Enginyeria Química, E.T.S. d’Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, 08028, Barcelona (Spain); Center for Research in Nano-Engineering, Universitat Politècnica de Catalunya, Campus Sud, Edifici C’, C/Pasqual i Vila s/n, Barcelona, E-08028 (Spain); and others

    2017-03-31

    Highlights: • Electrochemically inert polymers become electroactive after plasma functionalization. • Selective dopamine detection has been achieved functionalizing polymers with plasma. • Plasma-functionalized polymers are sensitive dopamine detectors. • XPS analyses reflect the transformation of inert polymers into electrosensors. - Abstract: We have fabricated potentially generalizable sensors based on polymeric-modified electrodes for the electrochemical detection of dopamine. Sensitive and selective sensors have been successfully obtained by applying a cold-plasma treatment during 1–2 min not only to conducting polymers but also to electrochemically inert polymers, such as polyethylene, polypropylene, polyvinylpyrrolidone, polycaprolactone and polystyrene. The effects of the plasma in the electrode surface activation, which is an essential requirement for the dopamine detection when inert polymers are used, have been investigated using X-ray photoelectron spectroscopy. Results indicate that exposure of polymer-modified electrodes to cold-plasma produces the formation of a large variety of reactive species adsorbed on the electrode surface, which catalyse the dopamine oxidation. With this technology, which is based on the application of a very simple physical functionalization, we have defined a paradox-based paradigm for the fabrication of electrochemical sensors by using inert and cheap plastics.

  16. Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network

    Directory of Open Access Journals (Sweden)

    Stefanos Stagkourakis

    2016-04-01

    Full Text Available 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 effects. Activation of dopamine receptors of the type 2 family (D2Rs at the cell-body level slowed TIDA oscillations through two mechanisms. First, they prolonged the depolarizing phase through a combination of presynaptic increases in inhibition and postsynaptic hyperpolarization. Second, they extended the discharge phase through presynaptic attenuation of calcium currents and decreased synaptic inhibition. Dopamine reuptake blockade similarly reconfigured the oscillation, indicating that ambient somatodendritic transmitter concentration determines electrical behavior. In the absence of D2R feedback, however, discharge was abolished by depolarization block. These results indicate the existence of an ultra-short feedback loop whereby neuroendocrine dopamine neurons tune network behavior to echoes of their own activity, reflected in ambient somatodendritic dopamine, and also suggest a mechanism for antipsychotic side effects.

  17. Dopamine neurons learn relative chosen value from probabilistic rewards

    Science.gov (United States)

    Lak, Armin; Stauffer, William R; Schultz, Wolfram

    2016-01-01

    Economic theories posit reward probability as one of the factors defining reward value. Individuals learn the value of cues that predict probabilistic rewards from experienced reward frequencies. Building on the notion that responses of dopamine neurons increase with reward probability and expected value, we asked how dopamine neurons in monkeys acquire this value signal that may represent an economic decision variable. We found in a Pavlovian learning task that reward probability-dependent value signals arose from experienced reward frequencies. We then assessed neuronal response acquisition during choices among probabilistic rewards. Here, dopamine responses became sensitive to the value of both chosen and unchosen options. Both experiments showed also the novelty responses of dopamine neurones that decreased as learning advanced. These results show that dopamine neurons acquire predictive value signals from the frequency of experienced rewards. This flexible and fast signal reflects a specific decision variable and could update neuronal decision mechanisms. DOI: http://dx.doi.org/10.7554/eLife.18044.001 PMID:27787196

  18. The dopamine motive system: implications for drug and food addiction.

    Science.gov (United States)

    Volkow, Nora D; Wise, Roy A; Baler, Ruben

    2017-11-16

    Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

  19. Three dopamine pathways induce aversive odor memories with different stability.

    Directory of Open Access Journals (Sweden)

    Yoshinori Aso

    Full Text Available Animals acquire predictive values of sensory stimuli through reinforcement. In the brain of Drosophila melanogaster, activation of two types of dopamine neurons in the PAM and PPL1 clusters has been shown to induce aversive odor memory. Here, we identified the third cell type and characterized aversive memories induced by these dopamine neurons. These three dopamine pathways all project to the mushroom body but terminate in the spatially segregated subdomains. To understand the functional difference of these dopamine pathways in electric shock reinforcement, we blocked each one of them during memory acquisition. We found that all three pathways partially contribute to electric shock memory. Notably, the memories mediated by these neurons differed in temporal stability. Furthermore, combinatorial activation of two of these pathways revealed significant interaction of individual memory components rather than their simple summation. These results cast light on a cellular mechanism by which a noxious event induces different dopamine signals to a single brain structure to synthesize an aversive memory.

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

    Science.gov (United States)

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

    2014-03-01

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

  1. Dopamine alleviates nutrient deficiency-induced stress in Malus hupehensis.

    Science.gov (United States)

    Liang, Bowen; Li, Cuiying; Ma, Changqing; Wei, Zhiwei; Wang, Qian; Huang, Dong; Chen, Qi; Li, Chao; Ma, Fengwang

    2017-10-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, root system architecture, nutrient uptake, and responses to nutrient deficiencies in Malus hupehensis Rehd. Under a nutrient deficiency, plants showed significant reductions in growth, chlorophyll concentrations, and net photosynthesis, along with disruptions in nutrient uptake, transport, and distribution. However, pretreatment with 100 μM dopamine markedly alleviated such inhibitions. Supplementation with that compound enabled plants to maintain their photosynthetic capacity and development of the root system while promoting the uptake of N, P, K, Ca, Mg, Fe, Mn, Cu, Zn, and B, altering the way in which those nutrients were partitioned throughout the plant. The addition of dopamine up-regulated genes for antioxidant enzymes involved in the ascorbate-glutathione cycle (MdcAPX, MdcGR, MdMDHAR, MdDHAR-1, and MdDHAR-2) but down-regulated genes for senescence (SAG12, PAO, and MdHXK). These results indicate that exogenous dopamine has an important antioxidant and anti-senescence effect that might be helpful for improving nutrient uptake. Our findings demonstrate that dopamine offers new opportunities for its use in agriculture, especially when addressing the problem of nutrient deficiencies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Genetic Variation in the Dopamine System Influences Intervention Outcome in Children with Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Rochellys Diaz Heijtz

    2018-02-01

    Interpretation: Naturally occurring genetic variation in the dopamine system can influence treatment outcomes in children with cerebral palsy. A polygenic dopamine score might be valid for treatment outcome prediction and for designing individually tailored interventions for children with cerebral palsy.

  3. Donor dopamine treatment limits pulmonary oedema and inflammation in lung allografts subjected to prolonged hypothermia

    NARCIS (Netherlands)

    Hanusch, Christine; Nowak, Kai; Toerlitz, Patrizia; Gill, Ishar S.; Song, Hui; Rafat, Neysan; Brinkkoetter, Paul T.; Leuvenink, Henri G.; Van Ackern, Klaus C.; Yard, Benito A.; Beck, Grietje C.

    2008-01-01

    Background. Endothelial barrier dysfunction severely compromises organ function after reperfusion. Because dopamine pretreatment improves hypothermia mediated barrier dysfunction, we tested the hypothesis that dopamine treatment of lung allografts positively affects tissue damage associated with

  4. The evolution of dopamine systems in chordates

    Directory of Open Access Journals (Sweden)

    Kei eYamamoto

    2011-03-01

    Full Text Available Dopamine (DA neurotransmission in the central nervous system (CNS is found throughout chordates, and its emergence predates the divergence of chordates. Many of the molecular components of DA systems, such as biosynthetic enzymes, transporters and receptors, are shared with those of other monoamine systems, suggesting the common origin of these systems. In the mammalian CNS, the DA neurotransmitter systems are diversified and serve for visual and olfactory perception, sensory-motor programming, motivation, memory, emotion, and endocrine regulations. Some of the functions are conserved among different vertebrate groups, while others are not, and this is reflected in the anatomical aspects of DA systems in the forebrain and midbrain. Recent findings concerning a second tyrosine hydroxylase gene (TH2 revealed new populations of DA synthesizing cells, as evidenced in the periventricular hypothalamic zones of teleost fish. It is likely that the ancestor of vertebrates possessed TH2 DA-synthesizing cells, and the TH2 gene has been lost secondarily in placental mammals. All the vertebrates possess DA cells in the olfactory bulb, retina and in the diencephalon. Midbrain DA cells are abundant in amniotes while absent in some groups, e.g. teleosts. Studies of protochordate DA cells suggest that the diencephalic DA cells were present before the divergence of the chordate lineage. In contrast, the midbrain cell populations have probably emerged in the vertebrate lineage following the development of the midbrain-hindbrain boundary. The functional flexibility of the DA systems, and the evolvability provided by duplication of the corresponding genes permitted a large diversification of these systems. These features were instrumental in the adaptation of brain functions to the very variable way of life of vertebrates.

  5. Iron-Restricted Diet Affects Brain Ferritin Levels, Dopamine Metabolism and Cellular Prion Protein in a Region-Specific Manner

    Directory of Open Access Journals (Sweden)

    Jessica M. V. Pino

    2017-05-01

    Full Text Available Iron is an essential micronutrient for several physiological functions, including the regulation of dopaminergic neurotransmission. On the other hand, both iron, and dopamine can affect the folding and aggregation of proteins related with neurodegenerative diseases, such as cellular prion protein (PrPC and α-synuclein, suggesting that deregulation of iron homeostasis and the consequential disturbance of dopamine metabolism can be a risk factor for conformational diseases. These proteins, in turn, are known to participate in the regulation of iron and dopamine metabolism. In this study, we evaluated the effects of dietary iron restriction on brain ferritin levels, dopamine metabolism, and the expression levels of PrPC and α-synuclein. To achieve this goal, C57BL/6 mice were fed with iron restricted diet (IR or with normal diet (CTL for 1 month. IR reduced iron and ferritin levels in liver. Ferritin reduction was also observed in the hippocampus. However, in the striatum of IR group, ferritin level was increased, suggesting that under iron-deficient condition, each brain area might acquire distinct capacity to store iron. Increased lipid peroxidation was observed only in hippocampus of IR group, where ferritin level was reduced. IR also generated discrete results regarding dopamine metabolism of distinct brain regions: in striatum, the level of dopamine metabolites (DOPAC and HVA was reduced; in prefrontal cortex, only HVA was increased along with the enhanced MAO-A activity; in hippocampus, no alterations were observed. PrPC levels were increased only in the striatum of IR group, where ferritin level was also increased. PrPC is known to play roles in iron uptake. Thus, the increase of PrPC in striatum of IR group might be related to the increased ferritin level. α-synuclein was not altered in any regions. Abnormal accumulation of ferritin, increased MAO-A activity or lipid peroxidation are molecular features observed in several neurological

  6. Sources Contributing to the Average Extracellular Concentration of Dopamine in the Nucleus Accumbens

    OpenAIRE

    Owesson-White, CA; Roitman, MF; Sombers, LA; Belle, AM; Keithley, RB; Peele, JL; Carelli, RM; Wightman, RM

    2012-01-01

    Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine due to phasic firing – that is, the measurement of dopa...

  7. Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources

    Science.gov (United States)

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

    2012-01-01

    Accumulating evidence indicates integration of dopamine function with metabolic signals, highlighting a potential role for dopamine in energy balance, frequently construed as modulating reward in response to homeostatic state. Though its precise role remains controversial, the reward perspective of dopamine has dominated investigation of motivational disorders, including obesity. In the hypothesis outlined here, we suggest instead that the primary role of dopamine in behavior is to modulate activity to adapt behavioral energy expenditure to the prevailing environmental energy conditions, with the role of dopamine in reward and motivated behaviors derived from its primary role in energy balance. Dopamine has long been known to modulate activity, exemplified by psychostimulants that act via dopamine. More recently, there has been nascent investigation into the role of dopamine in modulating voluntary activity, with some investigators suggesting that dopamine may serve as a final common pathway that couples energy sensing to regulated voluntary energy expenditure. We suggest that interposed between input from both the internal and external world, dopamine modulates behavioral energy expenditure along two axes: a conserve-expend axis that regulates generalized activity and an explore-exploit axes that regulates the degree to which reward value biases the distribution of activity. In this view, increased dopamine does not promote consumption of tasty food. Instead increased dopamine promotes energy expenditure and exploration while decreased dopamine favors energy conservation and exploitation. This hypothesis provides a mechanistic interpretation to an apparent paradox: the well-established role of dopamine in food seeking and the findings that low dopaminergic functions are associated with obesity. Our hypothesis provides an alternative perspective on the role of dopamine in obesity and reinterprets the “reward deficiency hypothesis” as a perceived energy deficit

  8. Dopamine dysregulation syndrome in Parkinson's disease: a systematic review of published cases.

    Science.gov (United States)

    Warren, Nicola; O'Gorman, Cullen; Lehn, Alexander; Siskind, Dan

    2017-12-01

    Dopamine dysregulation syndrome (DDS) is an uncommon complication of the treatment of Parkinson's disease, characterised by addictive behaviour and excessive use of dopaminergic medication. DDS may frequently go unrecognised or misdiagnosed. We aimed to clarify current understanding of presentation, risk factors, comorbidities and management of DDS. Case reports were identified through a systematic search of databases (PubMed, Embase) with the following terms: dopaminergic dysregulation syndrome, hedonistic homeostatic dysregulation, dopamine/levodopa addiction. We reviewed 390 articles, identifying 98 cases of DDS. Early-onset Parkinson's disease (67%) and male gender (83%) were common. DDS presented with significant physical and social impairment, actions to enable or prevent detection of overuse, as well as mood, anxiety and motor fluctuations. All DDS cases met DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) substance use disorder criteria. Past substance and psychiatric history was present in 15.3% and 10.2% of cases. Comorbid impulse control disorders (61%), psychosis (32%) and panic attacks (14%) were common. A large variety of management strategies were used; only 56% of cases resolving. Sodium valproate was successful in 5/5 cases. The response to deep brain stimulation varied. Given the functional impairment, medical and psychiatric consequences and the difficulties of treatment, early identification of DDS should be a priority. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

    Energy Technology Data Exchange (ETDEWEB)

    Fox, Donald A., E-mail: dafox@uh.edu [College of Optometry, University of Houston, Houston, TX (United States); Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX (United States); Hamilton, W. Ryan [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Johnson, Jerry E. [Department of Natural Sciences, University of Houston-Downtown, Houston, TX (United States); Xiao, Weimin [College of Optometry, University of Houston, Houston, TX (United States); Chaney, Shawntay; Mukherjee, Shradha [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Miller, Diane B.; O' Callaghan, James P. [Toxicology and Molecular Biology Branch, Health Effects Research Laboratory, Centers for Disease Control and Prevention-NIOSH, Morgantown, WV USA (United States)

    2011-11-15

    -Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased the number of TH-immunoreactive dopaminergic amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure selectively decreased dopaminergic, but not GABAergic, glycinergic or cholinergic, amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased retinal dopamine content, its metabolites and dopamine utilization Black-Right-Pointing-Pointer A decrease in dopamine can alter ERG amplitudes, circadian rhythms, dark/light adaptation and spatial contrast sensitivity.

  10. Raman Spectroscopic Signature Markers of Dopamine-Human Dopamine Transporter Interaction in Living Cells.

    Science.gov (United States)

    Silwal, Achut P; Yadav, Rajeev; Sprague, Jon E; Lu, H Peter

    2017-07-19

    Dopamine (DA) controls many psychological and behavioral activities in the central nervous system (CNS) through interactions with the human dopamine transporter (hDAT) and dopamine receptors. The roles of DA in the function of the CNS are affected by the targeted binding of drugs to hDAT; thus, hDAT plays a critical role in neurophysiology and neuropathophysiology. An effective experimental method is necessary to study the DA-hDAT interaction and effects of variety of drugs like psychostimulants and antidepressants that are dependent on this interaction. In searching for obtaining and identifying the Raman spectral signatures, we have used surface enhanced Raman scattering (SERS) spectroscopy to record SERS spectra from DA, human embryonic kidney 293 cells (HEK293), hDAT-HEK293, DA-HEK293, and DA-hDAT-HEK293. We have demonstrated a specific 2D-distribution SERS spectral analytical approach to analyze DA-hDAT interaction. Our study shows that the Raman modes at 807, 839, 1076, 1090, 1538, and 1665 cm -1 are related to DA-hDAT interaction, where Raman shifts at 807 and 1076 cm -1 are the signature markers for the bound state of DA to probe DA-hDAT interaction. On the basis of density function theory (DFT) calculation, Raman shift of the bound state of DA at 807 cm -1 is related to combination of bending modes α(C3-O10-H21), α(C2-O11-H22), α(C7-C8-H18), α(C6-C4-H13), α(C7-C8-H19), and α(C7-C8-N9), and Raman shift at 1076 cm -1 is related to combination of bending modes α(H19-N9-C8), γ(N9-H19), γ(C8-H19), γ(N9-H20), γ(C8-H18), and α(C7-C8-H18). These findings demonstrate that protein-ligand interactions can be confirmed by probing change in Raman shift of ligand molecules, which could be crucial to understanding molecular interactions between neurotransmitters and their receptors or transporters.

  11. Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

    Science.gov (United States)

    Kalaba, Predrag; Aher, Nilima Y; Ilić, Marija; Dragačević, Vladimir; Wieder, Marcus; Miklosi, Andras G; Zehl, Martin; Wackerlig, Judith; Roller, Alexander; Beryozkina, Tetyana; Radoman, Bojana; Saroja, Sivaprakasam R; Lindner, Wolfgang; Gonzalez, Eduardo Perez; Bakulev, Vasiliy; Leban, Johann Jakob; Sitte, Harald H; Urban, Ernst; Langer, Thierry; Lubec, Gert

    2017-11-22

    Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.

  12. Preparation of (7,8-3H) dopamine

    International Nuclear Information System (INIS)

    Shen Qiyuan; Tang Guozhong; Guo Zili

    1986-01-01

    Dopamine is a neurotransmitter in the central nervous system. (7,8- 3 H) dopamine is an important tracer for the study of physiological functions and metabolic processes. It was prepared by catalytic reduction of 3-hydroxy-4-methoxy-8-nitro-styrene with tritium gas. At the end of reaction, hydrobromic acid was added and heated to remove the methoxyl group. The crude product was purified by paper chromatography. The purity of (7,8- 3 H) dopamine was identified by IR, UV, PC and 3 H-NMR spectra. The radiochemical purity was over 95% and the specific activity was 1.26 x 10 12 Bq/mmol (34 Ci/mmol). The distribution of labelled tritium in molecule was shown as follows: 55.4% at position 7 and 44.6% at position 8

  13. Developmental origins of brain disorders: roles for dopamine

    Directory of Open Access Journals (Sweden)

    Kelli M Money

    2013-12-01

    Full Text Available Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.

  14. Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration

    Directory of Open Access Journals (Sweden)

    Caroline E Bass

    2013-11-01

    Full Text Available There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2 on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.

  15. Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus.

    Science.gov (United States)

    Dirkx, Michiel F; den Ouden, Hanneke E M; Aarts, Esther; Timmer, Monique H M; Bloem, Bastiaan R; Toni, Ivan; Helmich, Rick C

    2017-03-01

    Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role

  16. Encoding of aversion by dopamine and the nucleus accumbens

    Directory of Open Access Journals (Sweden)

    James Edgar Mccutcheon

    2012-09-01

    Full Text Available Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc and the dopamine projection to it are considered an integral part of the brain’s reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias towards reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area (VTA and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus – intraoral infusion of sucrose – has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion versus reward.

  17. Evaluation of potential agonist radioligands for imaging dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, J.P.

    2015-01-01

    Imaging dopamine receptors with PET and SPECT can shed light on the nature of neuropsychiatric disorders which are characterized by disturbances in dopamine D2/3 receptor functioning. Agonist radioligands are considered superior to antagonists because they are more sensitive to detect dopamine

  18. Study and development of retinal dopamine nervous system in experimental myopia

    International Nuclear Information System (INIS)

    Zhao Juan; Liu Xingdang

    2007-01-01

    Myopia is the most familiar ametropia. Animal experimental models include form deprivation myopia and defocus myopia. Experimental animals we often use are chicken and mammals. The retinal dopamine system and vision experience have close relations with the regulation of eyeball's growth after birth, while the change of dopamine transporter may reflect the change of dopamine in the synaptic cleft more directly. (authors)

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  20. Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

    NARCIS (Netherlands)

    de Jong, Johannes W.; Roelofs, Theresia J M; Mol, Frédérique M U; Hillen, Anne E J; Meijboom, Katharina E.; Luijendijk, Mieneke C M; Van Der Eerden, Harrie A M; Garner, Keith M.; Vanderschuren, Louk J M J; Adan, Roger A H

    2015-01-01

    Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area

  1. Dopamine efflux in nucleus accumbens shell and core in response to appetitive classical conditioning

    NARCIS (Netherlands)

    Cheng, J. J.; de Bruin, J. P. C.; Feenstra, M. G. P.

    2003-01-01

    Dopamine transmission within the nucleus accumbens has been implicated in associative reinforcement learning. We investigated the effect of appetitive classical conditioning on dopamine efflux in the rat nucleus accumbens shell and core, as dopamine may be differentially activated by conditioned and

  2. No association between striatal dopamine transporter binding and body mass index

    DEFF Research Database (Denmark)

    van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

    2013-01-01

    Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine tr...

  3. An indirect action of dopamine on the rat fundus strip mediated by 5-hydroxytryptamine

    NARCIS (Netherlands)

    Sonneville, P.F.

    Dopamine in a concentration of 10−7 molar produces a contraction of the rat stomach fundus preparation. This effect is blocked by the 5-HT antagonist methysergide. Repeated exposure to dopamine results in tachyphylaxis, but the sensitivity to dopamine can be restored by incubating the tissue with

  4. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more

  5. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists

  6. Study of dopamine reactivity on platinum single crystal electrode surfaces

    International Nuclear Information System (INIS)

    Chumillas, Sara; Figueiredo, Marta C.; Climent, Víctor; Feliu, Juan M.

    2013-01-01

    Dopamine is the biological molecule responsible, among other functions, of the heart beat and blood pressure regulation. Its loss, in the human body, can result in serious diseases such as Parkinson's, schizophrenia or depression. Structurally, this molecule belongs to the group of catecholamines, together with epinephrine (adrenaline) and norepinephrine (noradrenaline). The hydroquinone moiety of the molecule can be easily oxidized to quinone, rendering the electrochemical methods a convenient approach for the development of dopamine biosensors. The reactivity of similar aromatic molecules, such as catechol and hydroquinone, at well-ordered platinum surfaces, has recently been investigated in our group. In this paper, we extend these studies to the structurally related molecule dopamine. The study has been performed in neutral pH, since this is closer to the natural conditions for these molecules in biological media. Cyclic voltammetry and in situ infra-red spectroscopy have been combined to extract information about the behavior of this molecule on well-defined platinum surfaces. Dopamine appears to be electrochemically active and reveals interesting adsorption phenomena at low potentials (0.15–0.25 V vs RHE), sensitive to the single crystal orientation. The adsorption of dopamine on these surfaces is very strong, taking place at much lower potentials than the electron transfer from solution species. Specifically, the voltammetry of Pt(1 1 1) and Pt(1 0 0) in dopamine solutions shows an oxidation peak at potentials close to the onset of hydrogen evolution, which is related to the desorption of hydrogen and the adsorption of dopamine. On the other hand, adsorption on Pt(1 1 0) is irreversible and the surface appears totally blocked. Spectroscopic results indicate that dopamine is adsorbed flat on the surface. At potentials higher than 0.6 V vs RHE the three basal planes show a common redox process. The initial formation of the quinone moiety is followed by a

  7. Dietary dopamine causes ovary activation in queenless Apis mellifera workers

    OpenAIRE

    Dombroski, T.; Zila Luz Paulino Simões,; Marcia Marcia Gentile Bitondi,

    2003-01-01

    International audience; Groups of young honey bee workers were fed a diet containing dopamine while confined in small cages at 34 °C and 80% RH in absence of a queen for 8 to 13 days. The bees in eight pairs of cages, each pair containing an equal number of workers, received a pollen-rich diet supplemented with dopamine (10 $\\mu$g/g of diet) (DOP groups), or not supplemented (controls). The rate of consumption of the diet was monitored continuously during the confinement period, after which t...

  8. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    International Nuclear Information System (INIS)

    Volkow, N.D.; Fowler, J.S.; Wolf, A.P.; Schlyer, D.; Shiue, C.Y.; Alpert, R.; Dewey, S.L.; Logan, J.; Bendriem, B.; Christman, D.

    1990-01-01

    To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [ 18 F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [ 18 F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval

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

    DEFF Research Database (Denmark)

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

    1997-01-01

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

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

    DEFF Research Database (Denmark)

    Vendelboe, Trine Vammen

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

  11. Dopamine signaling in food addiction: role of dopamine D2 receptors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun Baik

    2013-11-01

    Full Text Available Dopamine (DA regulates emotional and motivationalbehavior through the mesolimbic dopaminergic pathway.Changes in DA signaling in mesolimbic neurotransmission arewidely believed to modify reward-related behaviors and aretherefore closely associated with drug addiction. Recentevidence now suggests that as with drug addiction, obesitywith compulsive eating behaviors involves reward circuitry ofthe brain, particularly the circuitry involving dopaminergicneural substrates. Increasing amounts of data from humanimaging studies, together with genetic analysis, havedemonstrated that obese people and drug addicts tend to showaltered expression of DA D2 receptors in specific brain areas,and that similar brain areas are activated by food-related anddrug-related cues. This review focuses on the functions of theDA system, with specific focus on the physiological interpretationand the role of DA D2 receptor signaling in foodaddiction. [BMB Reports 2013; 46(11: 519-526

  12. [11]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

    International Nuclear Information System (INIS)

    Fowler, Joanna S.; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

    2001-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2001-07-01

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

  14. Dopamine enhances duodenal epithelial permeability via the dopamine D5receptor in rodent.

    Science.gov (United States)

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

    2017-05-01

    The intestinal barrier is made up of epithelial cells and intercellular junctional complexes to regulate epithelial ion transport and permeability. Dopamine (DA) is able to promote duodenal epithelial ion transport through D1-like receptors, which includes subtypes of D 1 (D 1 R) and D 5 (D 5 R), but whether D1-like receptors influence the duodenal permeability is unclear. FITC-dextran permeability, short-circuit current (I SC ), Western blot, immunohistochemistry and ELISA were used in human D 5 R transgenic mice and hyperendogenous enteric DA (HEnD) rats in this study. Dopamine induced a downward deflection in I SC and an increase in FITC-dextran permeability of control rat duodenum, which were inhibited by the D1-like receptor antagonist, SCH-23390. However, DA decreased duodenal transepithelial resistance (TER), an effect also reversed by SCH-23390. A strong immunofluorescence signal for D 5 R, but not D 1 R, was observed in the duodenum of control rat. In human D 5 R knock-in transgenic mice, duodenal mucosa displayed an increased basal I SC with high FITC-dextran permeability and decreased TER with a lowered expression of tight junction proteins, suggesting attenuated duodenal barrier function in these transgenic mice. D 5 R knock-down transgenic mice manifested a decreased basal I SC with lowered FITC-dextran permeability. Moreover, an increased FITC-dextran permeability combined with decreased TER and tight junction protein expression in duodenal mucosa were also observed in HEnD rats. This study demonstrates, for the first time, that DA enhances duodenal permeability of control rat via D 5 R, which provides new experimental and theoretical evidence for the influence of DA on duodenal epithelial barrier function. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  15. Dopamine system: Manager of neural pathways

    Directory of Open Access Journals (Sweden)

    Simon eHong

    2013-12-01

    Full Text Available There are a growing number of roles that midbrain dopamine (DA neurons assume, such as, reward, aversion, alerting and vigor. Here I propose a theory that may be able to explain why the suggested functions of DA came about. It has been suggested that largely parallel cortico-basal ganglia-thalamo-cortico loops exist to control different aspects of behavior. I propose that (1 the midbrain DA system is organized in a similar manner, with different groups of DA neurons corresponding to these parallel neural pathways (NPs. The DA system can be viewed as the manager of these parallel NPs in that it recruits and activates only the task-relevant NPs when they are needed. It is likely that the functions of those NPs that have been consistently activated by the corresponding DA groups are facilitated. I also propose that (2 there are two levels of DA roles: the How and What roles. The How role is encoded in tonic and phasic DA neuron firing patterns and gives a directive to its target NP: how vigorously its function needs to be carried out. The tonic DA firing is to maintain a certain level of DA in the target NPs to support their expected behavioral and mental functions; it is only when a sudden unexpected boost or suppression of activity is required by the relevant target NP that DA neurons in the corresponding NP act in a phasic manner. The What role is the implementational aspect of the role of DA in the target NP, such as binding to D1 receptors to boost working memory. This What aspect of DA explains why DA seems to assume different functions depending on the region of the brain in which it is involved. In terms of the role of the lateral habenula (LHb, the LHb is expected to suppress maladaptive behaviors and mental processes by controlling the DA system. The demand-based smart management by the DA system may have given animals an edge in evolution with adaptive behaviors and a better survival rate in resource-scarce situations.

  16. Acute fasting increases somatodendritic dopamine release in the ventral tegmental area.

    Science.gov (United States)

    Roseberry, Aaron G

    2015-08-01

    Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. Copyright © 2015 the American Physiological Society.

  17. Determination of the cerebral dopamine-D2-receptor density by 123I-IBZM-SPECT in patients with Parkinson's disease

    International Nuclear Information System (INIS)

    Hierholzer, J.; Cordes, M.; Barzen, G.; Keske, U.; Felix, R.; Schelosky, L.; Poewe, H.; Henkes, H.; Horowski, R.

    1992-01-01

    An alteration of the dopaminergic nigrostriatal system is believed to be the main pathogenetic factor of Parkinson's disease (PD). We report on our initial results on the determination of the post-synapticdopamine-D2-receptor binding of 123 I-IBZM in patients with PD. Drug-native patients showed a significantly higher IBZM binding in the basal ganglia as compared to patients on specific dopaminergic medication. We conclude that 123 I-IBZM-SPECT is an extremely usuful tool for the evaluation of the functional state of cerebraldopamine-D2-receptors. 'orig./DG) [de

  18. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

    OpenAIRE

    Mencacci, Niccolò E.; Isaias, Ioannis U.; Reich, Martin M.; Ganos, Christos; Plagnol, Vincent; Polke, James M.; Bras, Jose; Hersheson, Joshua; Stamelou, Maria; Pittman, Alan M.; Noyce, Alastair J.; Mok, Kin Y.; Opladen, Thomas; Kunstmann, Erdmute; Hodecker, Sybille

    2014-01-01

    GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-...

  19. Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.

    OpenAIRE

    Mencacci, N. E.; Isaias, I. U.; Reich, M. M.; Ganos, C.; Plagnol, V.; Polke, J. M.; Bras, J.; Hersheson, J.; Stamelou, M.; Pittman, A. M.; Noyce, A. J.; Mok, K. Y.; Opladen, T.; Kunstmann, E.; Hodecker, S.

    2014-01-01

    GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-...

  20. Mast cells express tyrosine hydroxylase and store dopamine in a serglycin-dependent manner.

    Science.gov (United States)

    Rönnberg, Elin; Calounova, Gabriela; Pejler, Gunnar

    2012-01-01

    Here we show that mast cells contain dopamine and that mast cell activation causes dopamine depletion, indicating its presence within secretory granules. Dopamine storage increased during mast cell maturation from bone marrow precursors, and was dependent on the presence of serglycin. Moreover, the expression of tyrosine hydroxylase, the key enzyme in dopamine biosynthesis, was induced during mast cell maturation; histidine decarboxylase and tryptophan hydroxylase 1 were also induced. Mast cell activation caused a robust induction of histidine decarboxylase, but no stimulation of tyrosine hydroxylase or tryptophan hydroxylase 1 expression. The present study points toward a possible role of dopamine in mast cell function.

  1. Inverted-U-shaped correlation between dopamine receptor availability in striatum and sensation seeking

    DEFF Research Database (Denmark)

    Gjedde, Albert; Kumakura, Yoshitaka; Cumming, Paul

    2010-01-01

    Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D(2/3) receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability...... to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted individuals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of individuals with low binding potentials....

  2. Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

    Science.gov (United States)

    Kaasinen, Valtteri; Vahlberg, Tero

    2017-12-01

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

  3. The role of the dopamine D1 receptor in social cognition : Studies using a novel genetic rat model

    NARCIS (Netherlands)

    Homberg, J R; Olivier, J D A; VandenBroeke, M; Youn, J; Ellenbroek, A K; Karel, P; Shan, L; van Boxtel, R; Ooms, S; Balemans, M; Langedijk, J; Muller, M; Vriend, G; Cools, A R; Cuppen, E; Ellenbroek, B A

    2016-01-01

    Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1

  4. The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model

    NARCIS (Netherlands)

    Homberg, J.R.; Olivier, J.D.; VandenBroeke, M.; Youn, J.; Ellenbroek, A.K.; Karel, P.; Shan, L.; Boxtel, R. van; Ooms, S.; Balemans, M.; Langedijk, J.; Muller, M.; Vriend, G.; Cools, A.R.; Cuppen, E.; Ellenbroek, B.A.

    2016-01-01

    Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1

  5. The role of the dopamine D1 receptor in social cognition : Studies using a novel genetic rat model

    NARCIS (Netherlands)

    Homberg, Judith R.; Olivier, Jocelien D A; VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K.; Karel, Peter; Shan, Ling; Van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R.; Cuppen, Edwin; Ellenbroek, Bart A.

    2016-01-01

    Social cognitionisan endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1

  6. Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy.

    Science.gov (United States)

    Ding, Saidan; Yang, Jianjing; Huang, Xueli; Liu, Leping; Hu, Jiangnan; Xu, Zhu; Zhuge, Qichuan

    2017-07-01

    Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA-treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE.

  7. The dopamine metabolite 3-methoxytyramine is a neuromodulator.

    Directory of Open Access Journals (Sweden)

    Tatyana D Sotnikova

    2010-10-01

    Full Text Available Dopamine (3-hydroxytyramine is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT, can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1. Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia.

  8. Dopamine receptors - physiological understanding to therapeutic intervention potential

    NARCIS (Netherlands)

    Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

    1999-01-01

    There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a

  9. Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus

    NARCIS (Netherlands)

    Dirkx, M.F.M.; Ouden, H.E.M. den; Aarts, E.; Timmer, M.H.M.; Bloem, B.R.; Toni, I.; Helmich, R.C.G.

    2017-01-01

    Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic

  10. TFH-derived dopamine accelerates productive synapses in germinal centres.

    Science.gov (United States)

    Papa, Ilenia; Saliba, David; Ponzoni, Maurilio; Bustamante, Sonia; Canete, Pablo F; Gonzalez-Figueroa, Paula; McNamara, Hayley A; Valvo, Salvatore; Grimbaldeston, Michele; Sweet, Rebecca A; Vohra, Harpreet; Cockburn, Ian A; Meyer-Hermann, Michael; Dustin, Michael L; Doglioni, Claudio; Vinuesa, Carola G

    2017-07-20

    Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (T FH ) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human T FH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. T FH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human T FH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.

  11. Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux

    Directory of Open Access Journals (Sweden)

    Watson Cheryl S

    2009-06-01

    Full Text Available Abstract Background Neurological diseases and neuropsychiatric disorders that vary depending on female life stages suggest that sex hormones may influence the function of neurotransmitter regulatory machinery such as the dopamine transporter (DAT. Results In this study we tested the rapid nongenomic effects of several physiological estrogens [estradiol (E2, estrone (E1, and estriol (E3] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12 cell model that expresses membrane estrogen receptors (ERs α, β, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E2-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca2+-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs. Using kinase inhibitors we also showed that E2-mediated dopamine efflux is dependent on protein kinase C and MEK activation, but not on PI3K or protein kinase A. In plasma membrane there are ligand-independent associations of ERα and ERβ (but not GPR30 with DAT. Conditions which cause efflux (a 9 min 10-9 M E2 treatment cause trafficking of ERα (stimulatory to the plasma membrane and trafficking of ERβ (inhibitory away from the plasma membrane. In contrast, E1 and E3 can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane. Conclusion Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.

  12. Dopamine and Impulse Control Disorders in Parkinson’s Disease

    Science.gov (United States)

    Weintraub, Daniel

    2012-01-01

    There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs. PMID:19127573

  13. Regulation of dopamine transporter activity by carboxypeptidase E

    Directory of Open Access Journals (Sweden)

    Zhang Heping

    2009-05-01

    Full Text Available Abstract Background The dopamine transporter (DAT plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT can directly interact with other cellular proteins and regulate DAT function and trafficking. Results Here, we have identified that carboxypeptidase E (CPE, a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization. Conclusion Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.

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

    NARCIS (Netherlands)

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

    2014-01-01

    To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [(18)F]fluorometatyrosine (FMT), correlates with food-related

  15. Does activation of midbrain dopamine neurons promote or reduce feeding?

    NARCIS (Netherlands)

    Boekhoudt, L.; Roelofs, T. J.M.; de Jong, J. W.; de Leeuw, A. E.; Luijendijk, M. C.M.; Wolterink-Donselaar, I. G.; van der Plasse, G.; Adan, R. A.H.

    Background:Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced

  16. Does activation of midbrain dopamine neurons promote or reduce feeding?

    NARCIS (Netherlands)

    Boekhoudt, L.; Roelofs, T. J. M.; de Jong, J. W.; de Leeuw, A. E.; Luijendijk, M. C. M.; Wolterink-Donselaar, I. G.; van der Plasse, G.; Adan, R. A. H.

    2017-01-01

    BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced

  17. Preparation and characterization of dopamine-decorated hydrophilic carbon black

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Lijun; Lu Yonglai [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Beijing City on Preparation and Processing of Novel Polymer Materials, Beijing 100029 (China); Wang Yiqing [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, Beijing 100029 (China); Zhang Liqun [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Beijing City on Preparation and Processing of Novel Polymer Materials, Beijing 100029 (China); Wang Wencai, E-mail: wangw@mail.buct.edu.cn [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, Beijing 100029 (China)

    2012-05-01

    Inspired by the bio-adhesive proteins secreted by mussels for attachment to almost all wet substrates, a facile method involving oxidative polymerization of dopamine was proposed to prepare highly hydrophilic carbon black (CB) particles. A self-assembled polydopamine (PDA) ad-layer was formed via the oxidative polymerization of dopamine on the surface of CB simply by dipping the CB into an alkaline dopamine solution and mildly stirring at room temperature. The process is simple, controllable, and environment-friendly. The surface composition and structure of the CB were characterized by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The surface morphology of the CB was observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results showed that the PDA ad-layer was successfully deposited on the CB surfaces. The PDA-functionalized CB (CB-PDA) gave a stable colloidal dispersion in water. Contact angle measurement results indicated that the hydrophilicity of CB was significantly improved after dopamine modification. TGA results confirmed that the modified CB maintained good heat resistance. The method provided a facile route to prepare hydrophilic CB having terminal hydroxyl groups.

  18. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism

    Science.gov (United States)

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

  19. Aspects of dopamine and acetylcholine release induced by glutamate receptors

    International Nuclear Information System (INIS)

    Paes, Paulo Cesar de Arruda

    2002-01-01

    The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

  20. Dopamine and Impulse Control Disorders in Parkinson's Disease

    NARCIS (Netherlands)

    Weintraub, Daniel

    2008-01-01

    There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson's disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine

  1. Dynamic shaping of dopamine signals during probabilistic Pavlovian conditioning.

    Science.gov (United States)

    Hart, Andrew S; Clark, Jeremy J; Phillips, Paul E M

    2015-01-01

    Cue- and reward-evoked phasic dopamine activity during Pavlovian and operant conditioning paradigms is well correlated with reward-prediction errors from formal reinforcement learning models, which feature teaching signals in the form of discrepancies between actual and expected reward outcomes. Additionally, in learning tasks where conditioned cues probabilistically predict rewards, dopamine neurons show sustained cue-evoked responses that are correlated with the variance of reward and are maximal to cues predicting rewards with a probability of 0.5. Therefore, it has been suggested that sustained dopamine activity after cue presentation encodes the uncertainty of impending reward delivery. In the current study we examined the acquisition and maintenance of these neural correlates using fast-scan cyclic voltammetry in rats implanted with carbon fiber electrodes in the nucleus accumbens core during probabilistic Pavlovian conditioning. The advantage of this technique is that we can sample from the same animal and recording location throughout learning with single trial resolution. We report that dopamine release in the nucleus accumbens core contains correlates of both expected value and variance. A quantitative analysis of these signals throughout learning, and during the ongoing updating process after learning in probabilistic conditions, demonstrates that these correlates are dynamically encoded during these phases. Peak CS-evoked responses are correlated with expected value and predominate during early learning while a variance-correlated sustained CS signal develops during the post-asymptotic updating phase. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Increased dopamine tone during meditation-induced change of consciousness

    DEFF Research Database (Denmark)

    Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola

    2002-01-01

    This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a dep......This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized...... by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from...... the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C...

  3. Dopamine and impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Weintraub, Daniel

    2008-12-01

    There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson's disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs.

  4. Copper nanoparticle modified carbon electrode for determination of dopamine

    International Nuclear Information System (INIS)

    Oztekin, Yasemin; Tok, Mutahire; Bilici, Esra; Mikoliunaite, Lina; Yazicigil, Zafer; Ramanaviciene, Almira; Ramanavicius, Arunas

    2012-01-01

    This paper reports the synthesis and characterization of copper nanoparticles (CuNPs) and application of copper nanoparticle-modified glassy carbon electrode for the electrochemical determination of dopamine. Electrochemical measurements were performed using differently modified glassy carbon (GC) electrodes. Bare, oxidized before modification and copper nanoparticle-modified glassy carbon electrodes (bare-GC, ox-GC and CuNP/GC electrodes, respectively) were characterized by cyclic voltammetry and electrochemical impedance spectroscopy in the presence of redox probes. Atomic force microscopy was used for the visualization of electrode surfaces. The CuNP/GC electrode was found to be suitable for the selective determination of dopamine even in the presence of ascorbic acid, uric acid, and p-acetamidophenol. The observed linear range of CuNP/GC for dopamine was from 0.1 nM to 1.0 μM while the detection limit was estimated to be 50 pM. It was demonstrated that here reported glassy carbon electrode modified by copper nanoparticles is suitable for the determination of dopamine in real samples such as human blood serum.

  5. Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter

    DEFF Research Database (Denmark)

    Norregaard, Lene; Loland, Claus Juul; Gether, Ulrik

    2003-01-01

    . Inhibitors such as cocaine did not alter the effect of MTSET in M371C. The protection of M371C inactivation by dopamine required Na+. Because dopamine binding is believed to be Na+-independent, this suggests that dopamine induces a transport-associated conformational change that decreases the reactivity of M......371C with MTSET. In contrast to M371C, cocaine decreased the reaction rate of A399C with MTSET, whereas dopamine had no effect. The protection by cocaine can either reflect that Ala-399 lines the cocaine binding crevice or that cocaine induces a conformational change that decreases the reactivity of A...

  6. Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions

    Directory of Open Access Journals (Sweden)

    Dietrich Jeffrey A

    2011-01-01

    Full Text Available Abstract Background Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production. Methods We treated isolated mouse tibialis anterior (TA and medial gastrocnemius (MG muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production. Results In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force

  7. Enhanced striatal dopamine release during food stimulation in binge eating disorder

    Energy Technology Data Exchange (ETDEWEB)

    Wang, g.j.; Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

    2011-01-13

    Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [{sup 11}C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

  8. Enhanced striatal dopamine release during food stimulation in binge eating disorder

    International Nuclear Information System (INIS)

    Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, J.; Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

    2011-01-01

    Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [ 11 C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

  9. A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity.

    Science.gov (United States)

    Su, Ping; Liu, Fang

    2017-09-01

    Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity. Copyright © 2017. Published by Elsevier Inc.

  10. Dopamine Modulates the Activity of Sensory Hair Cells.

    Science.gov (United States)

    Toro, Cecilia; Trapani, Josef G; Pacentine, Itallia; Maeda, Reo; Sheets, Lavinia; Mo, Weike; Nicolson, Teresa

    2015-12-16

    The senses of hearing and balance are subject to modulation by efferent signaling, including the release of dopamine (DA). How DA influences the activity of the auditory and vestibular systems and its site of action are not well understood. Here we show that dopaminergic efferent fibers innervate the acousticolateralis epithelium of the zebrafish during development but do not directly form synapses with hair cells. However, a member of the D1-like receptor family, D1b, tightly localizes to ribbon synapses in inner ear and lateral-line hair cells. To assess modulation of hair-cell activity, we reversibly activated or inhibited D1-like receptors (D1Rs) in lateral-line hair cells. In extracellular recordings from hair cells, we observed that D1R agonist SKF-38393 increased microphonic potentials, whereas D1R antagonist SCH-23390 decreased microphonic potentials. Using ratiometric calcium imaging, we found that increased D1R activity resulted in larger calcium transients in hair cells. The increase of intracellular calcium requires Cav1.3a channels, as a Cav1 calcium channel antagonist, isradipine, blocked the increase in calcium transients elicited by the agonist SKF-38393. Collectively, our results suggest that DA is released in a paracrine fashion and acts at ribbon synapses, likely enhancing the activity of presynaptic Cav1.3a channels and thereby increasing neurotransmission. The neurotransmitter dopamine acts in a paracrine fashion (diffusion over a short distance) in several tissues and bodily organs, influencing and regulating their activity. The cellular target and mechanism of the action of dopamine in mechanosensory organs, such as the inner ear and lateral-line organ, is not clearly understood. Here we demonstrate that dopamine receptors are present in sensory hair cells at synaptic sites that are required for signaling to the brain. When nearby neurons release dopamine, activation of the dopamine receptors increases the activity of these mechanosensitive

  11. Effect of high potassium on dopamine receptor activity in bovine retina

    International Nuclear Information System (INIS)

    Ackerman, J.M.

    1989-01-01

    In the present study, the hypothesis that dopamine released by light caused a subsensitivity of the dopamine receptor was investigated. Bovine eyes were obtained from a slaughterhouse, and retinas were dissected in a dark room. Filter binding assays were developed to measure agonist and antagonist binding to the dopamine receptor using [ 3 H]dopamine and [ 3 H]SCH 23390, respectively, in a retinal membrane fraction. Adenylate cyclase activation was measured by the production of [ 32 P]cyclic AMP from 32 ATP. In desensitization experiments, bovine retinas were incubated for fifteen minutes with 56 mM potassium, which also causes a release of dopamine in retinas were washed, and membranes were prepared. The stimulation of adenylate cyclase evoked by dopamine and radiolabeled agonist and antagonist binding were measured. In the receptor binding characterization studies, the dissociation constant and the maximum number of binding sites were obtained for [ 3 H]dopamine and [ 3 H]SCH 23390 binding

  12. Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems

    Directory of Open Access Journals (Sweden)

    Sachie K. Ogawa

    2014-08-01

    Full Text Available Serotonin and dopamine are major neuromodulators. Here, we used a modified rabies virus to identify monosynaptic inputs to serotonin neurons in the dorsal and median raphe (DR and MR. We found that inputs to DR and MR serotonin neurons are spatially shifted in the forebrain, and MR serotonin neurons receive inputs from more medial structures. Then, we compared these data with inputs to dopamine neurons in the ventral tegmental area (VTA and substantia nigra pars compacta (SNc. We found that DR serotonin neurons receive inputs from a remarkably similar set of areas as VTA dopamine neurons apart from the striatum, which preferentially targets dopamine neurons. Our results suggest three major input streams: a medial stream regulates MR serotonin neurons, an intermediate stream regulates DR serotonin and VTA dopamine neurons, and a lateral stream regulates SNc dopamine neurons. These results provide fundamental organizational principles of afferent control for serotonin and dopamine.

  13. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  14. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  15. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    Science.gov (United States)

    Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

  16. The effects of dopamine on digit span in Parkinson's disease.

    Science.gov (United States)

    Warden, Clara; Hwang, Jaclyn; Marshall, Anisa; Fenesy, Michelle; Poston, Kathleen L

    2016-01-01

    Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span. We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria. Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected

  17. Mathematical model of dopamine autoreceptors and uptake inhibitors and their influence on tonic and phasic dopamine signaling

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Hounsgaard, Jørn Dybkjær

    2013-01-01

    Dopamine (DA) D2-like autoreceptors are an important component of the DA system, but their influence on postsynaptic DA signaling is not well understood. They are, directly or indirectly, involved in drug abuse and in treatment of schizophrenia and attention deficit hyperactive disorder: DA...

  18. Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors.

    Science.gov (United States)

    Shin, Jung Hoon; Adrover, Martin F; Alvarez, Veronica A

    2017-11-15

    Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivo SIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is

  19. Choking Prevention

    Science.gov (United States)

    ... Healthy Living Healthy Living Healthy Living Nutrition Fitness Sports Oral Health Emotional Wellness Growing Healthy Sleep Safety & Prevention Safety & Prevention Safety and Prevention Immunizations At Home ...

  20. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    Science.gov (United States)

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  1. Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

    International Nuclear Information System (INIS)

    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L.

    1990-01-01

    We examined the status of dopamine (DA) D1 and D2 receptors by using [3H]SCH 23390 and [3H]spiperone binding, respectively, and DA uptake sites by using [3H]mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher [3H]SCH 23390 and [3H]spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in [3H]mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal [3H]spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion

  2. Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

    Energy Technology Data Exchange (ETDEWEB)

    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L. (Columbia Univ., New York, NY (USA))

    1990-11-01

    We examined the status of dopamine (DA) D1 and D2 receptors by using (3H)SCH 23390 and (3H)spiperone binding, respectively, and DA uptake sites by using (3H)mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher (3H)SCH 23390 and (3H)spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in (3H)mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal (3H)spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

  3. Dopamine treatment attenuates acute kidney injury in a rat model of deep hypothermia and rewarming - The role of renal H2S-producing enzymes.

    Science.gov (United States)

    Dugbartey, George J; Talaei, Fatemeh; Houwertjes, Martin C; Goris, Maaike; Epema, Anne H; Bouma, Hjalmar R; Henning, Robert H

    2015-12-15

    Hypothermia and rewarming produces organ injury through the production of reactive oxygen species. We previously found that dopamine prevents hypothermia and rewarming-induced apoptosis in cultured cells through increased expression of the H2S-producing enzyme cystathionine β-Synthase (CBS). Here, we investigate whether dopamine protects the kidney in deep body cooling and explore the role of H2S-producing enzymes in an in vivo rat model of deep hypothermia and rewarming. In anesthetized Wistar rats, body temperature was decreased to 15°C for 3h, followed by rewarming for 1h. Rats (n≥5 per group) were treated throughout the procedure with vehicle or dopamine infusion, and in the presence or absence of a non-specific inhibitor of H2S-producing enzymes, amino-oxyacetic acid (AOAA). Kidney damage and renal expression of three H2S-producing enzymes (CBS, CSE and 3-MST) was quantified and serum H2S level measured. Hypothermia and rewarming induced renal damage, evidenced by increased serum creatinine, renal reactive oxygen species production, KIM-1 expression and influx of immune cells, which was accompanied by substantially lowered renal expression of CBS, CSE, and 3-MST and lowered serum H2S levels. Infusion of dopamine fully attenuated renal damage and maintained expression of H2S-producing enzymes, while normalizing serum H2S. AOAA further decreased the expression of H2S-producing enzymes and serum H2S level, and aggravated renal damage. Hence, dopamine preserves renal integrity during deep hypothermia and rewarming likely by maintaining the expression of renal H2S-producing enzymes and serum H2S. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward.

    Science.gov (United States)

    Kishida, Kenneth T; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R; Laxton, Adrian W; Tatter, Stephen B; White, Jason P; Ellis, Thomas L; Phillips, Paul E M; Montague, P Read

    2016-01-05

    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

  5. Development of an enzyme-radioimmunoassay for the measurement of dopamine in human plasma and urine

    International Nuclear Information System (INIS)

    Faraj, B.A.; Walker, W.R.; Camp, V.M.; Ali, F.M.; Cobbs, W.B. Jr.

    1978-01-01

    An enzyme-radioimmunoassay for the measurement of dopamine is described. It is based on the incubation of plasma or urine in the presence of catechol-0-methyltransferase and S-adenosylmethionine. The 0-methylated dopamine metabolite formed (3-0-methyldopamine) was characterized by radioimmunoassay. As little as 0.5 ng of dopamine can be detected. The assay was found to be specific, since no cross-reactivity was noted for several compounds related to dopamine. The enzyme-radioimmunoassay of dopamine was used to determine the concentrations of dopamine in urine and plasma of normal volunteers. In this group, urinary dopamine averaged 182.1 +- 2.2 μg/24 hr, and the plasma concentration 0.211 +- 0.052 ng/ml. However, in children wPth neuroblastoma, there was a several-fold increase over controls in the average urinary and plasma levels of dopamine (8,500 μ/24 hr and 2.3 ng/ml). The assay was also used to monitor blood levels of dopamine following the administration of L-dopa and dopamine to patients with cardiomyopathy

  6. Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

    Science.gov (United States)

    Kishida, Kenneth T.; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R.; Laxton, Adrian W.; Tatter, Stephen B.; White, Jason P.; Ellis, Thomas L.; Phillips, Paul E. M.; Montague, P. Read

    2016-01-01

    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID:26598677

  7. Kinetic diversity of dopamine transmission in the dorsal striatum.

    Science.gov (United States)

    Taylor, I Mitch; Nesbitt, Kathryn M; Walters, Seth H; Varner, Erika L; Shu, Zhan; Bartlow, Kathleen M; Jaquins-Gerstl, Andrea S; Michael, Adrian C

    2015-05-01

    Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked DA release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum (DS) of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein, we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The DS, therefore, exhibits a total of at least five distinct evoked responses (four fast types and one slow type). All five response types conform to kinetic models based entirely on first-order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the DS terminal field. We report also that functionally distinct subregions of the DS express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct subregions of this key DA terminal field. The dorsal striatum is composed of five significantly different dopamine domains (types 1-4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion

  8. Pharmacological differences between the D-2 autoreceptor and the D-1 dopamine receptor in rabbit retina

    International Nuclear Information System (INIS)

    Dubocovich, M.L.; Weiner, N.

    1985-01-01

    The effect of dopamine receptor agonists and antagonists was studied on the calcium-dependent release of [ 3 H]dopamine elicited by field stimulation at 3 Hz for a duration of 1 min (20 mA, 2 msec) from the rabbit retina in vitro and on adenylate cyclase activity in homogenates of rabbit retina. The relative order of potency of dopamine receptor agonists to inhibit the stimulation-evoked [ 3 H]dopamine release was pergolide greater than bromocriptine greater than apomorphine greater than LY 141865 greater than N,N-di-n-propyldopamine greater than or equal to dopamine. The relative order of potencies of dopamine receptor antagonists to increase [ 3 H]dopamine release was: S-sulpiride greater than or equal to domperidone greater than or equal to spiroperidol greater than metoclopramide greater than fluphenazine greater than or equal to R-sulpiride. alpha-Flupenthixol (0.01-1 microM) and (+)-butaclamol (0.01-1 microM) did not increase [ 3 H]dopamine overflow when added alone, but they antagonized the concentration-dependent inhibitory effect of apomorphine (0.1-10 microM). These results suggest that the dopamine inhibitory autoreceptor involved in the modulation of dopamine release from the rabbit retina possesses the pharmacological characteristics of a D-2 dopamine receptor. Maximal stimulation by 30 microM dopamine resulted in a 3-fold increase in adenylate cyclase activity with half-maximal stimulation occurring at a concentration of 2.46 microM. Apomorphine and pergolide elicited a partial stimulation of adenylate cyclase activity. However, at low concentrations both compounds were more potent than dopamine

  9. Systemic effects of low-dose dopamine during administration of cytarabine.

    Science.gov (United States)

    Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

    2017-09-01

    Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

  10. Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]raclopride to dopamine D2 receptors in the mouse brain

    International Nuclear Information System (INIS)

    Ishiwata, K.; Senda, M.; Saitoh, T.; Taguchi, K.; Toda, J.; Sano, T.; Koyanagi, Y.

    2001-01-01

    We investigated the effects of intraperitoneal injection of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogs and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the binding of [ 11 C]raclopride to striatal dopamine D 2 receptors in mice. The binding of [ 11 C]raclopride, but not of [ 11 C]N-methylspiperone or [ 11 C]nemonapride with higher affinity, to the receptors was significantly decreased immediately after TIQ injection. Neither a dopamine transporter blocker induced such effect nor TIQ affected the dopamine transporter-radioligand binding. Among the compounds investigated, including parkinsonism-inducing TIQ and (R/S)-1-benzyl-TIQ, parkinsonism-preventing (R)- and (S)-1-methyl-TIQ, and probable N-methylated metabolites of TIQ and 1-methyl-TIQ, TIQ and (S)-1-methyl-TIQ had the strongest effect on the binding of [ 11 C]raclopride, and N-methylated derivatives showed less of an effect than the respective parent compounds. The decrease in the binding of [ 11 C]raclopride continued for 7 hours and was followed by an increase until 10 days after the single and subchronic administration of TIQ. These findings suggest that TIQ analogs profoundly stimulated dopamine release which resulted in the competitive inhibition of the binding of [ 11 C]raclopride to dopamine D 2 receptors, but did not induce degeneration of the receptors. (author)

  11. Hypothyroidism leads to increased dopamine receptor sensitivity and concentration

    Energy Technology Data Exchange (ETDEWEB)

    Crocker, A.D.; Overstreet, D.H.; Crocker, J.M.

    1986-06-01

    Rats treated with iodine-131 were confirmed to be hypothyroid by their reduced baseline core body temperatures, reduced serum thyroxine concentrations and elevated serum thyroid stimulating hormone concentrations. When hypothyroid rats were compared to euthyroid controls they were more sensitive to the effects of apomorphine (1.0 mumol/kg) on stereotypy, operant responding and body temperature and showed a smaller reduction in locomotor activity after injection of haloperidol (0.25 mumol/kg). Receptor binding studies on striatal homogenates indicated that hypothyroid rats had increased concentrations of D2 dopamine receptors but there was no change in the affinity. It is concluded that hypothyroidism increases dopamine receptor sensitivity by increasing receptor concentration.

  12. Decoding the dopamine signal in macaque prefrontal cortex: a simulation study using the Cx3Dp simulator.

    Directory of Open Access Journals (Sweden)

    Isabelle Ayumi Spühler

    Full Text Available Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated 'teaching' signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson's disease, or induced through drugs blocking dopamine reuptake.

  13. Decoding the Dopamine Signal in Macaque Prefrontal Cortex: A Simulation Study Using the Cx3Dp Simulator

    Science.gov (United States)

    Spühler, Isabelle Ayumi; Hauri, Andreas

    2013-01-01

    Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake. PMID:23951205

  14. Exercise Prevents Mental Illness

    Science.gov (United States)

    Purnomo, K. I.; Doewes, M.; Giri, M. K. W.; Setiawan, K. H.; Wibowo, I. P. A.

    2017-03-01

    Multiple current studies show that neuroinflammation may contribute to mental illness such as depression, anxiety, and mood disorder. Chronic inflammation in peripheral tissues is indicated by the increase of inflammatory marker like cytokine IL-6, TNF-α, and IL-1β. Pro-inflammatory cytokine in peripheral tissues can reach brain tissues and activate microglia and it causes neuroinflammation. Psychological stress may led peripheral and central inflammation. Activated microglia will produce pro-inflammatory cytokine, ROS, RNS, and tryptophan catabolizes. This neuroinflammation can promote metabolism changes of any neurotransmitter, such as serotonin, dopamine, and glutamate that will influence neurocircuit in the brain including basal ganglia and anterior cingulated cortex. It leads to mental illness. Exercise give contribution to reduce tissue inflammation. When muscle is contracting in an exercise, muscle will produce the secretion of cytokine like IL-6, IL-1ra, and IL-10. It will react as anti-inflammation and influence macrophage, T cell, monosit, protein Toll-Like Receptor (TLR), and then reduce neuroinflammation, characterised by the decrease of pro-inflammatory cytokine and prevent the activation of microglia in the brain. The objective of the present study is to review scientific articles in the literature related to the contribution of exercise to prevent and ease mental illness.

  15. Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

    Science.gov (United States)

    Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

    2016-01-01

    Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

  16. Poly(dopamine) coating to biodegradable polymers for bone tissue engineering.

    Science.gov (United States)

    Tsai, Wei-Bor; Chen, Wen-Tung; Chien, Hsiu-Wen; Kuo, Wei-Hsuan; Wang, Meng-Jiy

    2014-02-01

    In this study, a technique based on poly(dopamine) deposition to promote cell adhesion was investigated for the application in bone tissue engineering. The adhesion and proliferation of rat osteoblasts were evaluated on poly(dopamine)-coated biodegradable polymer films, such as polycaprolactone, poly(l-lactide) and poly(lactic-co-glycolic acid), which are commonly used biodegradable polymers in tissue engineering. Cell adhesion was significantly increased to a plateau by merely 15 s of dopamine incubation, 2.2-4.0-folds of increase compared to the corresponding untreated substrates. Cell proliferation was also greatly enhanced by poly(dopamine) deposition, indicated by shortened cell doubling time. Mineralization was also increased on the poly(dopamine)-deposited surfaces. The potential of poly(dopamine) deposition in bone tissue engineering is demonstrated in this study.

  17. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

    Directory of Open Access Journals (Sweden)

    Roger Cachope

    2012-07-01

    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  18. Flow injection fluorescence determination of dopamine using a photo induced electron transfer (PET) boronic acid derivative

    International Nuclear Information System (INIS)

    Ebru Seckin, Z.; Volkan, Muervet

    2005-01-01

    An automated flow injection analysis system was developed for the fluorometric determination of dopamine in pharmaceutical injections. The method is based on the quenching effect of dopamine on m-dansylaminophenyl boronic acid (DAPB) fluorescence due to the reverse photo induced electron transfer (PET) mechanism. Effects of pH and interfering species on the determination of dopamine were examined. Calibration for dopamine, based on quenching data, was linear in the concentration range of 1.0 x 10 -5 to 1.0 x 10 -4 M. Detection limit (3 s) of the method was found to be 3.7 x 10 -6 M. Relative standard deviation of 1.2% (n = 10) was obtained with 1.0 x 10 -5 M dopamine standard solution. The proposed method was applied successfully for the determination of dopamine in pharmaceutical injection sample. The sampling rate was determined as 24 samples per hour

  19. Dopamine Signaling Regulates Fat Content through β-Oxidation in Caenorhabditis elegans

    Science.gov (United States)

    Barros, Alexandre Guimarães de Almeida; Bridi, Jessika Cristina; de Souza, Bruno Rezende; de Castro Júnior, Célio; de Lima Torres, Karen Cecília; Malard, Leandro; Jorio, Ado; de Miranda, Débora Marques; Ashrafi, Kaveh; Romano-Silva, Marco Aurélio

    2014-01-01

    The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots. PMID:24465759

  20. Quantum chemical study of TiO2/dopamine-DNA triads

    International Nuclear Information System (INIS)

    Vega-Arroyo, Manuel; LeBreton, Pierre R.; Zapol, Peter; Curtiss, Larry A.; Rajh, Tijana

    2007-01-01

    Photoinduced charge separation in triads of DNA covalently linked to an anatase nanoparticle via a dopamine bridge was studied by ab initio calculations of the oxidation potentials of carboxyl-DNA trimers and the TiO 2 /dopamine complex. Conjugation of dopamine to the TiO 2 surface results in a lower oxidation potential of the complex relative to the surface and in localization of photogenerated holes on dopamine, while photogenerated electrons are excited into the conduction band of TiO 2 . Linking dopamine to the DNA trimers at the 5' end of the oligonucleotide may lead to further hole migration to the DNA. Calculations show that for several different sequences hole migration is favorable in double stranded DNA and unfavorable in single-stranded DNA. This extended charge separation was shown to follow from the redox properties of DNA sequence rather than from the modification of DNA's electron donating properties by the dopamine linker, which explains experimental observations

  1. Ventral tegmental area dopamine revisited: effects of acute and repeated stress

    Science.gov (United States)

    Holly, Elizabeth N.; Miczek, Klaus A.

    2015-01-01

    Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the functional and anatomical heterogeneity of the VTA. We focus on VTA heterogeneity in anatomy, neurochemistry, electrophysiology, and afferent/efferent connectivity. Second, recent evidence for a critical role of VTA dopamine neurons in response to both acute and repeated stress will be discussed. Understanding which dopamine neurons are activated by stress, the neural mechanisms driving the activation, and where these neurons project will provide valuable insight into how stress can promote psychiatric disorders associated with the dopamine system, such as addiction and depression. PMID:26676983

  2. Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

    Science.gov (United States)

    Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

    2017-05-10

    Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

  3. Mesolimbic Dopamine Encodes Prediction Errors in a State-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Georgios K. Papageorgiou

    2016-04-01

    Full Text Available Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal’s current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet.

  4. Dopamine sensing and measurement using threshold and spectral measurements in random lasers.

    Science.gov (United States)

    Wan Ismail, Wan Zakiah; Liu, Guozhen; Zhang, Kai; Goldys, Ewa M; Dawes, Judith M

    2016-01-25

    We developed a novel dopamine sensing and measurement technique based on aggregation of gold nanoparticles in random lasers. Dopamine combined with copper ions triggers the aggregation of gold nanoparticles and thus affects the performance of random lasers. Dopamine sensing can be achieved using four parameters which are sensitive to the presence of dopamine, that is emission peak shift, emission linewidth, signal-to-noise ratio (peak emission intensity / noise) and random lasing threshold. The dopamine is most sensitively detected by a change in the emission linewidth with a limit of detection of 1 × 10(-7) M, as well as by an increase in the lasing threshold. The dopamine concentration from 1 × 10(-7) M to 1 × 10(-2) M can be determined by calibrating with the laser threshold.

  5. The Iowa Gambling Task and the three fallacies of dopamine in gambling disorder

    DEFF Research Database (Denmark)

    Linnet, Jakob

    2013-01-01

    prediction and reward uncertainty show a sustained dopamine response toward stimuli with maximum uncertainty, which may explain the continued dopamine release and gambling despite losses in gambling disorder. The findings from the studies presented here are consistent with the notion of dopaminergic......Gambling disorder sufferers prefer immediately larger rewards despite long term losses on the Iowa Gambling Task (IGT), and these impairments are associated with dopamine dysfunctions. Dopamine is a neurotransmitter linked with temporal and structural dysfunctions in substance use disorder, which...... has supported the idea of impaired decision-making and dopamine dysfunctions in gambling disorder. However, evidence from substance use disorders cannot be directly transferred to gambling disorder. This article focuses on three hypotheses of dopamine dysfunctions in gambling disorder, which appear...

  6. Inverted-U shaped dopamine actions on human working memory and cognitive control

    Science.gov (United States)

    Cools, R; D’Esposito, M

    2011-01-01

    Brain dopamine has long been implicated in cognitive control processes, including working memory. However, the precise role of dopamine in cognition is not well understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum dopamine level for cognitive function implicates the need to take into account baseline levels of dopamine when isolating dopamine’s effects. Second, cognitive control is a multi-factorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum respectively. Manipulating dopamine will thus have paradoxical consequences for distinct cognitive control processes depending on distinct basal or optimal levels of dopamine in different brain regions. PMID:21531388

  7. Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward.

    Science.gov (United States)

    Cagniard, Barbara; Balsam, Peter D; Brunner, Daniela; Zhuang, Xiaoxi

    2006-07-01

    Dopamine has been critically implicated in learning and motivation, although its precise role remains to be determined. In order to investigate the involvement of dopamine in learning and motivation for a food reward, we used dopamine transporter knockdown mice (DAT KD) that have chronically elevated levels of extracellular dopamine. The present study demonstrates that chronically elevated dopamine enhances tendency to work for a food reward without apparent effects on Pavlovian and operant learning for this reward. The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens. These data suggest that motivation to work, but not learning, for a food reward appears to be under the critical influence of tonic dopaminergic activity in discrete brain areas relevant for a reward-directed behavior.

  8. Benzene and dopamine catechol quinones could initiate cancer or neurogenic disease.

    Science.gov (United States)

    Zahid, Muhammad; Saeed, Muhammad; Rogan, Eleanor G; Cavalieri, Ercole L

    2010-01-15

    Catechol quinones of estrogens react with DNA by 1,4-Michael addition to form depurinating N3Ade and N7Gua adducts. Loss of these adducts from DNA creates apurinic sites that can generate mutations leading to cancer initiation. We compared the reactions of the catechol quinones of the leukemogenic benzene (CAT-Q) and N-acetyldopamine (NADA-Q) with 2'-deoxyguanosine (dG) or DNA. NADA was used to prevent intramolecular cyclization of dopamine quinone. Reaction of CAT-Q or NADA-Q with dG at pH 4 afforded CAT-4-N7dG or NADA-6-N7dG, which lost deoxyribose with a half-life of 3 h to form CAT-4-N7Gua or 4 h to form NADA-6-N7Gua. When CAT-Q or NADA-Q was reacted with DNA, N3Ade adducts were formed and lost from DNA instantaneously, whereas N7Gua adducts were lost over several hours. The maximum yield of adducts in the reaction of CAT-Q or NADA-Q with DNA at pH 4 to 7 was at pH 4. When tyrosinase-activated CAT or NADA was reacted with DNA at pH 5 to 8, adduct levels were much higher (10- to 15-fold), and the highest yield was at pH 5. Reaction of catechol quinones of natural and synthetic estrogens, benzene, naphthalene, and dopamine with DNA to form depurinating adducts is a common feature that may lead to initiation of cancer or neurodegenerative disease. Copyright 2009 Elsevier Inc. All rights reserved.

  9. Do dopamine gene variants and prenatal smoking interactively predict youth externalizing behavior?

    Science.gov (United States)

    O'Brien, T Caitlin; Mustanski, Brian S; Skol, Andrew; Cook, Edwin H; Wakschlag, Lauren S

    2013-01-01

    Externalizing behaviors (encompassing antisocial, impulsive, and substance use behaviors) are pervasive and impairing across a multitude of settings and developmental contexts. These behaviors, though often investigated separately, are highly comorbid. Prenatal tobacco exposure in interaction with various genetic influences has predicted later externalizing behavior, and recent evidence supports investigating sex differences in these patterns. In the current study, we extend this work by (a) examining two functional genetic markers in the dopamine system: the transporter gene (DAT1) and the dopamine receptor D4 gene (DRD4) in interaction with prenatal tobacco exposure to predict a latent composite of externalizing behavior and (b) testing whether these patterns differ by sex of youth in a community sample of adolescents (n=176). The relatively small sample is partially offset by high quality, multi-method prospective measurement. We assessed prenatal tobacco exposure using prospective repeated cotinine-corrected reports and externalizing behaviors were assessed utilizing multiple measures across three waves. The interaction between DAT1 (but not DRD4) and prenatal tobacco exposure was statistically significant in boys, and patterns appeared to differ by sex. Risk for externalizing behaviors for exposed boys increased linearly as a function of the 10r DAT1 allele. For exposed girls, there was a trend such that DAT1 heterozygotes had a marginally higher risk than homozygotes. This pattern was not explained by passive gene-environment correlation. Elucidating sex-specific pathways through which early adverse exposures and genetic susceptibilities contribute to externalizing behavior can inform early targeted prevention efforts for those children at highest risk. © 2013.

  10. Dopamine Receptor-Specific Contributions to the Computation of Value.

    Science.gov (United States)

    Burke, Christopher J; Soutschek, Alexander; Weber, Susanna; Raja Beharelle, Anjali; Fehr, Ernst; Haker, Helene; Tobler, Philippe N

    2017-12-18

    Dopamine is thought to play a crucial role in value-based decision making. However, the specific contributions of different dopamine receptor subtypes to the computation of subjective value remain unknown. Here we demonstrate how the balance between D1 and D2 dopamine receptor subtypes shapes subjective value computation during risky decision making. We administered the D2 receptor antagonist amisulpride or placebo before participants made choices between risky options. Compared with placebo, D2 receptor blockade resulted in more frequent choice of higher risk and higher expected value options. Using a novel model fitting procedure, we concurrently estimated the three parameters that define individual risk attitude according to an influential theoretical account of risky decision making (prospect theory). This analysis revealed that the observed reduction in risk aversion under amisulpride was driven by increased sensitivity to reward magnitude and decreased distortion of outcome probability, resulting in more linear value coding. Our data suggest that different components that govern individual risk attitude are under dopaminergic control, such that D2 receptor blockade facilitates risk taking and expected value processing.Neuropsychopharmacology advance online publication, 31 January 2018; doi:10.1038/npp.2017.302.

  11. [Dopamine dysregulation syndrome in Parkinson's disease and restless legs syndrome].

    Science.gov (United States)

    Bayard, Sophie; Cochen De Cock, Valérie; Dauvillers, Yves

    2011-06-01

    Dopamine replacement therapy in Parkinson's disease (PD) improves the motor symptoms. However, it has recently been shown that a small sub-group of patients suffers from motor and behavioral disturbances associated with the use of dopamine agonists (DAs). The behavioral disorders are incentive- or reward-based repetitive symptoms regrouped under the term « dopamine dysregulation syndrome » (DDS). They include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, punding, and compulsive medication use. Whether these behaviors are related to the dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson's disease play a role is not entirely understood. This review is devoted to the phenomenology of the DDS and factors influencing its susceptibility. We further review the literature studies that investigated the decision-making profile using the Iowa Gambling Task in Parkinson's disease, and the recent literature devoted to these abnormal behaviors in the restless legs syndrome (RLS). Given the potential substantial impact of the DDS on personal, familial, social, and financial well-being, patients with PD or RLS should be informed that DAs use may lead to the development of impulsive and compulsive disorders, and clinicians should include the investigation of these disorders as part of routine clinical care. The refinement of clinical strategies to predict, identify and manage DDS will help the future care of motor and non-motor symptoms of Parkinson's disease.

  12. Pathological Gambling Associated With Aripiprazole or Dopamine Replacement Therapy

    Science.gov (United States)

    Grall-Bronnec, Marie; Sauvaget, Anne; Perrouin, Fanny; Leboucher, Juliette; Etcheverrigaray, François; Challet-Bouju, Gaëlle; Gaboriau, Louise; Derkinderen, Pascal; Jolliet, Pascale; Victorri-Vigneau, Caroline

    2016-01-01

    Background In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD). Another medication, aripiprazole (ARI), has been more recently identified as another risk factor. Dopamine replacement therapy and ARI share a dopamine agonist action. Our work aimed at comparing patients with PG according to their treatment with DRT or ARI. Methods Two methods were combined—a systematic review concentrated on case reports and the analysis of a French disordered gamblers cohort focused on patients using ARI or DRT at inclusion. Results We reported 48 cases of GD possibly due to DRT and 17 cases of GD possibly due to ARI. Because of their standardized assessment, only the EVALJEU patients could be compared. Two clinical patterns emerged. Patients in the ARI group were young, impulsive, and high novelty seekers and had a history of substance misuse. Their first gambling experience occurred during adolescence. Conversely, patients in the DRT group were old, and they began gambling late in life. They showed low levels of gambling-related cognition. Conclusions Patients in the ARI group seemed to be more severe pathological gamblers than patients in the DRT group. Aripiprazole is a partial D2 receptor agonist, whereas DRT includes full D2 receptor agonist. The trigger mechanism of PG development is complex and cannot only be attributed only to the pharmacodynamic effects of dopaminergic drugs. Indeed, individual vulnerability factors and environmental factors need to be considered. PMID:26658263

  13. Efficacy of clozapine on dopamine supersensitivity psychosis in schizophrenia.

    Science.gov (United States)

    Nakata, Yusuke; Kanahara, Nobuhisa; Kimura, Hiroshi; Watanabe, Hiroyuki; Iyo, Masaomi

    2017-05-01

    Although the effectiveness of clozapine (CLZ) for patients with treatment-resistant schizophrenia (TRS) has been well established, its active mechanism has not been completely clarified. Several clinical studies showed that neuroleptic-induced dopamine supersensitivity psychosis (DSP) could be involved in the etiology of TRS. We preliminarily explored the possible beneficial effect of CLZ for dopamine supersensitivity schizophrenia. The present study is a case series. We followed 15 patients with DSP for about 2.5 years from the introduction of CLZ and compared the prevalence of episodes (particularly, rebound psychosis, tolerance to antipsychotic effects, or tardive dyskinesia) between the period before and during CLZ treatment. Our observation over 2.5 years following the introduction of CLZ showed that 13 of the 15 DSP patients presented no further DSP episodes. One patient showed continued tardive dyskinesia, which had already existed in the preperiod, and the other patient presented with rebound psychosis that appeared immediately after discontinuation of CLZ. The results of the present study indicated that DSP in schizophrenic patients treated with general antipsychotics disappeared over the subsequent 2.5 years under CLZ treatment, suggesting that the agent ameliorates the dopamine supersensitivity state induced by previous antipsychotic treatment.

  14. Dopamine negatively modulates the NCA ion channels in C. elegans.

    Science.gov (United States)

    Topalidou, Irini; Cooper, Kirsten; Pereira, Laura; Ailion, Michael

    2017-10-01

    The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

  15. Carbon nanopipette electrodes for dopamine detection in Drosophila.

    Science.gov (United States)

    Rees, Hillary R; Anderson, Sean E; Privman, Eve; Bau, Haim H; Venton, B Jill

    2015-04-07

    Small, robust, sensitive electrodes are desired for in vivo neurotransmitter measurements. Carbon nanopipettes have been previously manufactured and used for single-cell drug delivery and electrophysiological measurements. Here, a modified fabrication procedure was developed to produce batches of solid carbon nanopipette electrodes (CNPEs) with ∼250 nm diameter tips, and controllable lengths of exposed carbon, ranging from 5 to 175 μm. The electrochemical properties of CNPEs were characterized with fast-scan cyclic voltammetry (FSCV) for the first time. CNPEs were used to detect the electroactive neurotransmitters dopamine, serotonin, and octopamine. CNPEs were significantly more sensitive for serotonin detection than traditional carbon-fiber microelectrodes (CFMEs). Similar to CFMEs, CNPEs have a linear response for dopamine concentrations ranging from 0.1 to 10 μM and a limit of detection of 25 ± 5 nM. Recordings with CNPEs were stable for over 3 h when the applied triangle waveform was scanned between -0.4 and +1.3 V vs Ag/AgCl/Cl(-) at 400 V/s. CNPEs were used to detect endogenous dopamine release in Drosophila larvae using optogenetics, which verified the utility of CNPEs for in vivo neuroscience studies. CNPEs are advantageous because they are 1 order of magnitude smaller in diameter than typical CFMEs and have a sharp, tunable geometry that facilitates penetration and implantation for localized measurements in distinct regions of small organisms, such as the Drosophila brain.

  16. Regulation of the mesolimbic dopamine circuit by feeding peptides.

    Science.gov (United States)

    Liu, S; Borgland, S L

    2015-03-19

    Polypeptides produced in the gastrointestinal tract, stomach, adipocytes, pancreas and brain that influence food intake are referred to as 'feeding-related' peptides. Most peptides that influence feeding exert an inhibitory effect (anorexigenic peptides). In contrast, only a few exert a stimulating effect (orexigenic peptides), such as ghrelin. Homeostatic feeding refers to when food consumed matches energy deficits. However, in western society where access to palatable energy-dense food is nearly unlimited, food is mostly consumed for non-homeostatic reasons. Emerging evidence implicates the mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), as a key substrate for non-homeostatic feeding. VTA dopamine neurons encode cues that predict rewards and phasic release of dopamine in the ventral striatum motivates animals to forage for food. To elucidate how feeding-related peptides regulate reward pathways is of importance to reveal the mechanisms underlying non-homeostatic or hedonic feeding. Here, we review the current knowledge of how anorexigenic peptides and orexigenic peptides act within the VTA. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Ariane Park

    2011-01-01

    Full Text Available Nonmotor symptoms of Parkinson's disease (PD may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.

  18. DIRECT VISUALIZATION OF THE DOPAMINE TRANSPORTER IN CULTURED NEWBORN RAT MIDBRAIN NEURONS USING THE FLUORESCENT COCAINE ANALOGUE JHC 1-64

    DEFF Research Database (Denmark)

    Rasmussen, Søren; Vægter, Christian Bjerggaard; Cha, J

    In this study we have established methods for visualization and tracking of the dopamine transporter (DAT) in cultured dopaminergic neurons in real time using a fluorescent cocaine analogue JHC 1-64 and confocal fluorescence microscopy. The initial binding experiments in HEK 293 cells stably......-DAT was internalized, corroborating the usefulness of this cocaine analogue as a tool for monitoring DAT trafficking. In the cultured neurons JHC 1-64 labeled the surface of almost the entire dopaminergic neurons including the cell body, although not as strongly as some of the neuronal extensions. This labeling by JHC...... 1-64 was prevented by excess concentrations of dopamine, cocaine, mazindol, or RTI-55, whereas the norepinephrine and/or serotonin transporter specific inhibitors desmethylimipramine and citalopram did not affect fluorescent labeling of the neurons. This strongly supports that JHC 1-64 specifically...

  19. Design dopamine-modified polypropylene fibers towards removal of heavy metal ions from water

    OpenAIRE

    K. Liu; N. Y. Zhou; C. X. Xie; B. Mou; Y. N. Ai

    2017-01-01

    A simple approach to preparing dopamine-modified polypropylene fibers with a controllable polydopamine amount is supplied. By the dopamine modification, the hydrophobic polypropylene fibers have been changed into hydrophilic. The hydrophilicity can be improved by increasing the amount of polydopamine, as revealed by the contact angle evolutions. The hydrophilic dopamine-modified polypropylene fibers can rapidly and effectively remove copper and lead ions in water. Moreover, the performance of...

  20. Real-Time Dopamine Efflux in the Nucleus Accumbens Core During Pavlovian Conditioning

    OpenAIRE

    Sunsay, Ceyhun; Rebec, George V.

    2008-01-01

    To assess the role of dopamine input to the nucleus accumbens core in anticipatory learning, fast-scan cyclic voltammetry was combined with appetitive Pavlovian conditioning. One group of rats (Paired) received 16 tone-food pairings for at least four daily sessions while the control group (Unpaired) received the same number of unpaired tone and food presentations. Both groups showed transient dopamine responses during food presentation throughout training, confirming dopamine involvement in r...

  1. Cocaine produces conditioned place aversion in mice with a cocaine insensitive dopamine transporter

    OpenAIRE

    O’Neill, Brian; Tilley, Michael R.; Gu, Howard H.

    2012-01-01

    Cocaine is an inhibitor of the dopamine, norepinephrine, and serotonin reuptake transporters. Because its administration would therefore elevate signaling of all these three neurotransmitters, many studies have been aimed at attributing individual effects of cocaine to specific transmitter systems. Using mice with a cocaine insensitive dopamine transporter (DAT-CI mice), we previously showed that cocaine-induced dopamine elevations were necessary for its rewarding and stimulating effects. In ...

  2. A Combination of Dopamine Genes Predicts Success by Professional Wall Street Traders

    OpenAIRE

    Sapra, Steve; Beavin, Laura E.; Zak, Paul J.

    2012-01-01

    What determines success on Wall Street? This study examined if genes affecting dopamine levels of professional traders were associated with their career tenure. Sixty professional Wall Street traders were genotyped and compared to a control group who did not trade stocks. We found that distinct alleles of the dopamine receptor 4 promoter (DRD4P) and catecholamine-O-methyltransferase (COMT) that affect synaptic dopamine were predominant in traders. These alleles are associated with moderate, r...

  3. Classification of Dopamine Receptor Genes in Vertebrates: Nine Subtypes in Osteichthyes.

    Science.gov (United States)

    Yamamoto, Kei; Fontaine, Romain; Pasqualini, Catherine; Vernier, Philippe

    2015-01-01

    Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates. © 2015 S. Karger AG, Basel.

  4. Evaluating Dopamine Reward Pathway in ADHD; clinical implications

    International Nuclear Information System (INIS)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Kollins, S.H.; Wigal, T.L.; Newcorn, J.H.; Telang, F.; Fowler, J.S.; Zhu, W.; Logan, J.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

    2009-01-01

    Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D 2 /D 3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [ 11 C]cocaine and for D 2 /D 3 receptors using [ 11 C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P 2 /D 3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D 2 /D 3 for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D 2 /D 3 in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D 2 /D 3 in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain

  5. Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Che-Hung Yen

    Full Text Available Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST and Tridimensional Personality Questionnaire (TPQ were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001, as well as diminished performance on the WCST (p < 0.001. Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.

  6. Dopamine therapy is associated with impaired cerebral autoregulation in preterm infants

    DEFF Research Database (Denmark)

    Eriksen, Vibeke R; Hahn, Gitte H; Greisen, Gorm

    2014-01-01

    , but the anticipated difference in cerebral oxygenation was not detected. The need for mechanical ventilation in the first day of life and incidences of mortality was higher in the dopamine group. CONCLUSION: Dopamine therapy was associated with decreased CA in preterm infants. We were unable to determine whether......AIM: Hypotension is a common problem in newborn infants and is associated with increased mortality and morbidity. Dopamine is the most commonly used antihypotensive drug therapy, but has never been shown to improve neurological outcomes. This study tested our hypothesis that dopamine affects...

  7. Dopamine Development in the Mouse Orbital Prefrontal Cortex Is Protracted and Sensitive to Amphetamine in Adolescence.

    Science.gov (United States)

    Hoops, Daniel; Reynolds, Lauren M; Restrepo-Lozano, Jose-Maria; Flores, Cecilia

    2018-01-01

    The prefrontal cortex (PFC) is divided into subregions, including the medial and orbital prefrontal cortices. Dopamine connectivity in the medial PFC (mPFC) continues to be established throughout adolescence as the result of the continuous growth of axons that innervated the nucleus accumbens (NAcc) prior to adolescence. During this period, dopamine axons remain vulnerable to environmental influences, such as drugs used recreationally by humans. The developmental trajectory of the orbital prefrontal dopamine innervation remains almost completely unstudied. Nonetheless, the orbital PFC (oPFC) is critical for some of the most complex functions of the PFC and is disrupted by drugs of abuse, both in adolescent humans and rodents. Here, we use quantitative neuroanatomy, axon-initiated viral-vector recombination, and pharmacology in mice to determine the spatiotemporal development of the dopamine innervation to the oPFC and its vulnerability to amphetamine in adolescence. We find that dopamine innervation to the oPFC also continues to increase during adolescence and that this increase is due to the growth of new dopamine axons to this region. Furthermore, amphetamine in adolescence dramatically reduces the number of presynaptic sites on oPFC dopamine axons. In contrast, dopamine innervation to the piriform cortex is not protracted across adolescence and is not impacted by amphetamine exposure during adolescence, indicating that dopamine development during adolescence is a uniquely prefrontal phenomenon. This renders these fibers, and the PFC in general, particularly vulnerable to environmental risk factors during adolescence, such as recreational drug use.

  8. Dopamine and extinction: A convergence of theory with fear and reward circuitry

    Science.gov (United States)

    Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

    2014-01-01

    Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353

  9. Dopamine receptors in the guinea-pig heart. A binding study

    International Nuclear Information System (INIS)

    Sandrini, M.; Benelli, A.; Baraldi, M.

    1984-01-01

    The binding of dopaminergic agonists and antagonists to guinea-pig myocardial membrane preparations was studied using 3 H-dopamine and 3 H-spiperone as radioligand. 3 H-Dopamine bound specifically to heart membranes while 3 H-spiperone did not. A Scatchard analysis of 3 H-dopamine binding showed a curvilinear plot indicating the presence of two dopamine receptor populations that we have termed high- (K/sub d/ = 1.2 nM, B/sub mx/ = 52.9 fmol/mg prot.) and low- (K/sub d/ = 11.8 nM, B/sub mx/ = 267.3 fmol/gm prot.) affinity binding sites, respectively. The charactization of the high-affinity component of 3 H-dopamine binding indicated that the binding is rapid, saturable, stereospecific, pH- and temperature-dependent, and displaced by dopaminergic agonists and antagonists known to act similarly in vivo. The finding that pretreatment with dibenamine (which has been described as an α-adrenoceptor irreversible blocker) did not affect the binding of dopamine to cardiac membrane preparations suggests that α-adrenoceptors and dopamine receptors have separate recognition sites in the heart. It is concluded that 3 H-dopamine binds to specific dopamine receptors in the heart of guinea-pigs

  10. Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

    Science.gov (United States)

    Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

    2013-01-01

    Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

  11. Dopamine dynamics and cocaine sensitivity differ between striosome and matrix compartments of the striatum

    Science.gov (United States)

    Salinas, Armando G.; Davis, Margaret I.; Lovinger, David M.; Mateo, Yolanda

    2016-01-01

    The striatum is typically classified according to its major output pathways, which consist of dopamine D1 and D2 receptor-expressing neurons. The striatum is also divided into striosome and matrix compartments, based on the differential expression of a number of proteins, including the mu opioid receptor, dopamine transporter (DAT), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1). Numerous functional differences between the striosome and matrix compartments are implicated in dopamine-related neurological disorders including Parkinson’s disease and addiction. Using Nr4a1-eGFP mice, we provide evidence that electrically evoked dopamine release differs between the striosome and matrix compartments in a regionally-distinct manner. We further demonstrate that this difference is not due to differences in inhibition of dopamine release by dopamine autoreceptors or nicotinic acetylcholine receptors. Furthermore, cocaine enhanced extracellular dopamine in striosomes to a greater degree than in the matrix and concomitantly inhibited dopamine uptake in the matrix to a greater degree than in striosomes. Importantly, these compartment differences in cocaine sensitivity were limited to the dorsal striatum. These findings demonstrate a level of exquisite microanatomical regulation of dopamine by the DAT in striosomes relative to the matrix. PMID:27036891

  12. Dopamine regulation of [3H]acetylcholine release from guinea-pig stomach

    International Nuclear Information System (INIS)

    Kusunoki, M.; Taniyama, K.; Tanaka, C.

    1985-01-01

    The involvement of dopamine receptors in cholinergic transmission of guinea-pig stomach was investigated by analyzing the effects of dopamine receptor agonists and antagonists on acetylcholine (ACh) release from this organ. Electrical stimulation (1-20 Hz) of strips of guinea-pig stomach preloaded with [ 3 H] choline induced a [ 3 H]ACh release that was calcium dependent and tetrodotoxin sensitive. Dopamine inhibited this transmural stimulation-induced [ 3 H]ACh release in a concentration-dependent manner (10(-8)-10(-4) M). This effect of dopamine was not altered by 10(-5) M hexamethonium, thereby suggesting that the major dopamine receptors are located on the postganglionic cholinergic neurons. Concentration-response curves for dopamine on [ 3 H]ACh release were inhibited by haloperidol, sulpiride and domperidone but not by prazosin, yohimbine, propranolol and ketanserin. LY 171555, an agonist for the D2 dopamine receptor, but not SKF 38-393, an agonist for the D1 dopamine receptor, to some extent decreased the release of [ 3 H]ACh induced by transmural stimulation. In view of the results, the release of ACh from postganglionic cholinergic neurons is probably required through dopamine receptors antagonized by D2 antagonists but not by adrenergic or serotonin receptor antagonists

  13. Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

    Science.gov (United States)

    Wilson, Charles R E; Vezoli, Julien; Stoll, Frederic M; Faraut, Maïlys C M; Leviel, Vincent; Knoblauch, Kenneth; Procyk, Emmanuel

    2016-11-01

    Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

  14. Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

    Directory of Open Access Journals (Sweden)

    Charles R E Wilson

    2016-11-01

    Full Text Available Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

  15. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose.

    Science.gov (United States)

    Seeman, P

    2016-10-18

    Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.

  16. Dopamine, reward, and frontostriatal circuitry in impulse control disorders in Parkinson's disease: insights from functional imaging.

    Science.gov (United States)

    Ray, Nicola; Strafella, Antonio P

    2010-04-01

    Dopamine agonists have been implicated in the development of impulse control disorders (ICDs). This may be due to the ability of agonists to tonically stimulate dopamine receptors. Recent neuroimaging data provided evidence that dopamine agonists induce significant changes in those frontostriatal circuits that process reward and mediate our ability to control impulses. Tonic stimulation of dopamine receptors via agonists may impair reward processing and inhibitory control mechanisms in ways that promote pathological repetition of behaviors. We will provide an overview of the current understanding of the neurobiology underlying ICDs in Parkinson's disease (PD).

  17. Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence

    Science.gov (United States)

    Yen, Che-Hung; Yeh, Yi-Wei; Liang, Chih-Sung; Ho, Pei-Shen; Kuo, Shin-Chang; Huang, Chang-Chih; Chen, Chun-Yen; Shih, Mei-Chen; Ma, Kuo-Hsing; Peng, Giia-Sheun; Lu, Ru-Band; Huang, San-Yuan

    2015-01-01

    Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility. PMID:26120847

  18. Microwave-assisted deposition of silver nanoparticles on bamboo pulp fabric through dopamine functionalization

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Linghui [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Guo, Ronghui, E-mail: ronghuiguo214@126.com [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Lan, Jianwu [College of Light Industry, Textile and Food Engineering, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu (China); Jiang, Shouxiang [Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong (China); Lin, Shaojian [Institute for Technical and Macromolecular Chemistry, University of Hamburg Bundesstrasse 45, D-20146 Hamburg (Germany)

    2016-11-15

    Highlights: • Silver nanoparticles were synthesized on bamboo pulp fabric using dopamine as an adhesive and reducing agent under microwave radiation. • Silver coated bamboo pulp fabric modified with dopamine has good UV protection and hydrophobic property. • Silver nanoparticles can be strongly fixed on dopamine modified bamboo pulp fabric. - Abstract: Silver nanoparticles were synthesized on bamboo pulp fabric with dopamine as the adhesive and reducing agent under microwave radiation. The silver nanoparticle coated bamboo pulp fabrics were characterized by X-ray photoelectron spectroscopy, scanning electron microscope and X-ray diffraction. Ultraviolet (UV) protection, color and water contact angles of the silver nanoparticle coated bamboo pulp fabrics were evaluated. In addition, the influences of concentrations of dopamine and treatment time on color strength (K/S values) of the silver nanoparticle coated fabric were investigated. Fastness to washing was employed to evaluate the adhesive strength between the silver coating and the bamboo pulp fabric modified with dopamine. The results show that the dopamine modified bamboo pulp fabric is evenly covered with silver nanoparticles. The silver nanoparticle coated bamboo pulp fabric modified with dopamine shows the excellent UV protection with an ultraviolet protection factor of 157.75 and the hydrophobicity with a water contact angle of 132.4°. In addition, the adhesive strength between the silver nanoparticles and bamboo pulp fabric is significantly improved. Silver nanoparticles coating on bamboo pulp fabric modified with dopamine is environmentally friendly, easy to carry out and highly efficient.

  19. Fluctuation of the dopamine uptake inhibition potency of cocaine, but not amphetamine, at mammalian cells expressing the dopamine transporter

    Science.gov (United States)

    Ukairo, Okechukwu T.; Ramanujapuram, Suneetha; Surratt, Christopher K.

    2007-01-01

    Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalin™) and benztropine in CHO cells expressing wildtype DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by Bmax values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts. PMID:17169338

  20. Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine.

    Directory of Open Access Journals (Sweden)

    Dawn Thompson

    Full Text Available BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT and G protein coupled receptor associated sorting protein-1 (GASP-1 knock out (KO mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization.

  1. Fetal growth interacts with multilocus genetic score reflecting dopamine signaling capacity to predict spontaneous sugar intake in children.

    Science.gov (United States)

    Silveira, Patrícia P; Pokhvisneva, Irina; Gaudreau, Hélène; Atkinson, Leslie; Fleming, Alison S; Sokolowski, Marla B; Steiner, Meir; Kennedy, James L; Dubé, Laurette; Levitan, Robert D; Meaney, Michael J

    2018-01-01

    We have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods. Our aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status. 192 four-year old children from a community sample from Montreal and Hamilton, Canada, were classified according to birth weight and administered a snack test meal containing regular as well as palatable foods. Intrauterine growth restriction was based on the birth weight ratio below 0.85; children were genotyped for polymorphisms associated with dopamine (DA) signaling, with the hypofunctional variants (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10-repeat, Met/Met-COMT) receiving the lowest scores, and a composite score was calculated reflecting the total number of the five genotypes. Macronutrient intake during the Snack Test was the outcome. Adjusting for z-score BMI at 48 months and sex, there was a significant interaction of the genetic profile and fetal growth on sugar intake [βˆ = -4.56, p = 0.04], showing a positive association between the genetic score and sugar intake in IUGR children, and no association in non-IUGR children. No significant interactions were seen in other macronutrients. Variations in a genetic score reflecting DA signaling are associated with differences in sugar intake only in IUGR children, suggesting that DA function is involved in this behavioral feature in these children. This may have important implications for obesity prevention in this population. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Rape prevention

    Science.gov (United States)

    Date rape - prevention; Sexual assault - prevention ... Centers for Disease Control and Prevention website. Sexual assault and abuse and STDs. In: 2015 sexually transmitted diseases treatment guidelines 2015. www.cdc.gov/std/tg2015/sexual- ...

  3. Dengue Prevention

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Prevention Recommend on Facebook Tweet Share Compartir This photograph ... medications to treat a dengue infection. This makes prevention the most important step, and prevention means avoiding ...

  4. Changes in cardiovascular effects of dopamine in response to graded hypothermia in vivo.

    Science.gov (United States)

    Filseth, Ole Magnus; How, Ole-Jakob; Kondratiev, Timofei; Gamst, Tor Magne; Sager, Georg; Tveita, Torkjel

    2012-01-01

    Inotropic drugs are frequently administered in hypothermic patients to support an assumed inadequate circulation, but their pharmacologic properties at reduced temperatures are largely unknown. Thus we estimated dopamine pharmacokinetics as well as left ventricular function and global hemodynamics after dopamine infusions at various core temperatures in a pig model of surface cooling and rewarming. Prospective, randomized, open, placebo-controlled experimental study. University-affiliated animal research laboratory. Sixteen healthy, anesthetized juvenile (2-3 months) castrated male pigs. After normothermic infusions of dopamine at different doses (4, 8, and 16 μg/kg/min), effects of dopamine (n = 8) or saline (n = 8) were tested at 25 °C and during rewarming (30-34 °C). Dopamine half-time was 5.4 ± 0.7 min at normothermia, increased to 11.6 ± 0.8 min at 25 °C, but returned to control during rewarming at 34-35 °C. Dopamine infusion at 25 °C elevated dopamine plasma concentration four-fold compared to the same infusion rate at normothermia, leading to increased systemic vascular resistance index not seen at normothermia. Also, in contrast to the dopamine-mediated increase in cardiac index observed at normothermia, high-dose dopamine at 25 °C left cardiac index unchanged despite a concomitant increase in heart rate, since stroke index decreased by 43%. During rewarming, cardiovascular effects of dopamine at moderate hypothermia (30-34 °C) were principally similar to responses during normothermia. Pharmacodynamic effects and pharmacokinetics of dopamine are maintained during the rewarming phase at moderate hypothermia. However, at 25 °C dopamine pharmacokinetics were seriously altered and dopamine failed to increase cardiac index since stroke index was reduced with incrementing dosages. Properties of the low-flow, high-viscosity circulatory state, combined with altered pharmacokinetics of dopamine, may explain lack of beneficial--and potentially harmful

  5. Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.

    Science.gov (United States)

    Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V; Field, Bianca; Deutch, Ariel Y; Rayport, Stephen

    2015-12-09

    In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are

  6. Measurement of psychological state changes at low dopamine transporter occupancy following a clinical dose of mazindol.

    Science.gov (United States)

    Kimura, Y; Maeda, J; Yamada, M; Takahata, K; Yokokawa, K; Ikoma, Y; Seki, C; Ito, H; Higuchi, M; Suhara, T

    2017-02-01

    The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [ 18 F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [ 11 C]raclopride binding. Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24-25 %, and the binding potential of [ 11 C]raclopride was reduced by 2.8-4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [ 11 C]raclopride binding in the limbic striatum. A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [ 11 C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. TRIAL REGISTRATION HTTPS://UPLOAD.UMIN.AC.JP/CGI-OPEN-BIN/CTR_E/CTR_VIEW.CGI?RECPTNO=R000009703 : UMIN000008232.

  7. Salsolinol facilitates glutamatergic transmission to dopamine neurons in the posterior ventral tegmental area of rats.

    Directory of Open Access Journals (Sweden)

    Guiqin Xie

    Full Text Available Although in vivo evidence indicates that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse, the underlying mechanisms have not been fully elucidated. We have reported previously that salsolinol stimulates dopamine neurons in the posterior ventral tegmental area (p-VTA partly by reducing inhibitory GABAergic transmission, and that ethanol increases glutamatergic transmission to VTA-dopamine neurons via the activation of dopamine D(1 receptors (D(1Rs. In this study, we tested the hypothesis that salsolinol stimulates dopamine neurons involving activation of D(1Rs. By using whole-cell recordings on p-VTA-dopamine neurons in acute brain slices of rats, we found that salsolinol-induced increase in spike frequency of dopamine neurons was substantially attenuated by DL-2-amino-5-phosphono-valeric acid and 6, 7-dinitroquinoxaline-2, 3-dione, the antagonists of glutamatergic N-Methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, salsolinol increased the amplitude of evoked excitatory postsynaptic currents (EPSCs and the frequency but not the amplitude of spontaneous EPSCs. Additionally, SKF83566, a D(1R antagonist attenuated the salsolinol-induced facilitation of EPSCs and of spontaneous firing of dopamine neurons. Our data reveal that salsolinol enhances glutamatergic transmission onto dopamine neurons via activation of D(1Rs at the glutamatergic afferents in dopamine neurons, which contributes to salsolinol's stimulating effect on p-VTA dopamine neurons. This appears to be a novel mechanism which contributes toward rewarding properties of salsolinol.

  8. Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster.

    Science.gov (United States)

    Neckameyer, Wendi S; Bhatt, Parag

    2012-03-13

    In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit.

  9. Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Neckameyer Wendi S

    2012-03-01

    Full Text Available Abstract Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit.

  10. Plague Prevention

    Science.gov (United States)

    ... Healthcare Professionals Clinicians Public Health Officials Veterinarians Prevention History of Plague Resources FAQ Prevention Recommend on Facebook Tweet Share Compartir Reduce rodent habitat around your ...

  11. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Zpgmond, Michael J; Smith, Amanda; Liou, Anthony

    2007-01-01

    Parkinson's disease results in part from the loss of dopamine neurons. We hypothesize that exercise reduces the vulnerability of dopamine neurons to neurotoxin exposure, which is modulated by stress...

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

    Directory of Open Access Journals (Sweden)

    Ralf eBrisch

    2014-05-01

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

  13. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects

    NARCIS (Netherlands)

    Burke, S. M.; van de Giessen, E.; de Win, M.; Schilt, T.; van Herk, M.; van den Brink, W.; Booij, J.

    2011-01-01

    BACKGROUND: Serotonin and dopamine neurotransmitter systems are implicated in the regulation of mood, cognition and personality traits and their dysfunction is thought to be implicated in diverse psychopathologies. However, in healthy subjects the relationship between the serotonin and dopamine

  14. Predictive value of dopamine transporter SPECT imaging with [(123)I]PE2I in patients with subtle parkinsonian symptoms

    DEFF Research Database (Denmark)

    Ziebell, Morten; Andersen, Birgitte B; Thomsen, Gerda

    2012-01-01

    To examine the diagnostic sensitivity and specificity of dopamine transporter SPECT imaging with a highly dopamine transporter selective radioligand. The study included consecutively enrolled, drug-naive patients with an average short history of parkinsonian motor symptoms, referred for diagnostic...

  15. Evaluating Dopamine Reward Pathway in ADHD; clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Kollins, S.H., Wigal, t.L.; Newcorn, J.H.; Telang, F.; Fowler, J.S.; Zhu, W.; Logan, J.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

    2009-09-09

    Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D{sub 2}/D{sub 3} receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [{sup 11}C]cocaine and for D{sub 2}/D{sub 3} receptors using [{sup 11}C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P {le} .001); for D{sub 2}/D{sub 3} receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D{sub 2}/D{sub 3} for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0

  16. Oxidatively generated DNA damage after Cu(II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: Role of reactive oxygen species.

    Science.gov (United States)

    Spencer, Wendy A; Jeyabalan, Jeyaprakash; Kichambre, Sunita; Gupta, Ramesh C

    2011-01-01

    studies suggest a possible contributory role of oxidatively generated DNA damage by dopamine and related catechol neurotransmitters/neurotoxins in neurodegeneration and cell death. We also found that a naturally occurring broad-spectrum antioxidant, ellagic acid, was substantially effective (nearly 50% inhibition) at low doses (1μM) at preventing this dopamine/Cu(II)-mediated oxidatively generated DNA damage. Because dietary ellagic acid has been found to reduce oxidative stress in rat brains, a neuroprotective role of this polyphenol is plausible. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens

    NARCIS (Netherlands)

    Fusa, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2002-01-01

    Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies

  18. Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens.

    NARCIS (Netherlands)

    Fusa, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2002-01-01

    Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies

  19. Measuring dopamine release in the human brain with PET

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-12-01

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

  20. Sleep Deprivation Decreases [11C]Raclopride’s Binding to Dopamine D2/D3 Receptors in the Human Brain

    OpenAIRE

    Volkow, Nora D.; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Logan, Jean; Wong, Christopher; Ma, Jim; Pradhan, Kith; Tomasi, Dardo; Thanos, Peter K.; Ferré, Sergi; Jayne, Millard

    2008-01-01

    Sleep deprivation can markedly impair human performance contributing to accidents and poor productivity. The mechanisms underlying this impairment are not well understood but brain dopamine systems have been implicated. Here we test whether one night of sleep deprivation changes dopamine brain activity. We studied fifteen healthy subjects using positron emission tomography and [11C]raclopride (dopamine D2/3 receptor radioligand) and [11C]cocaine (dopamine transporter radioligand). Subjects we...

  1. Visual functions in phenylketonuria-evaluating the dopamine and long-chain polyunsaturated fatty acids depletion hypotheses.

    Science.gov (United States)

    Gramer, Gwendolyn; Förl, Birgit; Springer, Christina; Weimer, Petra; Haege, Gisela; Mackensen, Friederike; Müller, Edith; Völcker, Hans Eberhard; Hoffmann, Georg Friedrich; Lindner, Martin; Krastel, Hermann; Burgard, Peter

    2013-01-01

    In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes

    International Nuclear Information System (INIS)

    Minnema, D.J.; Greenland, R.D.; Michaelson, I.A.

    1986-01-01

    The effect of inorganic lead in vitro in several aspects of [ 3 H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel

  3. Disruption of Dopamine Neuron Activity Pattern Regulation through Selective Expression of a Human KCNN3 Mutation

    Science.gov (United States)

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

    2013-01-01

    Summary The calcium-activated small conductance potassium channel, SK3, plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior. PMID:24206670

  4. Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

    Science.gov (United States)

    Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

    2010-01-01

    Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…