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Sample records for activity dopaminergic systems

  1. NADPH oxidase and aging drive microglial activation, oxidative stress and dopaminergic neurodegeneration following systemic LPS administration

    OpenAIRE

    Qin, Liya; Liu, Yuxin; Hong, Jau-Shyong; Crews, Fulton T.

    2013-01-01

    Parkinson’s disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2+/+) mic...

  2. The dopaminergic system in the aging brain of Drosophila

    Directory of Open Access Journals (Sweden)

    Katherine E White

    2010-12-01

    Full Text Available Drosophila models of Parkinson’s disease are characterised by two principal phenotypes: the specific loss of dopaminergic neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analysed the dopaminergic system and motor behavior in aging Drosophila. Dopaminergic neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH>mCD8::GFP and cell type-specific MARCM clones revealed that dopaminergic neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, dopaminergic neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH>Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct dopaminergic behaviors in Drosophila. Moreover, dopaminergic neurons were maintained between early- and late life, as quantified by TH>mCD8::GFP and anti-TH labelling, indicating that adult onset, age-related degeneration of dopaminergic neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson’s disease as well as other disorders affecting dopaminergic neurons

  3. Dopaminergic system abnormalities Etiopathogenesis of dystonia

    Institute of Scientific and Technical Information of China (English)

    Shuhui Wu; Huifang Shang; Xiaoyi Zou

    2008-01-01

    BACKGROUND: Much research has focused on the close relationship between etiopathogenesis of dystonia and abnormalities of the dopaminergic system. Nevertheless, details of the mechanism are still not clear.OBJECTIVE: To review studies from the past few years about pathogenesis and molecular interactions involved in the relationship between dystonia and abnormalities of the dopaminergic system.RETRIEVAL STRATEGY: Using the key words "dystonia" and "dopamine", PubMed database and SCI databases were searched from January 1990 to December 2005 for relevant English publications. A total of 73 articles were searched and, initially, all articles were selected. Inclusive criteria: studies based on pathogenesis and molecular interactions involved in the relationship between dystonia and abnormalities of the dopaminergic system. Exclusive criteria: duplicated studies. A total of 19 articles were extracted after preliminary screening.LITERATURE EVALUATION: The data sources were the PubMed and SCI databases. The types of articles chosen were reviews and original articles.DATA SYNTHESIS: Metabolism and function of dopamine in the central nervous system: the chemical constitution of dopamine is a single benzene ring. The encephalic regions of dopamine synthesis and their fiber projections comprise four nervous system pathways. One of these pathways is the substantia nigra-striatum dopamine pathway, which is a side-loop of the basal ganglia circuitry that participates in movement control and plays a main role in the adjustment of extracorticospinal tract movement. Dopamine can lead to the facilitation of movement. Dystonia and abnormalities of the dopaminergic system: different modes of dopamine abnormality exist in various forms of dystonia. Abnormalities of the dopaminergic system in several primary dystonias: at present, fifteen gene loci of primary dystonia have been reported (DYT1-DYT15). The relationship between abnormalities of the dopaminergic system and the

  4. Assessment of renal dopaminergic system activity in the nitric oxide-deprived hypertensive rat model.

    OpenAIRE

    Soares-da-Silva, P.; Pestana, M; Vieira-Coelho, M A; Fernandes, M. H.; Albino-Teixeira, A

    1995-01-01

    1. The present paper reports changes in the urinary excretion of dopamine, 5-hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long-term administration of NG-nitro-L-arginine methyl ester (L-NAME). Aromatic L-amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly-formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined. 2. Twenty four hours after exposure to L-NAME, ...

  5. Renin angiotensin system and gender differences in dopaminergic degeneration

    Directory of Open Access Journals (Sweden)

    Rodriguez-Perez Ana I

    2011-08-01

    Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

  6. Decoding of dopaminergic mesolimbic activity and depressive behavior.

    Science.gov (United States)

    Friedman, Alexander; Deri, Ilana; Friedman, Yaakov; Dremencov, Eliyahu; Goutkin, Sophia; Kravchinsky, Elizabeth; Mintz, Matti; Levi, Dino; Overstreet, David H; Yadid, Gal

    2007-01-01

    Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Previously, we showed decreased limbic dopamine (DA) neurotransmission in an animal model of depression, Flinder sensitive line (FSL) rats. Here we describe a high correlation between phase-space algorithm of bursting-like activity of DA cells in the ventral tegmental area (VTA) and efficiency of DA release in the accumbens. This bursting-like activity of VTA DA cells of FSL rats is characterized by a low dimension complexity. Treatment with the antidepressant desipramine affected both the dimension complexity of cell firing in the VTA and rate of DA release in the accumbens, as well as alleviating depressive-like behavior. Our findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with non-linear analysis. Decoding the functionality of the dopaminergic system may help in development of future antidepressant drugs. PMID:17873290

  7. Dopaminergic Activity in the Medial Prefrontal Cortex Modulates Fear Conditioning

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    Parvin Babaei

    2011-07-01

    Full Text Available "nThe purpose of the present study was to determine the role of medial prefrontal cortex (mPFC dopaminergic system in fear conditioning response considering individual differences. Animals were initially counterbalanced and classified based on open field test, and then were given a single infusion of the dopamine agonist, amphetamine (AMPH and antagonist, clozapine (CLZ into the medial prefrontal cortex. Rats received tone-shock pairing in a classical fear conditioning test and then exposed to the tone alone. Freezing responses were measured as conditioned fear index. The results showed that both AMPH and CLZ infusion in mPFC reduced the expression of conditioned fear. This finding indicates that elevation or reduction in the dopaminergic activity is associated with the decrease of fear responses, despite preexisting individual-typological differences.

  8. Establishing diversity in the dopaminergic system.

    Science.gov (United States)

    Bodea, Gabriela O; Blaess, Sandra

    2015-12-21

    Midbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain. PMID:26431946

  9. Brain dopaminergic systems : imaging with positron tomography

    International Nuclear Information System (INIS)

    Imaging of the dopaminergic system in the human brain with the in vivo use of Positron Emission Tomography emerged in the late 1980s as a tool of major importance in clinical neurosciences and pharmacology. The last few years have witnessed rapid development of new radiotracers specific to receptors, reuptake sites and enzymes of the dopamine system; the application of these radiotracers has led to major break-troughs in the pathophysiology and therapy of movement disorders and schizophrenic-like psychoses. This book is the first to collect, in a single volume, state-of-the-art contributions to the various aspects of this research. Its contents address methodological issues related to the design, labelling, quantitative imaging and compartmental modeli-sation of radioligands of the post-synaptic, pre-synaptic and enzyme sites of the dopamine system and to their use in clinical research in the fields of Parkinson's disease as well as other movement disorders, psychoses and neuroleptic receptor occupancy. The chapters were written by leading European scientists in the field of PET, gathered together in Caen (France, November 1990) under the aegis of the EEC Concerted Action on PET Investigations of Cellular Regeneration and Degeneration. This book provides a current and comprehensive overview on PET studies of the brain dopamine system which should aid and interest neurologists , psychiatrists, pharmacologists and medical imaging scientists. (author). refs.; figs.; tabs

  10. PET tracers for imaging of the dopaminergic system

    NARCIS (Netherlands)

    Elsinga, Philip H.; Hatano, Kentaro; Ishiwata, Kiichi

    2006-01-01

    The dopaminergic system plays a major role in neurological and psychiatric disorders such as Parkinson's disease, Huntington's disease, tardive dyskinea and schizophrenia. Knowledge on altered dopamine synthesis, receptor densities and status are important for understanding the mechanisms underlying

  11. Desire, Disease, and the Origins of the Dopaminergic System

    OpenAIRE

    Sillitoe, Roy V.; Vogel, Michael W.

    2008-01-01

    The dopaminergic neurons in the midbrain region of the central nervous system project an extensive network of connections throughout the forebrain, including the neocortex. The midbrain-forebrain dopaminergic circuits are thought to regulate a diverse set of behaviors, from the control of movement to modulation of cognition and desire—because they relate to mood, attention, reward, and addiction. Defects in these pathways, including neurodegeneration, are implicated in a variety of psychiatri...

  12. Splenectomy modifies hyperactive states of the dopaminergic system induced by morphine in C57BL/6J-bg(J)/bg(J) (beige-J) mice.

    Science.gov (United States)

    Funada, Masahiko; Mori, Tomohisa; Maeda, Jun; Tsuda, Yuko; Komiya, Sachiko; Shimizu, Norifumi; Kamei, Junzo; Suzuki, Tsutomu

    2014-11-01

    Genetic factors affect the locomotor activity induced by morphine, which mainly depends on the activation of dopaminergic systems, and morphine has distinct pharmacological activities in C57BL/6J-bg(J)bg(J) (beige-J) mice, which have genetic deficiencies in immunological function. We previously showed that beige-J mice exhibited greater locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and that the spleen may contribute to the susceptibility to activation of the dopaminergic system. Furthermore, morphine can induce hyperlocomotion mediated by activation of the dopaminergic system. Therefore, we examined the effects of splenectomy on the hyperlocomotion and regulation of the dopaminergic system induced by morphine in beige-J mice. Morphine induced hyperlocomotion, which was accompanied by activation of the dopaminergic system, in beige-J mice. Furthermore, splenectomy enhanced the hyperlocomotion and activation of the mesolimbic dopaminergic system induced by morphine in beige-J mice. Our findings indicate that substances originating from the spleen may regulate both spontaneous activation of the mesolimbic dopaminergic system and the µ-opioidergic system-mediated activation of the mesolimbic dopaminergic system by morphine through different modes of action. These results imply that beige-J mice could be a practical animal model for investigating the interactions between immune-modulation and the µ-opioidergic system and/or dopaminergic system.

  13. Desire, disease, and the origins of the dopaminergic system.

    Science.gov (United States)

    Sillitoe, Roy V; Vogel, Michael W

    2008-03-01

    The dopaminergic neurons in the midbrain region of the central nervous system project an extensive network of connections throughout the forebrain, including the neocortex. The midbrain-forebrain dopaminergic circuits are thought to regulate a diverse set of behaviors, from the control of movement to modulation of cognition and desire--because they relate to mood, attention, reward, and addiction. Defects in these pathways, including neurodegeneration, are implicated in a variety of psychiatric and neurological diseases, such as schizophrenia, attention-deficit/hyperactivity disorder, drug addiction, and Parkinson disease. Based on the importance of the midbrain dopaminergic neurons to normal and pathological brain function, there is considerable interest in the molecular mechanisms that regulate their development. The goal of this short review is to outline new methods and recent advances in identifying the molecular networks that regulate midbrain dopaminergic neuron differentiation and fate. Midbrain dopaminergic neurons are descended from progenitor cells located near the ventral midline of the neural tube floor plate around the cephalic flexure. It is now clear that their initial formation is dependent on interactions between the signaling molecules Sonic hedgehog, WINGLESS 1, and FIBROBLAST growth factor 8, but there is still an extensive wider network of molecular interactions that must be resolved before the complete picture of dopaminergic neuron development can be described. PMID:18283047

  14. Chronic exposure to low levels of inorganic arsenic causes alterations in locomotor activity and in the expression of dopaminergic and antioxidant systems in the albino rat.

    Science.gov (United States)

    Rodríguez, Verónica Mireya; Limón-Pacheco, Jorge Humberto; Carrizales, Leticia; Mendoza-Trejo, María Soledad; Giordano, Magda

    2010-01-01

    Several studies have associated chronic arsenicism with decreases in IQ and sensory and motor alterations in humans. Likewise, studies of rodents exposed to inorganic arsenic ((i)As) have found changes in locomotor activity, brain neurochemistry, behavioral tasks, oxidative stress, and in sensory and motor nerves. In the current study, male Sprague-Dawley rats were exposed to environmentally relevant doses of (i)As (0.05, 0.5 mg (i)As/L) and to a high dose (50 mg (i)As/L) in drinking water for one year. Hypoactivity and increases in the striatal dopamine content were found in the group treated with 50 mg (i)As/L. Exposure to 0.5 and 50 mg (i)As/L increased the total brain content of As. Furthermore, (i)As exposure produced a dose-dependent up-regulation of mRNA for Mn-SOD and Trx-1 and a down-regulation of DAR-D₂ mRNA levels in the nucleus accumbens. DAR-D₁ and Nrf2 mRNA expression were down-regulated in nucleus accumbens in the group exposed to 50 mg (i)As/L. Trx-1 mRNA levels were up-regulated in the cortex in an (i)As dose-dependent manner, while DAR-D₁ mRNA expression was increased in striatum in the 0.5 mg (i)As/L group. These results show that chronic exposure to low levels of arsenic causes subtle but region-specific changes in the nervous system, especially in antioxidant systems and dopaminergic elements. These changes became behaviorally evident only in the group exposed to 50 mg (i)As/L.

  15. Increased dopaminergic activity in socially isolated rats: an electrophysiological study

    DEFF Research Database (Denmark)

    Fabricius, Katrine; Helboe, Lone; Fink-Jensen, Anders;

    2010-01-01

    The development of animal models mimicking symptoms associated with schizophrenia has been a critical step in understanding the neurobiological mechanisms underlying the disease. Long-term social isolation from weaning in rodents, a model based on the neurodevelopmental hypothesis of schizophrenia......, has been suggested to mimic some of the deficits seen in schizophrenic patients. We confirm in the present study that socially isolated rats display an increase in both spontaneous and d-amphetamine-induced locomotor activity, as well as deficits in sensorimotor gating as assessed in a pre......-pulse inhibition paradigm. In addition, in vivo electrophysiological studies revealed changes in dopaminergic cell firing activity in the ventral tegmental area of isolated rats when compared to group-housed controls. These alterations include an increase in the number of spontaneously active dopaminergic neurons...

  16. Alterations in Central Nervous System Serotonergic and Dopaminergic Synaptic Activity in Adulthood after Prenatal or Neonatal Chlorpyrifos Exposure

    OpenAIRE

    Aldridge, Justin E; Meyer, Armando; Seidler, Frederic J; Slotkin, Theodore A.

    2005-01-01

    Exposure to chlorpyrifos (CPF) alters neuronal development of serotonin (5HT) and dopamine systems, and we recently found long-term alterations in behaviors related to 5HT function. To characterize the synaptic mechanisms underlying these effects, we exposed developing rats to CPF regimens below the threshold for systemic toxicity, in three treatment windows: gestational days (GD) 17–20, postnatal days (PN) 1–4, or PN11–14. In early adulthood (PN60), we assessed basal neurotransmitter content...

  17. Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

    Directory of Open Access Journals (Sweden)

    Gevaerd M.S.

    1999-01-01

    Full Text Available The widespread consumption of anorectics and combined anorectic + alcohol misuse are problems in Brazil. In order to better understand the interactive effects of ethanol (EtOH and diethylpropion (DEP we examined the locomotion-activating effects of these drugs given alone or in combination in mice. We also determined whether this response was affected by dopamine (DA or opioid receptor antagonists. A total of 160 male Swiss mice weighing approximately 30 g were divided into groups of 8 animals per group. The animals were treated daily for 7 consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/kg, ip, EtOH (1.2 g/kg, ip, DEP (5.0 mg/kg, ip or the control solution coadministered with the DA antagonist haloperidol (HAL, 0.075 mg/kg, ip, the opioid antagonist naloxone (NAL, 1.0 mg/kg, ip, or vehicle. On days 1, 7 and 10 after the injections, mice were assessed in activity cages at different times (15, 30, 45 and 60 min for 5 min. The acute combination of EtOH plus DEP induced a significantly higher increase in locomotor activity (day 1: 369.5 ± 34.41 when compared to either drug alone (day 1: EtOH = 232.5 ± 23.79 and DEP = 276.0 ± 12.85 and to control solution (day 1: 153.12 ± 7.64. However, the repeated administration of EtOH (day 7: 314.63 ± 26.79 and day 10: 257.62 ± 29.91 or DEP (day 7: 309.5 ± 31.65 and day 10: 321.12 ± 39.24 alone or in combination (day 7: 459.75 ± 41.28 and day 10: 427.87 ± 33.0 failed to induce a progressive increase in the locomotor response. These data demonstrate greater locomotion-activating effects of the EtOH + DEP combination, probably involving DA and/or opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH + DEP = 395.62 ± 11.92 and EtOH + DEP + HAL = 371.5 ± 6.76; day 7: EtOH + DEP = 502.5 ± 42.27 and EtOH + DEP + HAL = 281.12 ± 16.08; day 10: EtOH + DEP = 445.75 ± 16.64 and EtOH + DEP + HAL = 376.75 ± 16.4 and NAL (day 1: EtOH + DEP = 553.62 ± 38.15 and Et

  18. Sexually dimorphic activation of dopaminergic areas depends on affiliation during courtship and pair formation

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    Mai eIwasaki

    2014-06-01

    Full Text Available For many species, dyadic interaction during courtship and pair bonding engage intense emotional states that control approach or avoidance behavior. Previous studies have shown that one component of a common social brain network (SBN, dopaminergic areas, are highly engaged during male songbird courtship of females. We tested whether the level of activity in dopaminergic systems of both females and males during courtship is related to their level of affiliation. In order to objectively quantify affiliative behaviors, we developed a system for tracking the position of both birds during free interaction sessions. During a third successive daily interaction session, there was a range of levels of affiliation among bird pairs, as quantified by several position and movement parameters. Because both positive and negative social interactions were present, we chose to characterize affiliation strength by pair valence. As a potential neural system involved in regulating pair valence, the level of activity of the dopaminergic group A11 (within the central gray was selectively reduced in females of positive valence pairs. Further, activation of non-dopaminergic neurons in VTA was negatively related to valence, with this relationship strongest in ventral VTA of females. Together, these results suggest that inhibition of fear or avoidance networks may be associated with development of close affiliation, and highlight the importance of negative as well as positive emotional states in the process of courtship, and in development of long-lasting social bonds.

  19. Dopaminergic modulation of the spectral characteristics in the rat brain oscillatory activity

    International Nuclear Information System (INIS)

    Highlights: ► The oscillatory activity recorded at different locations of the rat brain present a power law characteristic (PLC). ► Dopaminergic drugs are able to modify the power law spectral characteristic of the oscillatory activity. ► Drugs with opposite effects over the dopaminergic system (agonists/antagonists), induce opposite changes in the PLC. ► There is a fulcrum point for the modulation of the PLC around 20 Hz. ► The brain operates in a state of self-organized criticality (SOC) sensitive to dopaminergic modulation. - Abstract: Oscillatory activity can be widely recorded in the brain. It has been demonstrated to play an important role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of a variety of diseases. In frequency domain, neurophysiological recordings show a power spectrum (PSD) following a log (PSD) ∝ log (f)−β, that reveals an intrinsic feature of many complex systems in nature: the presence of a scale-free dynamics characterized by a power-law component (PLC). Here we analyzed the influence of dopaminergic drugs over the PLC of the oscillatory activity recorded from different locations of the rat brain. Dopamine (DA) is a neurotransmitter that is required for a number of physiological functions like normal feeding, locomotion, posturing, grooming and reaction time. Alterations in the dopaminergic system cause vast effects in the dynamics of the brain activity, that may be crucial in the pathophysiology of neurological (like Parkinson’s disease) or psychiatric (like schizophrenia) diseases. Our results show that drugs with opposite effects over the dopaminergic system, induce opposite changes in the characteristics of the PLC: DA agonists/antagonists cause the PLC to swing around a fulcrum point in the range of 20 Hz. Changes in the harmonic component of the spectrum were also detected. However, differences between recordings are better explained by the modulation of the PLC than

  20. The dopaminergic system and aggression in laying hens

    Science.gov (United States)

    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  1. Dynamics of the dopaminergic system as a key component to the understanding of depression.

    Science.gov (United States)

    Yadid, Gal; Friedman, Alexander

    2008-01-01

    For decades, clinical treatment of depression has usually involved antidepressants that target noradrenergic and serotonergic neurotransmission. Over the past half century, no genuinely ground-breaking progress has been made in the pharmacological development of antidepressant drugs. Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Recent findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with mathematical analysis. In this chapter comprehensive review of data from animal models, genetics, neuroimaging and human clinical trials that strengthen the case for dopaminergic dysfunction in the pathophysiology of major depression. This chapter focuses on recent convergence of data describing the fluctuation in activity of the mesolimbic dopaminergic system, and discusses its crucial role in manifestation of depressive-like behavior. Decoding the functionality of the dopaminergic system is important to the understanding of depression and the development of future efficient antidepressant treatments. PMID:18772037

  2. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis

    Directory of Open Access Journals (Sweden)

    Jose Carlos Pereira Jr.

    2010-01-01

    Full Text Available Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones.

  3. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis.

    Science.gov (United States)

    Pereira, Jose Carlos; Pradella-Hallinan, Marcia; Lins Pessoa, Hugo de

    2010-05-01

    Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones. PMID:20535374

  4. Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner.

    Science.gov (United States)

    Zhang, Yunpeng; Guo, Jing; Guo, Aike; Li, Yan

    2016-09-22

    Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition. However, the underlying neural basis and molecular mechanisms for these effects remain poorly understood. Here, using a video recording system, we find that acute nicotine administration induces locomotor hyperactivity in Drosophila, similar to observations made in higher model organisms. Suppressing dopaminergic neurons or down-regulating dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, we show that dopaminergic neurons possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the β1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, our results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila β1 nAChR subunit plays a crucial role in this nicotine response. These findings provide important insights into the molecular and neural basis of acute nicotine effects, and the underlying mechanisms may play conserved roles across species. PMID:27365175

  5. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells

    Energy Technology Data Exchange (ETDEWEB)

    Afeseh Ngwa, Hilary; Kanthasamy, Arthi [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States); Gu, Yan; Fang, Ning [Department of Chemistry, Iowa State University, Ames, IA 50011 (United States); Anantharam, Vellareddy [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States); Kanthasamy, Anumantha G., E-mail: akanthas@iastate.edu [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States)

    2011-11-15

    activate mitochondrial cell death signaling in dopaminergic neuron. Black-Right-Pointing-Pointer Mn nanoparticles activate caspase-mediated proteolytic cleavage of PKC{delta} cascade. Black-Right-Pointing-Pointer Mn nanoparticles induce autophagy in dopaminergic neuronal cells. Black-Right-Pointing-Pointer Mn nanoparticles induce loss of TH{sup +} neurons in primary mesencephalic cultures. Black-Right-Pointing-Pointer Study emphasizes neurotoxic risks of Mn nanoparticles to nigral dopaminergic system.

  6. The effects of dihydropyridine compounds in behavioural tests of dopaminergic activity.

    OpenAIRE

    Bourson, A.; Gower, A. J.; Mir, A. K.; Moser, P C

    1989-01-01

    1. The effects of the dihydropyridine calcium channel blocker nifedipine and the activator Bay K 8644 were investigated in different behavioural tests involving dopaminergic systems. These were the discriminative stimulus induced by amphetamine, rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions and apomorphine-induced yawning in rats. 2. The yawning induced by apomorphine (40 micrograms kg-1 s.c.) was significantly potentiated by nifedipine (5-10 mgkg-1 i.p.). Ba...

  7. Dopaminergic parameters during social isolation in low- and high-active mice.

    Science.gov (United States)

    Rilke, O; Jähkel, M; Oehler, J

    1998-06-01

    Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to locomotor activity, [3H]-spiperone binding in the striatum, striatal, and cortical dopamine metabolism, and presynaptic dopaminergic sensitivity to apomorphine (0.75 mg/kg; i.p.). Isolated HAM and LAM showed increased locomotor activity compared to group-housed mice after long-term isolation (6-18 weeks). Considering the studied dopaminergic parameters, it has been found that social isolation did not affect striatal D2 receptors, striatal and cortical dopamine metabolism, and apomorphine-mediated reduction of dopaminergic metabolism. The change of housing conditions was generally associated with an increase of cortical dopamine metabolism after 1 week. Activity type specific differences in group-housed LAM and HAM were found in the basal striatal dopamine metabolism and in the sensitivity of the nigrostriatal system to autoreceptor activation. The reduced striatal dopamine metabolism and the higher presynaptic sensitivity of HAM may be related to their high active running wheel behavior.

  8. Imaging of the dopaminergic system in differential diagnosis of dementia

    Energy Technology Data Exchange (ETDEWEB)

    Tatsch, Klaus [University of Munich Hospital - Campus Grosshadern, Department of Nuclear Medicine, Munich (Germany)

    2008-03-15

    specifically dealing with imaging of the dopaminergic system in the differential diagnosis of dementia. (orig.)

  9. Imaging of the dopaminergic system in differential diagnosis of dementia

    International Nuclear Information System (INIS)

    specifically dealing with imaging of the dopaminergic system in the differential diagnosis of dementia. (orig.)

  10. Full Anatomical Recovery of the Dopaminergic System after a Complete Spinal Cord Injury in Lampreys

    Directory of Open Access Journals (Sweden)

    Blanca Fernández-López

    2015-01-01

    Full Text Available Following a spinal injury, lampreys at first are paralyzed below the level of transection. However, they recover locomotion after several weeks, and this is accompanied by the regeneration of descending axons from the brain and the production of new neurons in the spinal cord. Here, we aimed to analyse the changes in the dopaminergic system of the sea lamprey after a complete spinal transection by studying the changes in dopaminergic cell numbers and dopaminergic innervation in the spinal cord. Changes in the expression of the D2 receptor were also studied. We report the full anatomical regeneration of the dopaminergic system after an initial decrease in the number of dopaminergic cells and fibres. Numbers of dopaminergic cells were recovered rostrally and caudally to the site of injury. Quantification of dopaminergic profiles revealed the full recovery of the dopaminergic innervation of the spinal cord rostral and caudal to the site of injury. Interestingly, no changes in the expression of the D2 receptor were observed at time points in which a reduced dopaminergic innervation of the spinal cord was observed. Our observations reveal that in lampreys a spinal cord injury is followed by the full anatomical recovery of the dopaminergic system.

  11. Age-related changes in midbrain dopaminergic regulation of the human reward system

    OpenAIRE

    Dreher, Jean-Claude; Meyer-Lindenberg, Andreas; Kohn, Philip; Berman, Karen Faith

    2008-01-01

    The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharm...

  12. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship?

    Directory of Open Access Journals (Sweden)

    Marcelo Roberto Choi

    2014-01-01

    Full Text Available Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways.

  13. Contribution of dopaminergic and adenosinergic systems in the antinociceptive effect of p-chloro-selenosteroid.

    Science.gov (United States)

    Marcondes Sari, Marcel Henrique; Guerra Souza, Ana Cristina; Gonçalves Rosa, Suzan; Souza, Diego; Dorneles Rodrigues, Oscar Endrigo; Wayne Nogueira, Cristina

    2014-02-15

    This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and opioid systems was investigated. It was evaluated if the administration of PCS triggers toxic effect. Treatment with PCS (10mg/kg) reduced writhing induced by acetic acid and its effect lasts up to 48 h after treatment. The compound caused an inhibition in neurogenic and inflammatory phases of nociception and in paw edema induced by formalin. The licking behavior triggered by glutamate was reduced by PCS. In the tail-immersion test, PCS elicited an increase in delta latency response. Pretreatment with caffeine (3mg/kg, intraperitoneally [i.p.]) and SCH58261 (3mg/kg, i.p.), antagonist at adenosinergic receptors, SCH23390 (0.05 mg/kg, i.p.) and sulpiride (5mg/kg, i.p.), antagonist at dopaminergic receptors, caused a reduction in the antinociceptive action of PCS in the glutamate test. By contrast, pretreatment with WAY100635 (0.7 mg/kg, i.p.), ketanserin (0.3mg/kg, i.p.), ondasentron (0.5mg/kg, i.p.), l-arginine (600 mg/kg, i.p.) and naloxone (1mg/kg, subcutaneous [s.c.]) did not abolish the antinociceptive effect caused by PCS (10mg/kg, i.g.) administration. The animals treated with PCS did not show alterations in locomotor and exploratory activities, in biochemical parameters evaluated, food and water consumption, as well as in the body weight. These results clearly showed the antinociceptive action of PCS in different animal models without causing acute toxic effects in mice. Adenosinergic and dopaminergic systems seem to be related to the mechanisms by which PCS elicits antinociception. PMID:24440690

  14. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system.

    Science.gov (United States)

    Ismaiel, Afrah A K; Espinosa-Oliva, Ana M; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J; Herrera, Antonio J; Venero, José L; de Pablos, Rocío M

    2016-05-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. PMID:26971375

  15. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system.

    Science.gov (United States)

    Ismaiel, Afrah A K; Espinosa-Oliva, Ana M; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J; Herrera, Antonio J; Venero, José L; de Pablos, Rocío M

    2016-05-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.

  16. Dopaminergic reward sensitivity can promote adolescent health: A new perspective on the mechanism of ventral striatum activation

    Directory of Open Access Journals (Sweden)

    Eva H. Telzer

    2016-02-01

    Full Text Available The prevailing view in the field of adolescent brain development is that heightened activity in the mesolimbic dopaminergic reward system serves as a liability, orienting adolescents toward risky behaviors, increasing their sensitivity to social evaluation and loss, and resulting in compromised well-being. Several findings inconsistent with this deficit view challenge the perspective that adolescent reward sensitivity largely serves as a liability and highlights the potential adaptive function that heightened striatal reactivity can serve. The goal of this review is to refine our understanding of dopaminergic reward sensitivity in adolescence. I review several studies showing that ventral striatum activation serves an adaptive function for adolescents’ health and well being relating to declines in both risk taking and depression and increases in cognitive persistence and achievement.

  17. The Dopaminergic Reward System and Leisure Time Exercise Behavior: A Candidate Allele Study

    Directory of Open Access Journals (Sweden)

    Charlotte Huppertz

    2014-01-01

    Full Text Available Purpose. Twin studies provide evidence that genetic influences contribute strongly to individual differences in exercise behavior. We hypothesize that part of this heritability is explained by genetic variation in the dopaminergic reward system. Eight single nucleotide polymorphisms (SNPs in DRD1: rs265981, DRD2: rs6275, rs1800497, DRD3: rs6280, DRD4: rs1800955, DBH: rs1611115, rs2519152, and in COMT: rs4680 and three variable number of tandem repeats (VNTRs in DRD4, upstream of DRD5, and in DAT1 were investigated for an association with regular leisure time exercise behavior. Materials and Methods. Data on exercise activities and at least one SNP/VNTR were available for 8,768 individuals aged 7 to 50 years old that were part of the Netherlands Twin Register. Exercise behavior was quantified as weekly metabolic equivalents of task (MET spent on exercise activities. Mixed models were fitted in SPSS with genetic relatedness as a random effect. Results. None of the genetic variants were associated with exercise behavior (P>.02, despite sufficient power to detect small effects. Discussion and Conclusions. We did not confirm that allelic variants involved in dopaminergic function play a role in creating individual differences in exercise behavior. A plea is made for large genome-wide association studies to unravel the genetic pathways that affect this health-enhancing behavior.

  18. Rotenone induces degeneration of photoreceptors and impairs the dopaminergic system in the rat retina.

    Science.gov (United States)

    Esteve-Rudd, Julián; Fernández-Sánchez, Laura; Lax, Pedro; De Juan, Emilio; Martín-Nieto, José; Cuenca, Nicolás

    2011-10-01

    Rotenone is a widely used pesticide and a potent inhibitor of mitochondrial complex I (NADH-quinone reductase) that elicits the degeneration of dopaminergic neurons and thereby the appearance of a parkinsonian syndrome. Here we have addressed the alterations induced by rotenone at the functional, morphological and molecular levels in the retina, including those involving both dopaminergic and non-dopaminergic retinal neurons. Rotenone-treated rats showed abnormalities in equilibrium, postural instability and involuntary movements. In their outer retina we observed a loss of photoreceptors, and a reduced synaptic connectivity between those remaining and their postsynaptic neurons. A dramatic loss of mitochondria was observed in the inner segments, as well as in the axon terminals of photoreceptors. In the inner retina we observed a decrease in the expression of dopaminergic cell molecular markers, including loss of tyrosine hydroxylase immunoreactivity, associated with a reduction of the dopaminergic plexus and cell bodies. An increase in immunoreactivity of AII amacrine cells for parvalbumin, a Ca(2+)-scavenging protein, was also detected. These abnormalities were accompanied by a decrease in the amplitude of scotopic and photopic a- and b-waves and an increase in the b-wave implicit time, as well as by a lower amplitude and greater latency in oscillatory potentials. These results indicate that rotenone induces loss of vision by promoting photoreceptor cell death and impairment of the dopaminergic retinal system.

  19. ROLE OF CHOLINERGIC SYSTEM ON THE CONSTRUCTION OF MEMORY AND ITS INTERACTION WITH DOPAMINERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    F. Z. Zangeneh

    2006-07-01

    Full Text Available The central cholinergic system has been associated with cognitive function and memory and acetylcholine plays an important role during the early stages of memory consolidation. In this study, after training mice were tested with one way active avoidance procedure and retention were tested at 4, 8, 12, 16 and 24 hours of training and compared with non-shocked mice, in which it took 24 hours, a suitable time for retention test. Low dose administration of arecoline and physostigmine pre-training, immediate post-training and before retrieval showed that muscarinic agonist arecoline can potentiated memory in post trained and retrieval phases and reversible cholinesterase inhibitor physostigmine potentiated memory only in retrieval phase. Scopolamine disrupted acetylcholine potentiation only in retrieval phase. In the second part of this study, the effect of dopaminergic system was investigated. Low dose of apomorphine and D2 agonist bromocriptine potentiated memory when administered immediately post-training, and D2 antagonist sulpiride impaired memory. When the cholinergic system was blocked by scopolamine immediately post-training, apomorphine and bromocriptine potentiated memory and sulpiride impaired it. In conclusion, these results suggest that, cholinergic system in retrieval phase is very critical and there was no interaction between the two systems in the post-training phase.

  20. Antinociceptive Activity of Trichilia catigua Hydroalcoholic Extract: New Evidence on Its Dopaminergic Effects

    Directory of Open Access Journals (Sweden)

    Alice F. Viana

    2011-01-01

    Full Text Available Trichilia catigua is a native plant of Brazil; its barks are used by some local pharmaceutical companies to prepare tonic drinks, such as Catuama. The present study was addressed to evaluate the effects of T. catigua hydroalcoholic extract in mouse nociception behavioral models, and to evaluate the possible mechanisms involved in its actions. Male Swiss mice were submitted to hot-plate, writhing and von Frey tests, after oral treatment with T. catigua extract (200 mg kg−1, p.o.. The extract displayed antinociceptive effect in all three models. For characterization of the mechanisms involved in the antinociceptive action of the extract, the following pharmacological treatments were done: naloxone (2.5 mg kg−1, s.c., SR141716A (10 mg kg−1, i.p., SCH23390 (15 μg kg−1, i.p., sulpiride (50 mg kg−1, i.p., prazosin (1 mg kg−1, i.p., bicuculline (1 mg kg−1, i.p. or dl-p-chlorophenylalanine methyl ester (PCPA, 100 mg kg−1, i.p.. In these experiments, the action of T. catigua extract was evaluated in the hot-plate test. The treatment with SCH23390 completely prevented the antinociceptive effect, while naloxone partially prevented it. The possible involvement of the dopaminergic system in the actions of T. catigua extract was substantiated by data showing the potentiation of apomorphine-induced hypothermia and by the prevention of haloperidol-induced catalepsy. In conclusion, the antinociceptive effects of T. catigua extract seem to be mainly associated with the activation of dopaminergic system and, to a lesser extent, through interaction with opioid pathway.

  1. Age-related changes in midbrain dopaminergic regulation of the human reward system

    Science.gov (United States)

    Dreher, Jean-Claude; Meyer-Lindenberg, Andreas; Kohn, Philip; Berman, Karen Faith

    2008-01-01

    The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[18F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging. PMID:18794529

  2. Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and efect of perineuronal net loss

    Directory of Open Access Journals (Sweden)

    Pascal eSteullet

    2014-08-01

    Full Text Available Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in  band in slices of the mouse anterior cingulate cortex (ACC. We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia patients who display prefrontal anomalies of both the dopaminergic system and the perineuronal nets.

  3. Endogenous 17ß-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    Directory of Open Access Journals (Sweden)

    Alessandro eTozzi

    2015-05-01

    Full Text Available 17β-estradiol (E2, a neurosteroid synthesized by P450-aromatase (ARO, modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs and dopamine (DA receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP in both medium spiny neurons (MSNs and cholinergic interneurons (ChIs. Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.

  4. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

    Science.gov (United States)

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease. PMID:26074768

  5. Hyperactivity of the Dopaminergic System in NTS1 and NTS2 Null Mice

    OpenAIRE

    Liang, Yanqi; Boules, Mona; Li, Zhimin; Williams, Katrina; Miura, Tomofumi; Oliveros, Alfredo; Richelson, Elliott

    2010-01-01

    Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1−/−) or NTS2 (NTS2−/−). Basal and amphe...

  6. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice

    OpenAIRE

    Sidor, Michelle M.; Spencer, Sade M.; Dzirasa, Kafui; Parekh, Puja K.; Tye, Kay M; Warden, Melissa R.; Arey, Rachel N.; Enwright, John F; Jacobsen, Jacob PR; Kumar, Sunil; Remillard, Erin M; Marc G Caron; Deisseroth, Karl; McClung, Colleen A.

    2014-01-01

    Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of e...

  7. Preparation of radiopharmaceuticals labelled with bromine positron emitting isotopes for the study of dopaminergic receptors of the central nervous system using positron emission tomography

    International Nuclear Information System (INIS)

    The in vivo study of dopaminergic receptors of the central nervous system using positron emission tomography requires the preparation of radiopharmaceuticals labelled with β+ emitting isotopes. The chemical and pharmacological properties of these ligands are evaluated. Cyclotron produced 75 and 76 bromine β+ emitting isotopes are incorporated into dopaminergic ligands by electrophilic substitution using peracetic acid in a no-carrier added form. Purity, lipophilicity and specific activity are analyzed. Pharmacological criteria (specificity, saturability, displacement, localization) required for ligand-receptor binding studies are evaluated in vitro on striatal membranes and in vivo in the rat. Positron emission tomographic studies show that the study of dopaminergic D2 receptors is possible using 75 and 76 bromine labelled bromospiperone and bromolisuride. These ligands are used in physiological and pharmacological studies of the central nervous system

  8. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.

    Science.gov (United States)

    Samikkannu, Thangavel; Rao, Kurapati V K; Salam, Abdul Ajees Abdul; Atluri, Venkata S R; Kaftanovskaya, Elena M; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D; Ding, Hong; Nair, Madhavan P N

    2015-01-01

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID:26057350

  9. Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron.

    Science.gov (United States)

    Wang, Jing; Liu, Huaide; Jin, Weihua; Zhang, Hong; Zhang, Quanbin

    2016-01-01

    Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (Pneuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity.

  10. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

    Science.gov (United States)

    Sidor, M M; Spencer, S M; Dzirasa, K; Parekh, P K; Tye, K M; Warden, M R; Arey, R N; Enwright, J F; Jacobsen, J P R; Kumar, S; Remillard, E M; Caron, M G; Deisseroth, K; McClung, C A

    2015-11-01

    Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder. PMID:25560763

  11. Obesity, Attention Deficit-Hyperactivity Disorder and the Dopaminergic Reward System

    OpenAIRE

    Campbell, Benjamin Charles; Eisenberg, Dan

    2007-01-01

    The obesity epidemic has focused attention on obesity’s health consequences beyond cardio-vascular disease and diabetes. To evaluate the potential consequences of obesity for Attention Deficit-Hyperactivity Disorder (ADHD), we surveyed the literature. Current findings link both obesity and ADHD to the dopamine system and implicate dopamine genes in body weight, eating, and ADHD. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals wi...

  12. Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

    Science.gov (United States)

    Clements, S.; Schreck, C.B.

    2004-01-01

    The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

  13. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Planeta, C.S. [Laboratório de Neuropsicofarmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Lepsch, L.B.; Alves, R.; Scavone, C. [Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-10-15

    Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

  14. Influence of the dopaminergic system, CREB, and transcription factor-B on cocaine neurotoxicity

    Directory of Open Access Journals (Sweden)

    C.S. Planeta

    2013-11-01

    Full Text Available Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake, lidocaine (a local anesthetic, and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

  15. Investigations into potential extrasynaptic communication between the dopaminergic and nitrergic systems

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    Miso eMitkovski

    2012-09-01

    Full Text Available Nitric oxide is unconstrained by cell membranes and can therefore act along a broad distance as a volume transmitter. Spillover of nitric oxide between neurons may have a major impact on central nervous system diseases and particularly on neurodegeneration. There is evidence whereby communication between nitrergic and dopaminergic systems plays an essential role in the control of the nigrostriatal pathway. However, there is sparse information for either the coexistence or overlap of nitric oxide and dopaminergic structures. The present study used double-labeling immunofluorescent microscopy to investigate the degree of cellular co-localization between nitric oxide synthase and tyrosine hydroxylase, enzymes responsible for the synthesis of nitric oxide and dopamine, respectively, was examined in neurons of the nigrostriatal pathway regions in the rat brain. After perfusional fixation, the brains were cut and double immunostained. A proximity analysis of tyrosine hydroxylase and nitric oxide synthase structures was made using confocal laser scanning microscopy, in nigrostriatal regions of the rat brain. We used image acquired at the optical limit and generated binary masks at 2µm-wide margin from the respective maximum projections. Co-localization between the two antigens was infrequent (<10% in most areas examined. However, tyrosine hydroxylase labeling was particularly concentrated close to nitric oxide synthase dendrites/axons and the cell bodies. These results further substantiate an extrasynaptic substrate for interaction between nitrergic and dopaminergic systems, thereby modulating sensitivity to neural inputs and its gene expression.

  16. Influence of a long-term powdered diet on the social interaction test and dopaminergic systems in mice.

    Science.gov (United States)

    Niijima-Yaoita, Fukie; Tsuchiya, Masahiro; Saito, Hiroko; Nagasawa, Yuka; Murai, Shigeo; Arai, Yuichiro; Nakagawasai, Osamu; Nemoto, Wataru; Tadano, Takeshi; Tan-No, Koichi

    2013-10-01

    It is well known that the characteristics of mastication are important for the maintenance of our physical well-being. In this study, to assess the importance of the effects of food hardness during mastication, we investigated whether a long-term powdered diet might cause changes in emotional behavior tests, including spontaneous locomotor activity and social interaction (SI) tests, and the dopaminergic system of the frontal cortex and hippocampus in mice. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The dopamine turnover and expression of dopamine receptors mRNA in the frontal cortex were also evaluated. Spontaneous locomotor activity, SI time and dopamine turnover of the frontal cortex were increased in powdered diet-fed mice. On the other hand, the expression of dopamine-4 (D4) receptors mRNA in the frontal cortex was decreased in powdered diet-fed mice. Moreover, we examined the effect of PD168077, a selective D4 agonist, on the increased SI time in powdered diet-fed mice. Treatment with PD168077 decreased the SI time. These results suggest that the masticatory dysfunction induced by long-term powdered diet feeding may cause the increased SI time and the changes in the dopaminergic system, especially dopamine D4 receptor subtype in the frontal cortex.

  17. Anatomical and functional characterisation of a dopaminergic system in the suprachiasmatic nucleus of the neonatal Siberian hamster.

    Science.gov (United States)

    Duffield, G E; McNulty, S; Ebling, F J

    1999-05-24

    in Syrian hamster tissue (+138%+/-28%) than in Siberian hamster tissue (+43%+/-11%). Although the anatomical studies demonstrate the existence of a dopaminergic system in the SCN of the early postnatal Siberian hamster, the unresponsiveness of c-fos expression and the relative lack of phosphorylation of CREB after D1-R activation suggests a diminished role for dopamine in the regulation of circadian events during the postnatal period in this species.

  18. Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings.

    Science.gov (United States)

    Hou, Haifeng; Wang, Chunyan; Jia, Shaowei; Hu, Shu; Tian, Mei

    2014-10-01

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the first technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major findings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms. PMID:25260796

  19. Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones

    DEFF Research Database (Denmark)

    Bauer, M; Suppmann, S; Meyer, M;

    2002-01-01

    Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurones against toxic and physical damage. In addition, GDNF promotes differentiation and structural integrity of dopaminergic neurones. Here we show that GDNF can support the function of primary dopaminergic neurones...... by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GDNF stimulation of primary dopaminergic neurones expressing both tyrosine 3-monooxygenase and GTPCH I resulted in a dose-dependent doubling of GTPCH I activity, and a concomitant increase...... in tetrahydrobiopterin levels whereas tyrosine 3-monooxygenase activity was not altered. Actinomycin D, asan inhibitor of de novo biosynthesis, abolished any GDNF-mediated up-regulation of GTPCH I activity. However, GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting...

  20. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

    Science.gov (United States)

    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease.

  1. Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system.

    Science.gov (United States)

    Patriquin, Michelle A; Bauer, Isabelle E; Soares, Jair C; Graham, David P; Nielsen, David A

    2015-10-01

    Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are effective in treating substance use disorders, thus highlighting a need for improved treatment practices. Substance use treatment response depends on multiple factors such as genetic, biological, and social factors. It is essential that each component is represented in treatment plans. The dopaminergic system plays a critical role in the pharmacotherapy for addictions, and an understanding of the role of variation of genes involved in this system is essential for its success. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement guidelines. A computerized literature search was conducted using PubMed and Scopus (all databases). Articles published up to April 2015 that examined the role of dopaminergic gene variation in the pharmacotherapy of alcohol, opioid, and cocaine use disorders were reviewed. Search terms were dopamine, gene, polymorphism, substance abuse, treatment, and response. Polymorphisms of the DRD2, ANKK1, DAT1, DBH, and DRD4 genes have been found to moderate the effects of pharmacotherapy of alcohol, opioid, and cocaine use disorders. The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapeutic intervention for substance use disorders. More studies are needed to confirm and extend these findings. PMID:26146874

  2. Ganoderma lucidum Protects Dopaminergic Neuron Degeneration through Inhibition of Microglial Activation

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    Ruiping Zhang

    2011-01-01

    Full Text Available Abundant evidence has suggested that neuroinflammation participates in the pathogenesis of Parkinson's disease (PD. The emerging evidence has supported that microglia may play key roles in the progressive neurodegeneration in PD and might be a promising therapeutic target. Ganoderma lucidum (GL, a traditional Chinese medicinal herb, has been shown potential neuroprotective effects in our clinical trials that make us to speculate that it might possess potent anti-inflammatory and immunomodulating properties. To test this hypothesis, we investigated the potential neuroprotective effect of GL and possible underlying mechanism of action through protecting microglial activation using co-cultures of dopaminergic neurons and microglia. The microglia is activated by LPS and MPP+-treated MES 23.5 cell membranes. Meanwhile, GL extracts significantly prevent the production of microglia-derived proinflammatory and cytotoxic factors [nitric oxide, tumor necrosis factor-α (TNF-α, interlukin 1β (IL-1β] in a dose-dependent manner and down-regulate the TNF-α and IL-1β expressions on mRNA level as well. In conclusion, our results support that GL may be a promising agent for the treatment of PD through anti-inflammation.

  3. Dopaminergic receptor agents and the basal ganglia : pharmacological properties and interactions with the GABA-ergic system

    NARCIS (Netherlands)

    Timmerman, Wigerline

    1992-01-01

    In the present series of studies, attention was focussed particularly on dopaminergic D2 receptor compounds, with emphasis on the enantiomers of the potent and selective dopamine D2 receptor agonist N-0437. Drugs that display activity at D2 receptors are of great interest as potentially new therapeu

  4. Effects of early and late neonatal bromocriptine treatment on hypothalamic neuropeptides, dopaminergic reward system and behavior of adult rats.

    Science.gov (United States)

    Carvalho, Janaine C; Lisboa, Patricia C; de Oliveira, Elaine; Peixoto-Silva, Nayara; Pinheiro, Cintia R; Fraga, Mabel C; Claudio-Neto, Sylvio; Franci, Celso R; Manhães, Alex C; Moura, Egberto G

    2016-06-14

    In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes. PMID:27038750

  5. Acrylamide increases dopamine levels by affecting dopamine transport and metabolism related genes in the striatal dopaminergic system.

    Science.gov (United States)

    Pan, Xiaoqi; Guo, Xiongxiong; Xiong, Fei; Cheng, Guihong; Lu, Qing; Yan, Hong

    2015-07-01

    Dopaminergic system dysfunction is proved to be a possible mechanism in acrylamide (ACR) -induced neurotoxicity. The neurotransmitter dopamine (DA) has an increasingly important role in the dopaminergic system. Thus, the goal of this study is to evaluate effects of ACR on dopamine and its metabolite levels, dopamine transport and metabolic gene expression in dopaminergic neurons. Male Sprague-Dawley (SD) rats were dosed orally with ACR at 0 (saline), 20, 30, and 40 mg/kg/day for 20 days. Splayed hind limbs, reduced tail flick time and abnormal gait which preceded other neurologic parameters were observed in the above rats. ACR significantly increased dopamine levels, decreased 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) contents in an area dependent manner in rat striatum. Immunohistochemical staining of the striatum revealed that the number of tyrosine hydroxylase (TH) positive cells significantly increased, while monoamine oxidase (MAO) positive cells were drastically reduced, which was consistent with changes in their mRNA and protein expressions. In addition, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression levels were both down-regulated in the striatum. These results suggest that dopamine levels increase significantly in response to ACR, presumably due to changes in the dopamine transport and metabolism related genes expression in the striatal dopaminergic neurons.

  6. Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation

    Directory of Open Access Journals (Sweden)

    Gordon Richard

    2012-04-01

    Full Text Available Abstract Background The mechanisms of progressive dopaminergic neuronal loss in Parkinson’s disease (PD remain poorly understood, largely due to the complex etiology and multifactorial nature of disease pathogenesis. Several lines of evidence from human studies and experimental models over the last decade have identified neuroinflammation as a potential pathophysiological mechanism contributing to disease progression. Tumor necrosis factor α (TNF has recently emerged as the primary neuroinflammatory mediator that can elicit dopaminergic cell death in PD. However, the signaling pathways by which TNF mediates dopaminergic cell death have not been completely elucidated. Methods In this study we used a dopaminergic neuronal cell model and recombinant TNF to characterize intracellular signaling pathways activated during TNF-induced dopaminergic neurotoxicity. Etanercept and neutralizing antibodies to tumor necrosis factor receptor 1 (TNFR1 were used to block TNF signaling. We confirmed the results from our mechanistic studies in primary embryonic mesencephalic cultures and in vivo using the stereotaxic lipopolysaccharide (LPS model of nigral dopaminergic degeneration. Results TNF signaling in dopaminergic neuronal cells triggered the activation of protein kinase Cδ (PKCδ, an isoform of the novel PKC family, by caspase-3 and caspase-8 dependent proteolytic cleavage. Both TNFR1 neutralizing antibodies and the soluble TNF receptor Etanercept blocked TNF-induced PKCδ proteolytic activation. Proteolytic activation of PKCδ was accompanied by translocation of the kinase to the nucleus. Notably, inhibition of PKCδ signaling by small interfering (siRNA or overexpression of a PKCδ cleavage-resistant mutant protected against TNF-induced dopaminergic neuronal cell death. Further, primary dopaminergic neurons obtained from PKCδ knockout (−/− mice were resistant to TNF toxicity. The proteolytic activation of PKCδ in the mouse substantia nigra in the

  7. An Efficient and Versatile System for Visualization and Genetic Modification of Dopaminergic Neurons in Transgenic Mice.

    Directory of Open Access Journals (Sweden)

    Karsten Tillack

    Full Text Available The brain dopaminergic (DA system is involved in fine tuning many behaviors and several human diseases are associated with pathological alterations of the DA system such as Parkinson's disease (PD and drug addiction. Because of its complex network integration, detailed analyses of physiological and pathophysiological conditions are only possible in a whole organism with a sophisticated tool box for visualization and functional modification.Here, we have generated transgenic mice expressing the tetracycline-regulated transactivator (tTA or the reverse tetracycline-regulated transactivator (rtTA under control of the tyrosine hydroxylase (TH promoter, TH-tTA (tet-OFF and TH-rtTA (tet-ON mice, to visualize and genetically modify DA neurons. We show their tight regulation and efficient use to overexpress proteins under the control of tet-responsive elements or to delete genes of interest with tet-responsive Cre. In combination with mice encoding tet-responsive luciferase, we visualized the DA system in living mice progressively over time.These experiments establish TH-tTA and TH-rtTA mice as a powerful tool to generate and monitor mouse models for DA system diseases.

  8. Nicotinic, glutamatergic and dopaminergic synaptic transmission and plasticity in the mesocorticolimbic system: focus on nicotine effects.

    Science.gov (United States)

    Pistillo, Francesco; Clementi, Francesco; Zoli, Michele; Gotti, Cecilia

    2015-01-01

    Cigarette smoking is currently the leading cause of preventable deaths and disability throughout the world, being responsible for about five million premature deaths/year. Unfortunately, fewer than 10% of tobacco users who try to stop smoking actually manage to do so. The main addictive agent delivered by cigarette smoke is nicotine, which induces psychostimulation and reward, and reduces stress and anxiety. The use of new technologies (including optogenetics) and the development of mouse models characterised by cell-specific deletions of receptor subtype genes or the expression of gain-of-function nAChR subunits has greatly increased our understanding of the molecular mechanisms and neural substrates of nicotine addiction first revealed by classic electrophysiological, neurochemical and behavioural approaches. It is now becoming clear that various aspects of nicotine dependence are mediated by close interactions of the glutamatergic, dopaminergic and γ-aminobutyric acidergic systems in the mesocorticolimbic system. This review is divided into two parts. The first provides an updated overview of the circuitry of the ventral tegmental area, ventral striatum and prefrontal cortex, the neurotransmitter receptor subtypes expressed in these areas, and their physiological role in the mesocorticolimbic system. The second will focus on the molecular, functional and behavioural mechanisms involved in the acute and chronic effects of nicotine on the mesocorticolimbic system.

  9. Effects of Exposure to Heavy Particles on a Behavior Mediated by the Dopaminergic System

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.; McEwen, J.

    The effects of exposure to heavy particles on behaviors mediated by the central nervous system (CNS) are qualitatively different than the effects produced by exposure to other types of radiation. One behavior mediated by the CNS is the amphetamine-induced taste aversion, which is produced by pairing a novel tasting solution with injection of amphetamine. When the conditioning day is three days following irradiation, exposing rats to low doses of 56Fe particles (600 MeV/n or 1 GeV/n) eliminates the taste aversion produced by injection of amphetamine, which is dependent upon the integrity of the central dopaminergic system, but has no effect on the aversion produced by injection of lithium chloride which is mediated by the gastrointestinal system. In contrast to the effects obtained using heavy particles, exposing rats to 60Co gamma rays or to fission spectrum neutrons has no selective effect upon the acquisition of either amphetamine- or lithium chloride-induced taste aversions. When the conditioning day occurs four months following exposure to 1 GeV/n 56Fe particles, there is an enhancement of the amphetamine-induced taste aversion. The implications of these findings for approaches to risk assessment are considered

  10. Sex-related differences in striatal dopaminergic system after traumatic brain injury.

    Science.gov (United States)

    Xu, Xiupeng; Cao, Shengwu; Chao, Honglu; Liu, Yinlong; Ji, Jing

    2016-06-01

    Several studies have demonstrated alterations in the dopamine (DA) system after traumatic brain injury (TBI). Additionally, the existence of significant sex-related differences in the dopaminergic system has long been recognized. Accordingly, the purpose of the present study was to investigate whether TBI would differentially alter, in female and male mice, the expression and the function of the striatal vesicular monoamine transporter-2 (VMAT-2), an important DA transporter. After controlled cortical impact (CCI) injury, female mice showed significantly lower striatal DA concentrations and K(+)-evoked DA output. By contrast, no significant sex-related differences were observed in the mRNA and protein levels of striatal dopamine transporter (DAT) and VMAT-2 and the methamphetamine (MA)-evoked DA output. These results demonstrated clear sex-related differences in striatal VMAT-2 function in response to TBI and suggested that female mice may be more sensitive to the TBI-induced inhibition of the VMAT-2 function, as indicated by the greater degree of deficits observed when the VMAT-2 DA-storage function was inhibited by TBI. Moreover, the TBI-induced suppression of locomotion was more pronounced than female mice. Such findings highlight the need for sex-specific considerations when examining differences among brain injury conditions. PMID:27210290

  11. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis

    OpenAIRE

    Jose Carlos Pereira Jr.; Marcia Pradella-Hallinan; Hugo de Lins Pessoa

    2010-01-01

    Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregn...

  12. The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

    OpenAIRE

    Braak, Breg; Booij, Jan; Klooker, Tamira K.; van den Wijngaard, Rene M. J.; Boeckxstaens, Guy E. E.

    2011-01-01

    Purpose Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. Methods In FD pat...

  13. Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks

    OpenAIRE

    Boardman, Jason D.; Menard, Scott; Roettger, Michael E.; Knight, Kelly E.; Boutwell, Brian B.; Smolen, Andrew

    2014-01-01

    This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framewor...

  14. Subchronic Polychlorinated Biphenyl (Aroclor 1254) Exposure Produces Oxidative Damage and Neuronal Death of Ventral Midbrain Dopaminergic Systems

    OpenAIRE

    Lee, Donna W.; Notter, Sarah A.; Thiruchelvam, Mona; Dever, Daniel P.; Fitzpatrick, Richard; Kostyniak, Paul J.; Cory-Slechta, Deborah A.; Opanashuk, Lisa A.

    2011-01-01

    Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson’s disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult ...

  15. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression

    Directory of Open Access Journals (Sweden)

    Anders H. Andersen

    2015-01-01

    Full Text Available Parkinson’s disease (PD is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD patients. Participants included 18 ndPD patients (11 men, 7 women and 10 dPD patients (7 men, 3 women. Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN. DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients.

  16. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression.

    Science.gov (United States)

    Andersen, Anders H; Smith, Charles D; Slevin, John T; Kryscio, Richard J; Martin, Catherine A; Schmitt, Frederick A; Blonder, Lee X

    2015-01-01

    Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients. PMID:26793404

  17. The long-term effects of the herbicide atrazine on the dopaminergic system following exposure during pubertal development.

    Science.gov (United States)

    Li, Yanshu; Sun, Yan; Yang, Junwei; Wu, Yanping; Yu, Jia; Li, Baixiang

    2014-03-15

    Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. Atrazine has been shown to cause dopaminergic neurotoxicity. The juvenile period is particularly vulnerable to environmental agents, but only few studies have investigated the long-term effects of atrazine following exposure during the pubertal development. Therefore, we evaluated the effects of a 41-day exposure to atrazine on the dopaminergic system in rats. Sprague-Dawley rats were treated orally with atrazine at 25 or 50mg/kg bw, daily from postnatal day 22 to 62. The content of dopamine (DA) was examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT) and vesicular monoaminetransporter 2 (VMAT2) were examined in samples of the ventral mid-brain by use of fluorescence PCR and Western-blot analysis when the rats reached the age of one year. Exposure of juvenile rats to the high dose of atrazine led to reduced levels of DA and mRNA of Nurr1 in one-year-old animals. This study shows that the long-term adverse effects of atrazine on the dopaminergic system have a special relevance after juvenile exposure.

  18. Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System

    Science.gov (United States)

    Koizumi, So; Onozuka, Minoru

    2015-01-01

    The present study examined the effects of chewing on stress-induced long-term depression (LTD) and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior. PMID:26075223

  19. Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System

    Directory of Open Access Journals (Sweden)

    Yumie Ono

    2015-01-01

    Full Text Available The present study examined the effects of chewing on stress-induced long-term depression (LTD and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior.

  20. Increased Mesohippocampal Dopaminergic Activity and Improved Depression-Like Behaviors in Maternally Separated Rats Following Repeated Fasting/Refeeding Cycles

    Directory of Open Access Journals (Sweden)

    Jeong Won Jahng

    2012-01-01

    Full Text Available We have previously reported that rats that experienced 3 h of daily maternal separation during the first 2 weeks of birth (MS showed binge-like eating behaviors with increased activity of the hypothalamic-pituitary-adrenal axis when they were subjected to fasting/refeeding cycles repeatedly. In this study, we have examined the psychoemotional behaviors of MS rats on the fasting/refeeding cycles, together with their brain dopamine levels. Fasting/refeeding cycles normalized the ambulatory activity of MS rats, which was decreased by MS experience. Depression-like behaviors, but not anxiety, by MS experience were improved after fasting/refeeding cycles. Fasting/refeeding cycles did not significantly affect the behavioral scores of nonhandled (NH control rats. Fasting/refeeding cycles increased dopamine levels not only in the hippocampus but also in the midbrain dopaminergic neurons in MS rats, but not in NH controls. Results demonstrate that fasting/refeeding cycles increase the mesohippocampal dopaminergic activity and improve depression-like behaviors in rats that experienced MS. Together with our previous paper, it is suggested that increased dopamine neurotransmission in the hippocampus may be implicated in the underlying mechanisms by which the fasting/refeeding cycles induce binge-like eating and improve depression-like behaviors in MS rats.

  1. Paradoxical dopaminergic drug effects in extraversion: Dose- and time-dependent effects of Sulpiride on EEG theta activity

    Directory of Open Access Journals (Sweden)

    Mira-Lynn eChavanon

    2013-04-01

    Full Text Available Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: Depending on the personality trait agentic extraversion (aE; i.e. assertiveness, dominance, ambition, positive emotionality the selective dopamine D2 receptor antagonist sulpiride (200 mg had opposite effects on resting posterior versus anterior theta activity in the electroencephalogram (EEG. In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over five hours in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50 mg, 200 mg, or 400 mg. The findings suggest a model postulating stronger pre- versus postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- versus postsynaptic dopamine D2 subreceptor sensitivities and densities.

  2. Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS: a commentary

    Directory of Open Access Journals (Sweden)

    Waite Roger L

    2008-11-01

    Full Text Available Abstract Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc dopamine receptors (D1-D5, whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing

  3. Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system

    OpenAIRE

    V. Khanh eDoan; Yun-Hee eChoi; Ann W. eKinyua; Sang Hyun eMoh; Ki Woo eKim

    2014-01-01

    The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin’ and insulin’s actions on mediating the feeding behaviors and therefore affecting the energy balan...

  4. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP

    Science.gov (United States)

    Filichia, Emily; Hoffer, Barry; Qi, Xin; Luo, Yu

    2016-01-01

    Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson’s disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation. PMID:27619562

  5. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    International Nuclear Information System (INIS)

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [11C]-DTBZ, [11C]-RAC, and [18F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use

  6. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    Science.gov (United States)

    Lara-Camacho, V. M.; Ávila-García, M. C.; Ávila-Rodríguez, M. A.

    2014-11-01

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [11C ]-DTBZ, [11C ]-RAC, and [18F ]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  7. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Lara-Camacho, V. M., E-mail: victormlc13@hotmail.com; Ávila-García, M. C., E-mail: victormlc13@hotmail.com; Ávila-Rodríguez, M. A., E-mail: victormlc13@hotmail.com [Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, México, D.F. (Mexico)

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  8. Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

    Science.gov (United States)

    Oliveira, Lucas Rangel; Dias, Flávia Regina Cruz; Santos, Breno Garone; Silva, Jade Leal Loureiro; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-09-15

    Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.

  9. Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

    Science.gov (United States)

    Oliveira, Lucas Rangel; Dias, Flávia Regina Cruz; Santos, Breno Garone; Silva, Jade Leal Loureiro; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-09-15

    Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects. PMID:27173428

  10. Omission of expected reward sensitizes the brain dopaminergic system of classically conditioned Atlantic salmon

    DEFF Research Database (Denmark)

    Vindas, M.A.; Höglund, Erik; Folkedal, O.;

    in fishes. Here we show that the omission of expected reward (OER) leads to increased aggression towards conspecifics in classically conditioned Atlantic salmon (Salmo salar). Furthermore, in response to an acute stressor, OER fish displayed increased dopaminergic (DA) neurotransmission compared to controls....... There was also a general downregulation of dopamine receptor D1 gene expression in the telencephalon of OER groups, which suggests a coping mechanism in response to unbalanced DA metabolism. These results indicate that animals subjected to unpredictable reward conditions develop a senzitation of the DA...

  11. In vivo imaging of brain dopaminergic neurotransmission system in small animals with high-resolution single photon emission computed tomography

    International Nuclear Information System (INIS)

    High-resolution single photon emission computed tomography (SPECT) provides a unique capability to image the biodistribution of radiolabeled molecules in small laboratory animals. Thus, we applied the high-resolution SPECT to in vivo imaging of the brain dopaminergic neurotransmission system in common marmosets using two radiolabeled ligands, [123I]2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) as a dopamine transporter(DAT) ligand and [123I]iodobenzamide (IBZM) as a dopamine D2 receptor (D2R) ligand. Specific images of the striatum, a region with a high density of dopaminergic synapses, were obtained at 240 min and 60 min after injection of [123I]β-CIT and [123I]IBZM, respectively. Furthermore, a significantly low accumulation of [123I]β-CIT in the striatum was observed in MPTP-treated animals compared with results for a control group, and a similar accumulation in the control group was observed with the pretreatment of deprenyl in the MPTP-treated animals. However, the striatal accumulation of [123I]IBZM showed no changes among the control, MPTP-treated, and deprenyl-MPTP-treated groups. These SPECT imaging results agreed well with those of DA concentration and motor behavior. Since MPTP destroys nigrostriatal dopamine nerves and produces irreversible neurodegeneration associated with Parkinsonian syndrome, SPECDT imaging data in this study demonstrated that deprenyl shows its neuroprotective effect on Parkinsonism by protecting against the destruction of presynaptic dopamine neutrons. (author)

  12. The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice.

    Science.gov (United States)

    Yan, Tingxu; Xu, Mengjie; Wu, Bo; Liao, Zhengzheng; Liu, Zhi; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-15

    Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems.

  13. The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice.

    Science.gov (United States)

    Yan, Tingxu; Xu, Mengjie; Wu, Bo; Liao, Zhengzheng; Liu, Zhi; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-15

    Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems. PMID:27225351

  14. Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC{delta} in cell culture and animal models of Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun; Kanthasamy, Anumantha; Kanthasamy, Arthi, E-mail: arthik@iastate.edu

    2011-11-15

    The neurotoxicant 6-hydroxydopamine (6-OHDA) is used to investigate the cellular and molecular mechanisms underlying selective degeneration of dopaminergic neurons in Parkinson's disease (PD). Oxidative stress and caspase activation contribute to the 6-OHDA-induced apoptotic cell death of dopaminergic neurons. In the present study, we sought to systematically characterize the key downstream signaling molecule involved in 6-OHDA-induced dopaminergic degeneration in cell culture and animal models of PD. Treatment of mesencephalic dopaminergic neuronal N27 cells with 6-OHDA (100 {mu}M) for 24 h significantly reduced mitochondrial activity and increased cytosolic cytochrome c, followed by sequential activation of caspase-9 and caspase-3. Co-treatment with the free radical scavenger MnTBAP (10 {mu}M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC{delta}) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 {mu}M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC{delta}{sup D327A} and kinase dead PKC{delta}{sup K376R} or siRNA-mediated knockdown of PKC{delta} protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC{delta} promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC{delta} expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC{delta} cleavage was also observed in the substantia nigra of 6-OHDA-injected C57 black mice but not in control animals. Viral-mediated delivery of PKC{delta}{sup D327A} protein protected against 6-OHDA-induced PKC{delta} activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC{delta} is a key downstream event in dopaminergic degeneration, and these results may have important translational value for

  15. Disinhibition Bursting of Dopaminergic Neurons

    Directory of Open Access Journals (Sweden)

    Collin J Lobb

    2011-05-01

    Full Text Available Substantia nigra pars compacta (SNpc dopaminergic neurons receive strong tonic inputs from GABAergic neurons in the substantia nigra pars reticulata (SNpr and globus pallidus (GP, and glutamatergic neurons in the subthalamic nucleus. The presence of these tonic inputs raises the possibility that phasic disinhibition may trigger phasic bursts in dopaminergic neurons. We first applied constant NMDA and GABAA conductances onto a two-compartment single cell model of the dopaminergic neuron (Kuznetsov et al., 2006. The model exhibited disinhibition bursting upon stepwise removal of inhibition. A further bifurcation analysis suggests that disinhibition may be more robust than excitation alone in that for most levels of NMDA conductance, the cell remains capable of bursting even after a complete removal of inhibition, whereas too much excitatory input will drive the cell into depolarization block. To investigate the network dynamics of disinhibition, we used a modified version of an integrate-and-fire based model of the basal ganglia (Humphries et al., 2006. Synaptic activity generated in the network was delivered to the two-compartment single cell dopaminergic neuron. Phasic activation of the D1-expressing medium spiny neurons in the striatum (D1STR produced disinhibition bursts in dopaminergic neurons through the direct pathway (D1STR to SNpr to SNpc. Anatomical studies have shown that D1STR neurons have collaterals that terminate in GP. Adding these collaterals to the model, we found that striatal activation increased the intra-burst firing frequency of the disinhibition burst as the weight of this connection was increased. Our studies suggest that striatal activation is a robust means by which disinhibition bursts can be generated by SNpc dopaminergic neurons, and that recruitment of the indirect pathway via collaterals may enhance disinhibition bursting.

  16. Activated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF.

    Science.gov (United States)

    Yang, Fan; Liu, Yunhui; Tu, Jie; Wan, Jun; Zhang, Jie; Wu, Bifeng; Chen, Shanping; Zhou, Jiawei; Mu, Yangling; Wang, Liping

    2014-12-17

    Astrocytes provide neuroprotective effects against degeneration of dopaminergic (DA) neurons and play a fundamental role in DA differentiation of neural stem cells. Here we show that light illumination of astrocytes expressing engineered channelrhodopsin variant (ChETA) can remarkably enhance the release of basic fibroblast growth factor (bFGF) and significantly promote the DA differentiation of human embryonic stem cells (hESCs) in vitro. Light activation of transplanted astrocytes in the substantia nigra (SN) also upregulates bFGF levels in vivo and promotes the regenerative effects of co-transplanted stem cells. Importantly, upregulation of bFGF levels, by specific light activation of endogenous astrocytes in the SN, enhances the DA differentiation of transplanted stem cells and promotes brain repair in a mouse model of Parkinson's disease (PD). Our study indicates that astrocyte-derived bFGF is required for regulation of DA differentiation of the stem cells and may provide a strategy targeting astrocytes for treatment of PD.

  17. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System

    Science.gov (United States)

    Matzkin, María E.; Muñiz, Javier A.; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J.; Vitullo, Alfredo D.; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  18. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System.

    Directory of Open Access Journals (Sweden)

    Candela R González

    Full Text Available Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg, cocaine (3×10mg/kg, or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology.

  19. Dopaminergic Circuitry Underlying Mating Drive.

    Science.gov (United States)

    Zhang, Stephen X; Rogulja, Dragana; Crickmore, Michael A

    2016-07-01

    We develop a new system for studying how innate drives are tuned to reflect current physiological needs and capacities, and how they affect sensory-motor processing. We demonstrate the existence of male mating drive in Drosophila, which is transiently and cumulatively reduced as reproductive capacity is depleted by copulations. Dopaminergic activity in the anterior of the superior medial protocerebrum (SMPa) is also transiently and cumulatively reduced in response to matings and serves as a functional neuronal correlate of mating drive. The dopamine signal is transmitted through the D1-like DopR2 receptor to P1 neurons, which also integrate sensory information relevant to the perception of females, and which project to courtship motor centers that initiate and maintain courtship behavior. Mating drive therefore converges with sensory information from the female at the point of transition to motor output, controlling the propensity of a sensory percept to trigger goal-directed behavior. PMID:27292538

  20. The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

    Energy Technology Data Exchange (ETDEWEB)

    Braak, Breg; Klooker, Tamira K. [Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam (Netherlands); Booij, Jan [Academic Medical Center, Department of Nuclear Medicine, Amsterdam (Netherlands); Wijngaard, Rene M.J. van den [Academic Medical Center, Tytgat Institute of Liver and Intestinal Research, Amsterdam (Netherlands); Boeckxstaens, Guy E.E. [Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam (Netherlands); University Hospital Leuven, Catholic University Leuven, Department of Gastroenterology, Leuven (Belgium)

    2012-04-15

    Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [{sup 123}I]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. The HV subjects comprised 12 women and 8 men (mean age 31 {+-} 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 {+-} 5 years). The FD patients had a lower left plus right average striatal binding potential (BP{sub NP}) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BP{sub NP} in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathways. (orig.)

  1. PKCδ mediates paraquat-induced Nox1 expression in dopaminergic neurons

    OpenAIRE

    Cristóvão, Ana Clara; Barata, Joana; Je, Goun; Kim, Yoon-Seong

    2013-01-01

    Our previous works have shown that the (NADPH) oxidase (Nox) enzyme, in particular Nox1, plays an important role in oxidative stress and subsequent dopaminergic cell death elicited by paraquat (PQ). In non-neuronal and glial cells, protein kinase C δ (PKCδ) shows the ability to regulate the activity of the Nox system. Herein we aimed to investigate if also in dopaminergic neurons exposed to PQ, PKCδ can regulate Nox1expression.

  2. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans

    Science.gov (United States)

    Tanimoto, Yuki; Zheng, Ying Grace; Fei, Xianfeng; Fujie, Yukako; Hashimoto, Koichi; Kimura, Koutarou D.

    2016-05-01

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification.

  3. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans

    Science.gov (United States)

    Tanimoto, Yuki; Zheng, Ying Grace; Fei, Xianfeng; Fujie, Yukako; Hashimoto, Koichi; Kimura, Koutarou D.

    2016-01-01

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification. PMID:27193056

  4. Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity

    Science.gov (United States)

    Air pollution is linked to central nervous system (CNS) disease, but the mechanisms responsible are poorly understood. Rats exposed to Diesel Exhaust (DE, 2.0,0.5, and 0 mg/m3) by inhalation over 4 weeks demonstrated elevated levels of whole brain IL-6 protein, nitrated proteins,...

  5. Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect

    Directory of Open Access Journals (Sweden)

    Rajiv Jash

    2014-01-01

    Full Text Available Background: An increased inclination has been observed for the use of herbal drugs in chronic and incurable diseases. Treatment of psychiatric diseases like schizophrenia is largely palliative and more importantly, a prominent adverse effect prevails with the majority of anti-psychotic drugs, which are the extrapyramidal motor disorders. Existing anti-psychotic drug therapy is not so promising, and their adverse effect is a matter of concern for continuing the therapy for long duration. Objective: This experimental study was done to evaluate the neuroleptic activity of the ethanolic extracts of two plants Alstonia Scholaris and Bacopa Monnieri with different anti-psychotic animal models with a view that these plant extracts shall have no or at least reduced adverse effect so that it can be used for long duration. Materials and Methods: Two doses of both the extracts (100 and 200 mg/kg and also standard drug haloperidol (0.2 mg/kg were administered to their respective groups once daily with 5 different animal models. After that, the concentration of the dopamine neurotransmitter was estimated in two different regions of the brain viz. frontal cortex and striatum. Results: The result of the study indicated a significant reduction of amphetamine-induced stereotype and conditioned avoidance response for both the extracts compared with the control group, but both did not have any significant effect in phencyclidine-induced locomotor activity and social interaction activity. However, both the extracts showed minor signs of catalepsy compared to the control group. The study also revealed that the neuroleptic effect was due to the reduction of the dopamine concentration in the frontal cortex region of the rat brain. The results largely pointed out the fact that both the extract may be having the property to alleviate the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain. Conclusion: The estimation of

  6. The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

    Science.gov (United States)

    Pesarico, Ana Paula; Sampaio, Tuane Bazanella; Stangherlin, Eluza Curte; Mantovani, Anderson C; Zeni, Gilson; Nogueira, Cristina Wayne

    2014-10-01

    The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems.

  7. Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

    Science.gov (United States)

    Ek, Fredrik; Malo, Marcus; Åberg Andersson, Madelene; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per; Olsson, Roger

    2016-05-18

    Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID

  8. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

    Science.gov (United States)

    Ojha, Shreesh; Javed, Hayate; Azimullah, Sheikh; Haque, M Emdadul

    2016-07-01

    Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities. PMID:27316720

  9. High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring.

    Science.gov (United States)

    Sánchez-Hernández, Diana; Poon, Abraham N; Kubant, Ruslan; Kim, Hwanki; Huot, Pedro S P; Cho, Clara E; Pannia, Emanuela; Reza-López, Sandra A; Pausova, Zdenka; Bazinet, Richard P; Anderson, G Harvey

    2016-01-01

    High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake.

  10. Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks.

    Science.gov (United States)

    Boardman, Jason D; Menard, Scott; Roettger, Michael E; Knight, Kelly E; Boutwell, Brian B; Smolen, Andrew

    2014-06-01

    This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framework. We extend previous work in this area by providing a testable typology of gene-environment interactions derived from current theories in this area. We find consistent evidence that the associations between putatively risky genotypes and delinquent behavior are suppressed within protective social environments. We also provide some evidence that supports the differential susceptibility hypothesis for these outcomes. Our findings largely confirm the conclusions of previous work and continue to highlight the critical role of the social environment within candidate gene studies of complex behaviors. PMID:25419014

  11. Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

    OpenAIRE

    Chavanon, Mira-Lynn; Wacker, Jan; Stemmler, Gerhard

    2013-01-01

    Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype, or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: depending on the personality trait agentic extraversion (agentic facet, aE; i.e., assertiveness, dominance, ambition, positive emotionality) the selective dopamine D2 receptor antagonist sulpiride (20...

  12. Smoking-specific parenting and smoking onset in adolescence: the role of genes from the dopaminergic system (DRD2, DRD4, DAT1 genotypes.

    Directory of Open Access Journals (Sweden)

    Marieke Hiemstra

    Full Text Available Although only few studies have shown direct links between dopaminergic system genes and smoking onset, this does not rule out the effect of a gene-environment interaction on smoking onset. Therefore, the aim of this study was to examine the associations between smoking-specific parenting (i.e., frequency and quality of communication and house rules and smoking onset while considering the potential moderating role of dopaminergic system genes (i.e., DRD2, DRD4, and DAT1 genotypes. Data from five annual waves of the 'Family and Health' project were used. At time 1, the sample comprised 365 non-smoking adolescents (200 younger adolescents, mean age = 13.31, SD = .48; 165 older adolescents, mean age = 15.19, SD = .57. Advanced longitudinal analyses were used (i.e., logistic regression analyses, (dual latent growth curves, and cross-lagged path models. The results showed a direct effect of quality of communication on smoking onset. No direct effects were found for frequency of communication and house rules. Furthermore, no direct and moderating effects of the DRD2, DRD4, or DAT1 genotypes were found. In conclusion, the findings indicated that the effects of smoking-specific parenting on smoking are similar for adolescent carriers and non-carriers of the dopaminergic system genes.

  13. Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

    Science.gov (United States)

    Cisbani, G; Drouin-Ouellet, J; Gibrat, C; Saint-Pierre, M; Lagacé, M; Badrinarayanan, S; Lavallée-Bourget, M H; Charest, J; Chabrat, A; Boivin, L; Lebel, M; Bousquet, M; Lévesque, M; Cicchetti, F

    2015-10-01

    The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing. PMID:26232588

  14. Dopaminergic agonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  15. Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function

    OpenAIRE

    Ciron, C.; Lengacher, S; Dusonchet, J.; Aebischer, P.; Schneider, B. L.

    2012-01-01

    Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain...

  16. Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra

    OpenAIRE

    Jeong, Hey-Kyeong; Jou, Ilo; Joe, Eun-hye

    2010-01-01

    It has been suggested that brain inflammation is important in aggravation of brain damage and/or that inflammation causes neurodegenerative diseases including Parkinson's disease (PD). Recently, systemic inflammation has also emerged as a risk factor for PD. In the present study, we evaluated how systemic inflammation induced by intravenous (iv) lipopolysaccharides (LPS) injection affected brain inflammation and neuronal damage in the rat. Interestingly, almost all brain inflammatory response...

  17. Do Substantia Nigra Dopaminergic Neurons Differentiate Between Reward and Punishment?

    Institute of Scientific and Technical Information of China (English)

    Michael J. Frank; D. James Surmeier

    2009-01-01

    The activity of dopaminergic neurons are thought to be increased by stimuli that predict reward and decreased by stimuli that predict aversive outcomes. Recent work by Matsumoto and Hikosaka challenges this model by asserting that stimuli associated with either rewarding or aversive outcomes increase the activity of dopaminergic neurons in the substantia nigra pars compacta.

  18. Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia

    Science.gov (United States)

    Hamburg, Hannah; Trossbach, Svenja V.; Bader, Verian; Chwiesko, Caroline; Kipar, Anja; Sauvage, Magdalena; Crum, William R.; Vernon, Anthony C.; Bidmon, Hans J.; Korth, Carsten

    2016-01-01

    To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1), and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia. PMID:27721451

  19. Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jintanaporn Wattanathorn

    2014-01-01

    Full Text Available To date, the therapeutic strategy against cognitive impairment in Parkinson’s disease (PD is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180–220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

  20. Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Shuichi; Kurosaki, Kunihiko; Kuriiwa, Fumi; Endo, Takahiko [Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 (Japan); Mukai, Toshiji [Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-0015 (Japan)

    2002-10-01

    Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na{sup +} channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na{sup +}-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species

  1. Early specification of dopaminergic phenotype during ES cell differentiation

    Directory of Open Access Journals (Sweden)

    Li Meng

    2007-07-01

    Full Text Available Abstract Background Understanding how lineage choices are made during embryonic stem (ES cell differentiation is critical for harnessing strategies for controlled production of therapeutic somatic cell types for cell transplantation and pharmaceutical drug screens. The in vitro generation of dopaminergic neurons, the type of cells lost in Parkinson's disease patients' brains, requires the inductive molecules sonic hedgehog and FGF8, or an unknown stromal cell derived inducing activity (SDIA. However, the exact identity of the responding cells and the timing of inductive activity that specify a dopaminergic fate in neural stem/progenitors still remain elusive. Results Using ES cells carrying a neuroepithelial cell specific vital reporter (Sox1-GFP and FACS purification of Sox1-GFP neural progenitors, we have investigated the temporal aspect of SDIA mediated dopaminergic neuron specification during ES cell differentiation. Our results establish that SDIA induces a dopaminergic neuron fate in nascent neural stem or progenitor cells at, or prior to, Sox1 expression and does not appear to have further instructive role or neurotrophic activity during late neuronal differentiation of neural precursors. Furthermore, we show that dopaminergic neurons could be produced efficiently in a monolayer differentiation paradigm independent of SDIA activity or exogenous signalling molecules. In this case, the competence for dopaminergic neuron differentiation is also established at the level of Sox1 expression. Conclusion Dopaminergic neurons are specified early during mouse ES cell differentiation. The subtype specification seems to be tightly linked with the acquisition of a pan neuroectoderm fate.

  2. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    Science.gov (United States)

    dos Santos Pereira, Maurício; Sathler, Matheus Figueiredo; Valli, Thais da Rosa; Marques, Richard Souza; Ventura, Ana Lucia Marques; Peccinalli, Ney Ronner; Fraga, Mabel Carneiro; Manhães, Alex C; Kubrusly, Regina

    2015-01-01

    Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life

  3. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    Directory of Open Access Journals (Sweden)

    Maurício dos Santos Pereira

    Full Text Available Methylphenidate (MPD is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD. However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii to establish the neurochemical consequences of short- (24 hours and long-term (10 days MPD withdrawal after a subchronic treatment (30 days with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally, (iii to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p. presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult

  4. Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study

    International Nuclear Information System (INIS)

    Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D2 type in mammals. The present study assessed, in the frog, both the anatomical localization of D2-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [125I]iodosulpride-labelled D2 binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D2 antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity.In the frog olfactory bulb, both anatomical localization of D2-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  5. Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study

    Energy Technology Data Exchange (ETDEWEB)

    Duchamp, A.; Moyse, E.; Delaleu, J.-C.; Coronas, V.; Duchamp-Viret, P. [Laboratoire de Physiologie Neurosensorielle, Universite Claude Bernard and CNRS, F69622 Villeurbanne (France)

    1997-04-28

    Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D{sub 2} type in mammals. The present study assessed, in the frog, both the anatomical localization of D{sub 2}-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [{sup 125}I]iodosulpride-labelled D{sub 2} binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D{sub 2} antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity.In the frog olfactory bulb, both anatomical localization of D{sub 2}-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio. (Copyright (c) 1997 Elsevier Science B

  6. Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury

    Directory of Open Access Journals (Sweden)

    de Reggi Max

    2010-04-01

    Full Text Available Abstract Background The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. Results We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals. Conclusions These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.

  7. Dopaminergic D2 receptor is a key player in the substantia nigra pars compacta neuronal activation mediated by REM sleep deprivation.

    Science.gov (United States)

    Proença, Mariana B; Dombrowski, Patrícia A; Da Cunha, Claudio; Fischer, Luana; Ferraz, Anete C; Lima, Marcelo M S

    2014-01-01

    Currently, several studies addresses the novel link between sleep and dopaminergic neurotransmission, focusing most closely on the mechanisms by which Parkinson's disease (PD) and sleep may be intertwined. Therefore, variations in the activity of afferents during the sleep cycles, either at the level of DA cell bodies in the ventral tegmental area (VTA) and/or substantia nigra pars compacta (SNpc) or at the level of dopamine (DA) terminals in limbic areas may impact functions such as memory. Accordingly, we performed striatal and hippocampal neurochemical quantifications of DA, serotonin (5-HT) and metabolites of rats intraperitoneally treated with haloperidol (1.5 mg/kg) or piribedil (8 mg/kg) and submitted to REM sleep deprivation (REMSD) and sleep rebound (REB). Also, we evaluated the effects of REMSD on motor and cognitive parameters and SNpc c-Fos neuronal immunoreactivity. The results indicated that DA release was strongly enhanced by piribedil in the REMSD group. In opposite, haloperidol prevented that alteration. A c-Fos activation characteristic of REMSD was affected in a synergic manner by piribedil, indicating a strong positive correlation between striatal DA levels and nigral c-Fos activation. Hence, we suggest that memory process is severely impacted by both D2 blockade and REMSD and was even more by its combination. Conversely, the activation of D2 receptor counteracted such memory impairment. Therefore, the present evidence reinforce that the D2 receptor is a key player in the SNpc neuronal activation mediated by REMSD, as a consequence these changes may have direct impact for cognitive and sleep abnormalities found in patients with PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

  8. Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

    OpenAIRE

    Löschmann, P A; Smith, L A; Klaus W. Lange; Jaehnig, P.; Jenner, P.; Marsden, C. D.

    1991-01-01

    In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apom...

  9. Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Lie-Hang Shen

    2012-01-01

    Full Text Available Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET and single photon emission computed tomography (SPECT radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinson’s disease (PD and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD. Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D2 receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders.

  10. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    Energy Technology Data Exchange (ETDEWEB)

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  11. Maternal separation and early stress cause long-lasting effects on dopaminergic and endocannabinergic systems and alters dendritic morphology in the nucleus accumbens and frontal cortex in rats.

    Science.gov (United States)

    Romano-López, Antonio; Méndez-Díaz, Mónica; García, Fabio García; Regalado-Santiago, Citlalli; Ruiz-Contreras, Alejandra E; Prospéro-García, Oscar

    2016-08-01

    A considerable amount experimental studies have shown that maternal separation (MS) is associated with adult offspring abnormal behavior and cognition disorder. Accordingly, this experimental procedure has been proposed as a predictor for alcohol and drug dependence based on the neurodevelopmental soon after birth. Endocannabinoid system (eCBs) has been implicated in reward processes, including drug abuse and dependence. MS and associated stress causes changes in the eCBs that seem to facilitate alcohol consumption. In this study, we seek to evaluate potential morphological changes in neurons of the frontal cortex (FCx) and nucleus accumbens (NAcc), in the expression of receptors and enzymes of the endocannabinoid and dopamine systems and in second messengers, such as Akt, in adult rats subjected to MS and early stress (MS + ES; 2 × 180 min daily) vs. nonseparated rats (NMS). Results showed that MS + ES induces higher D2R expression and lower D3R, FAAH, and MAGL expression compared with NMS rats. Alterations in total dendritic length were also detected and were characterized by increases in the NAcc while there were decreases in the FCx. We believe MS + ES-induced changes in the dopaminergic and endocannabinergic systems and in the neuronal microstructure might be contributing to alcohol seeking behavior and, potential vulnerability to other drugs in rats. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 819-831, 2016. PMID:26539755

  12. Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins α-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators.

    Directory of Open Access Journals (Sweden)

    Duraisamy Kempuraj

    Full Text Available Parkinson's disease (PD is characterized by the presence of Lewy bodies and degeneration of dopaminergic neurons. 1-methyl-4-phenylpyridinium (MPP+, a metabolite of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and Lewy body component α-synuclein activates glia in PD pathogenesis. Mast cells and glia maturation factor (GMF are implicated in neuroinflammatory conditions including Multiple Sclerosis. However, the role of mast cells in PD is not yet known. We have analyzed the effect of recombinant GMF, MPP+, α-synuclein and interleukin-33 (IL-33 on mouse bone marrow-derived cultured mast cells (BMMCs, human umbilical cord blood-derived cultured mast cells (hCBMCs and mouse brain-derived cultured astrocytes by quantifying cytokines/chemokines released using ELISA or by detecting the expression of co-stimulatory molecules CD40 and CD40L by flow cytometry. GMF significantly released chemokine (C-C motif ligand 2 (CCL2 from BMMCs but its release was reduced in BMMCs from GMF knockout mice. GMF, α-synuclein and MPP+ released IL-1β, β-hexosaminidase from BMMCs, and IL-8 from hCBMCs. GMF released CCL5, and IL-33- induced the expression of GMF from hCBMCs. Novel GMF expression was detected in hCBMCs and BMMCs by immunocytochemistry. GMF released tumor necrosis factor-alpha (TNF-α from mouse astrocytes, and this release was greater in BMMC- astrocyte coculture than in individual cultures. Flow cytometry results showed increased IL-33 expression by GMF and MPP+, and GMF-induced CD40 expression in astrocytes. Proinflammatory mediator release by GMF, MPP+ and α-synuclein, as well as GMF expression by mast cells indicate a potential therapeutic target for neurodegenerative diseases including PD.

  13. Increased Mesohippocampal Dopaminergic Activity and Improved Depression-Like Behaviors in Maternally Separated Rats Following Repeated Fasting/Refeeding Cycles

    OpenAIRE

    Jeong Won Jahng; Sang Bae Yoo; Jin Young Kim; Bom-Taeck Kim; Jong-Ho Lee

    2012-01-01

    We have previously reported that rats that experienced 3 h of daily maternal separation during the first 2 weeks of birth (MS) showed binge-like eating behaviors with increased activity of the hypothalamic-pituitary-adrenal axis when they were subjected to fasting/refeeding cycles repeatedly. In this study, we have examined the psychoemotional behaviors of MS rats on the fasting/refeeding cycles, together with their brain dopamine levels. Fasting/refeeding cycles normalized the ambulatory act...

  14. Dopaminergic modulation of the striatal microcircuit: receptor-specific configuration of cell assemblies.

    Science.gov (United States)

    Carrillo-Reid, Luis; Hernández-López, Salvador; Tapia, Dagoberto; Galarraga, Elvira; Bargas, José

    2011-10-19

    Selection and inhibition of motor behaviors are related to the coordinated activity and compositional capabilities of striatal cell assemblies. Striatal network activity represents a main step in basal ganglia processing. The dopaminergic system differentially regulates distinct populations of striatal medium spiny neurons (MSNs) through the activation of D(1)- or D(2)-type receptors. Although postsynaptic and presynaptic actions of these receptors are clearly different in MSNs during cell-focused studies, their activation during network activity has shown inconsistent responses. Therefore, using electrophysiological techniques, functional multicell calcium imaging, and neuronal population analysis in rat corticostriatal slices, we describe the effect of selective dopaminergic receptor activation in the striatal network by observing cell assembly configurations. At the microcircuit level, during striatal network activity, the selective activation of either D(1)- or D(2)-type receptors is reflected as overall increases in neuronal synchronization. However, graph theory techniques applied to the transitions between network states revealed receptor-specific configurations of striatal cell assemblies: D(1) receptor activation generated closed trajectories with high recurrence and few alternate routes favoring the selection of specific sequences, whereas D(2) receptor activation created trajectories with low recurrence and more alternate pathways while promoting diverse transitions among neuronal pools. At the single-cell level, the activation of dopaminergic receptors enhanced the negative-slope conductance region (NSCR) in D(1)-type-responsive cells, whereas in neurons expressing D(2)-type receptors, the NSCR was decreased. Consequently, receptor-specific network dynamics most probably result from the interplay of postsynaptic and presynaptic dopaminergic actions.

  15. Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration

    Science.gov (United States)

    Gordon, Richard; Neal, Matthew L.; Luo, Jie; Langley, Monica R.; Harischandra, Dilshan S.; Panicker, Nikhil; Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Woodruff, Trent M.; Zhou, Qun-Yong; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

    2016-01-01

    Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD. PMID:27703142

  16. Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons

    OpenAIRE

    Piccart, Elisabeth; Courtney, Nicholas A.; Branch, Sarah Y.; Ford, Christopher P.; Beckstead, Michael J.

    2015-01-01

    Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed pat...

  17. An imperfect dopaminergic error signal can drive temporal-difference learning.

    Science.gov (United States)

    Potjans, Wiebke; Diesmann, Markus; Morrison, Abigail

    2011-05-01

    An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards. PMID:21589888

  18. An imperfect dopaminergic error signal can drive temporal-difference learning.

    Directory of Open Access Journals (Sweden)

    Wiebke Potjans

    2011-05-01

    Full Text Available An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards.

  19. Quantification of dopaminergic neurotransmission SPECT studies with {sup 123}I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation

    Energy Technology Data Exchange (ETDEWEB)

    Crespo, Cristina; Aguiar, Pablo [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); Gallego, Judith [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); Institut de Bioenginyeria de Catalunya, Barcelona (Spain); Cot, Albert [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); Universitat Politecnica de Catalunya, Seccio d' Enginyeria Nuclear, Departament de Fisica i Enginyeria Nuclear, Barcelona (Spain); Falcon, Carles; Ros, Domenec [Universitat de Barcelona - IDIBAPS, Unitat de Biofisica i Bioenginyeria, Departament de Ciencies Fisiologiques I, Facultat de Medicina, Barcelona (Spain); CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); Bullich, Santiago [Hospital del Mar, Center for Imaging in Psychiatry, CRC-MAR, Barcelona (Spain); Pareto, Deborah [CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); PRBB, Institut d' Alta Tecnologia, Barcelona (Spain); Sempau, Josep [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); Lomena, Francisco [IDIBAPS, Servei de Medicina Nuclear, Hospital Clinic, Barcelona (Spain); Calvino, Francisco [Universitat Politecnica de Catalunya, Institut de Tecniques Energetiques, Barcelona (Spain); Universitat Politecnica de Catalunya, Seccio d' Enginyeria Nuclear, Departament de Fisica i Enginyeria Nuclear, Barcelona (Spain); Pavia, Javier [CIBER en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona (Spain); IDIBAPS, Servei de Medicina Nuclear, Hospital Clinic, Barcelona (Spain)

    2008-07-15

    {sup 123}I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation. The SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed. For both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV. Our findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies. (orig.)

  20. An Imperfect Dopaminergic Error Signal Can Drive Temporal-Difference Learning

    OpenAIRE

    Wiebke Potjans; Markus Diesmann; Abigail Morrison

    2011-01-01

    An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. ...

  1. Dopaminergic axon guidance: which makes what?

    Directory of Open Access Journals (Sweden)

    Laetitia ePrestoz

    2012-07-01

    Full Text Available Mesotelencephalic pathways in the adult central nervous system have been studied in great detail because of their implication in major physiological functions as well as in psychiatric, neurological and neurodegenerative diseases. However, the ontogeny of these pathways and the molecular mechanisms that guide dopaminergic axons during embryogenesis have been only recently studied. This line of research is of crucial interest for the repair of lesioned circuits in adulthood following neurodegenerative diseases or common traumatic injuries. For instance, in the adult, the anatomic and functional repair of the nigrostriatal pathway following dopaminergic embryonic neuron transplantation suggests that specific guidance cues exist which govern embryonic fibers outgrowth, and suggests that axons from transplanted embryonic cells are able to respond to theses cues, which then guide them to their final targets. In this review, we first synthesize the work that has been performed in the last few years on developing mesotelencephalic pathways, and summarize the current knowledge on the identity of cellular and molecular signals thought to be involved in establishing mesotelencephalic dopaminergic neuronal connectivity during embryogenesis in the central nervous system of rodents. Then, we review the modulation of expression of these molecular signals in the lesioned adult brain and discuss their potential role in remodeling the mesotelencephalic dopaminergic circuitry, with a particular focus on Parkinson’s disease. Identifying guidance molecules involved in the connection of grafted cells may be useful for cellular therapy in Parkinsonian patients, as these molecules may help direct axons from grafted cells along the long distance they have to travel from the substantia nigra to the striatum.

  2. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    Science.gov (United States)

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

  3. Necrostatin-1 protection of dopaminergic neurons

    Directory of Open Access Journals (Sweden)

    Jing-ru Wu

    2015-01-01

    Full Text Available Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson′s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range (5-30 μM elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson′s disease.

  4. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    Science.gov (United States)

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  5. Discovery of nigral dopaminergic neurogenesis in adult mice

    Directory of Open Access Journals (Sweden)

    Brad E Morrison

    2016-01-01

    Full Text Available Parkinson′s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neurodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with popular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What′s more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inflammatory response mouse model. This observation may indicate that neuron loss in Parkinson′s disease results from inhibition of neurogenesis.

  6. Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli

    OpenAIRE

    Oei, Nicole Y. L.; Rombouts, Serge ARB; Soeter, Roelof P.; van Gerven, Joop M; Both, Stephanie

    2012-01-01

    Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive–compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the ‘reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. You...

  7. Pathological gambling: Relation of skin conductance response to dopaminergic neurotransmission and sensation-seeking

    DEFF Research Database (Denmark)

    Peterson, Ericka; Møller, Arne; Doudet, Doris;

    2010-01-01

    Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active...

  8. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    OpenAIRE

    Radhakishun, F.S.; de Ree, J M

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not change motor activity in placebo-treated rats. Pretreatment of the nucleus caudatus with the same neuroleptics or DEγE did not diminish the effect of subcutaneously administered low doses of apomorphi...

  9. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    NARCIS (Netherlands)

    Radhakishun, F.S.; Ree, J.M. van

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not cha

  10. S6K Promotes Dopaminergic Neuronal Differentiation Through PI3K/Akt/mTOR-Dependent Signaling Pathways in Human Neural Stem Cells.

    Science.gov (United States)

    Lee, Jeong Eun; Lim, Mi Sun; Park, Jae Hyun; Park, Chang Hwan; Koh, Hyun Chul

    2016-08-01

    It has recently been reported that the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway regulates neuronal differentiation of neural stem cells (NSCs) derived from rats or mice and is essential for the self-renewal of human embryonic stem cells (hESCs). However, the roles of PI3K/Akt/mTOR signaling pathways during proliferation and dopaminergic neuronal differentiation of human neural stem cells (hNSCs) are poorly understood. In this study, we examined the effect of regulation of these intracellular signaling pathways in hNSCs on the potential to maintain proliferation and induce dopaminergic neuronal differentiation. Dopaminergic neuronal differentiation depended on the concentration of insulin in our culture system. Inhibition of PI3K/Akt with LY294002 reduced proliferation and inhibited dopaminergic neuronal differentiation of these cells. We also found that rapamycin, a specific inhibitor of mTOR, significantly reduced neuronal differentiation without affecting proliferation. Inhibition of the Akt/mTOR signaling pathway led to inhibition of p70 ribosomal S6 kinase (S6K) signaling, which reduced dopaminergic neuronal differentiation in hNSCs. Inhibition of S6K by a specific chemical inhibitor, PF-4708671 inhibited dopaminergic neuronal differentiation of hNSCs. As expected, transduction with a dominant negative S6K1 (S6K1-DN) construct impaired dopaminergic neuronal differentiation of hNSCs. Conversely, overexpression of constitutively active S6K1 (S6K1-CA) promoted dopaminergic neuronal differentiation of these cells. In a survival study, 4 weeks after transplantation, no or very few donor cells were viable in striata grafted with S6K1-DN-transduced hNSCs. In contrast, S6K1-CA-transduced hNSCs survived, integrated into striata to generate tubular masses of grafts and differentiated toward TH-positive cells. Taken together, these data demonstrated that insulin promotes dopaminergic neuronal differentiation through a PI

  11. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    International Nuclear Information System (INIS)

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [18F[-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant Ki (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.)

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

    DEFF Research Database (Denmark)

    Fitzpatrick, Ciarán Martin

    2016-01-01

    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...

  13. Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion. A possible compensatory mechanism in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Javier eBlesa

    2011-11-01

    Full Text Available The onset of Parkinson's disease (PD is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory interdependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 18F-DOPA PET was associated with a higher threshold (i.e. greater dopaminergic loss for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity.Control and MPTP-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with 18F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods.Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric interdependence in the compensation of striatal DA deficit in PD.

  14. Olfactory impairment in the rotenone model of Parkinson's disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation

    Directory of Open Access Journals (Sweden)

    Laís Soares Rodrigues

    2014-12-01

    Full Text Available Olfactory and rapid eye movement (REM sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson's disease (PD. Besides different studies reported declines in olfactory performances during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood although the impairment in the dopamine (DA neurotransmission in the olfactory bulb and in the nigrostriatal pathway may have important roles in olfactory as well as in REM sleep disturbances. Therefore, we have led to the hypothesis that a modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and after a short period of REM sleep deprivation (REMSD. We decided to investigate the olfactory, neurochemical and histological alterations generated by the administration of piribedil (a selective D2 agonist or raclopride (a selective D2 antagonist, within the glomerular layer of the olfactory bulb, in rats submitted to intranigral rotenone and REMSD. Our findings provided a remarkable evidence of the occurrence of a negative correlation (r = - 0.52, P = 0.04 between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham groups. A significant positive correlation (r = 0.34, P = 0.03 was observed between nigral DA and olfactory discrimination index (DI, for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc are associated to enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA induced by piribedil in the rotenone control and rotenone REMSD groups were consistent with reduced amounts of DI. The present evidence reinforce that DA produced by periglomerular neurons, and particularly the bulbar dopaminergic D2 receptors, are essential participants in the olfactory discrimination processes, as well as SNpc

  15. Olfactory impairment in the rotenone model of Parkinson's disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation.

    Science.gov (United States)

    Rodrigues, Lais S; Targa, Adriano D S; Noseda, Ana Carolina D; Aurich, Mariana F; Da Cunha, Cláudio; Lima, Marcelo M S

    2014-01-01

    Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson's disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = -0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum.

  16. Olfactory impairment in the rotenone model of Parkinson’s disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation

    Science.gov (United States)

    Rodrigues, Lais S.; Targa, Adriano D. S.; Noseda, Ana Carolina D.; Aurich, Mariana F.; Da Cunha, Cláudio; Lima, Marcelo M. S.

    2014-01-01

    Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson’s disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = −0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum. PMID:25520618

  17. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

    Science.gov (United States)

    Dodson, Paul D; Dreyer, Jakob K; Jennings, Katie A; Syed, Emilie C J; Wade-Martins, Richard; Cragg, Stephanie J; Bolam, J Paul; Magill, Peter J

    2016-04-12

    Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits. PMID:27001837

  18. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

    Science.gov (United States)

    Dodson, Paul D; Dreyer, Jakob K; Jennings, Katie A; Syed, Emilie C J; Wade-Martins, Richard; Cragg, Stephanie J; Bolam, J Paul; Magill, Peter J

    2016-04-12

    Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.

  19. Protective effect of alpha-synuclein knockdown on methamphetamine-induced neurotoxicity in dopaminergic neurons

    Institute of Scientific and Technical Information of China (English)

    Yunchun Tai; Ling Chen; Enping Huang; Chao Liu; Xingyi Yang; Pingming Qiu; Huijun Wang

    2014-01-01

    The over-expression of α-synuclein is a major factor in the death of dopaminergic neurons in a methamphetamine-induced model of Parkinson’s disease. In the present study, α-synuclein knockdown rats were created by injecting α-synuclein-shRNA lentivirus stereotaxically into the right striatum of experimental rats. At 2 weeks post-injection, the rats were injected intraper-itoneally with methamphetamine to establish the model of Parkinson’s disease. Expression ofα-synuclein mRNA and protein in the right striatum of the injected rats was significantly down-regulated. Food intake and body weight were greater in α-synuclein knockdown rats, and water intake and stereotyped behavior score were lower than in model rats. Striatal dopamine and tyrosine hydroxylase levels were significantly elevated in α-synuclein knockdown rats. Moreover, superoxide dismutase activity was greater in α-synuclein knockdown rat striatum, but the levels of reactive oxygen species, malondialdehyde, nitric oxide synthase and nitrogen monoxide were lower compared with model rats. We also found that α-synuclein knockdown inhibited metham-phetamine-induced neuronal apoptosis. These results suggest that α-synuclein has the capacity to reverse methamphetamine-induced apoptosis of dopaminergic neurons in the rat striatum by inhibiting oxidative stress and improving dopaminergic system function.

  20. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    Energy Technology Data Exchange (ETDEWEB)

    Cordes, M. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Strahlenklinik und Poliklinik, Universitaetsklinikum Rudolf Virchow, Freie Univ. Berlin (Germany); Wszolek, Z.K. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Pfeiffer, R.F. [Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Calne, D.B. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)

    1993-12-31

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [{sup 18}F]-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant K{sub i} (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.) [Deutsch] Wir berichten ueber Untersuchungen der praesynaptischen dopaminergen Funktion mit der Positronenemissionstomographie bei einer grossen Familie mit autosomal-dominant vererbtem Parkinsonismus und Demenz. Die Erkrankung ist pathologisch-anatomisch gekennzeichnet durch eine pallido-ponto-nigrale Degeneration. Klinisch bestehen ein Parkinsonismus, Dystonien, eine Apraxie der Augenoeffnung und -schliessung, pyramidale Dysfunktionen und eine Harninkontinenz. Die praesynaptische dopaminerge Funktion wurde untersucht und quantifiziert mittels [{sup 18}F]-L-6-Fluorodopa (6FD) PET bei fuenf erkrankten Patienten, 13 Risikopatienten und 15 Kontrollpersonen vergleichbaren Alters. Die Transportkonstante K{sub i} (ml/Striatum/min) fuer die striatale Aufnahme des Radiotracers war bei allen erkrankten Patienten erniedrigt. Von den 13 Risikopatienten hatte keiner eine reduzierte Aufnahme von 6FD. Drei Risikopatienten zeigten sogar Werte fuer K{sub i}, die oberhalb des Referenzbereiches der Kontrollpersonen lagen

  1. Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.

    Science.gov (United States)

    Hermann, Wieland; Eggers, Birk; Barthel, Henryk; Clark, Daniel; Villmann, Thomas; Hesse, Swen; Grahmann, Friedrich; Kühn, Hans-Jürgen; Sabri, Osama; Wagner, Armin

    2002-08-01

    Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation. PMID:12195459

  2. The experimental study of the damage of environmental neurotoxins on the cultured rat dopaminergic neurons

    Institute of Scientific and Technical Information of China (English)

    WANG Jian; LU Chuanzhen; JIANG Yuping

    2000-01-01

    Objective To establish the culture system of rat dopaminergic neurons. and to determine whether Paraquat and Dieldrin selectively destroy cultured rat dopaminergic neurons respectively. Methods The cultured rat dopaminergic neurons were treated for 24h with Paraquat and Dieldrin(0.001 to 100 μ mol/L) respectively, Data were expressed as percentage of surviving TH-positive(TH+) cells and other cells per culture dish. Results Paraquat was not effective in selectively destroying TH+ neurons. Dieldrin (1 μ mol/L) selectively decreased the number of TH+ neurons without affecting other cells. The EC50 of Dieldrin on TH+ neurons was 27.6 l mol/L. Conclusion: Paraquat can not selectively destroy dopaminergic neurons in culture. Dieldrin (1 μ mol/L) can selectively destroy the dopaminergic neurons in culture, which make it a potential etiological agent for PD. The possible parkinsonogenic effect of Dieldrin is deserved for further investigation.

  3. Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

    DEFF Research Database (Denmark)

    Jensen, Pia; Gramsbergen, Jan-Bert; Zimmer, Jens;

    2011-01-01

    Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation o...... enzyme activity, which may explain the elevated dopamine levels. Our findings demonstrate that modulation of oxygen tension is a recognizable factor for in vitro expansion and dopaminergic differentiation of rat embryonic midbrain precursor cells....

  4. Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

    Directory of Open Access Journals (Sweden)

    Thiago Berti Kirsten

    Full Text Available Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS, which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.

  5. Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

    Science.gov (United States)

    Kirsten, Thiago Berti; Chaves-Kirsten, Gabriela P; Bernardes, Suene; Scavone, Cristoforo; Sarkis, Jorge E; Bernardi, Maria Martha; Felicio, Luciano F

    2015-01-01

    Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism. PMID:26218250

  6. Dopaminergic Input to the Inferior Colliculus in Mice

    Directory of Open Access Journals (Sweden)

    Alexander A Nevue

    2016-01-01

    Full Text Available The response of sensory neurons to stimuli can be modulated by a variety of factors including attention, emotion, behavioral context, and disorders involving neuromodulatory systems. For example, patients with Parkinson’s disease have disordered speech processing, suggesting that dopamine alters normal representation of these salient sounds. Understanding the mechanisms by which dopamine modulates auditory processing is thus an important goal. The principal auditory midbrain nucleus, the inferior colliculus (IC, is a likely location for dopaminergic modulation of auditory processing because it contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis. However, the sources of dopaminergic input to the IC are unknown. In this study, we iontophoretically injected a retrograde tracer into the IC of mice and then stained the tissue for TH. We also immunostained for dopamine beta-hydroxylase (DBH, an enzyme critical for the conversion of dopamine to norepinephrine, to differentiate between dopaminergic and noradrenergic inputs. Retrogradely labeled neurons that were positive for TH were seen bilaterally, with strong ipsilateral dominance, in the subparafascicular thalamic nucleus (SPF. All retrogradely labeled neurons that we observed in other brain regions were TH-negative. Projections from the SPF were confirmed using an anterograde tracer, revealing TH-positive and DBH-negative anterogradely labeled fibers and terminals in the IC. While the functional role of this dopaminergic input to the IC is not yet known, it provides a potential mechanism for context dependent modulation of auditory processing.

  7. Remote control of induced dopaminergic neurons in parkinsonian rats.

    Science.gov (United States)

    Dell'Anno, Maria Teresa; Caiazzo, Massimiliano; Leo, Damiana; Dvoretskova, Elena; Medrihan, Lucian; Colasante, Gaia; Giannelli, Serena; Theka, Ilda; Russo, Giovanni; Mus, Liudmila; Pezzoli, Gianni; Gainetdinov, Raul R; Benfenati, Fabio; Taverna, Stefano; Dityatev, Alexander; Broccoli, Vania

    2014-07-01

    Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.

  8. 甲基苯丙胺依赖与中脑边缘多巴胺神经系统相关研究%Methamphetamine Dependence and Mesocorticolimbic Dopaminergic System

    Institute of Scientific and Technical Information of China (English)

    陈群; 周文华

    2012-01-01

    以甲基苯丙胺为代表的苯胺类中枢兴奋剂滥用问题日益突出,文章对甲基苯丙胺依赖的作用途径和机制进行了概述,包括中脑边缘系统多巴胺神经通路、多巴胺受体、多巴胺转运体及其他神经递质,最后提出了当前甲基苯丙胺成瘾治疗研究的主要方向.%As one of the amphetamine type stimulants, methamphetamine has been abused widely in China. The methamphetamine dependence is related to the mesocorticolimbic dopaminergic system. This paper describes the mechanisms underlying methamphetamine dependence on the dopamine release, dopamine receptors and dopamine transporter.

  9. CyPPA, a positive SK3/SK2 modulator, reduces activity of dopaminergic neurons, inhibits dopamine release, and counteracts hyperdopaminergic behaviors induced by methylphenidate

    Directory of Open Access Journals (Sweden)

    Kjartan F. Herrik

    2012-02-01

    Full Text Available Dopamine (DA containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder (ADHD, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson’s disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca2+-activated K+ channels (SK channels, in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA-signaling and DA-related behaviors. Here we show that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl-6-methyl-pyrimidin-4-yl]-amine, a subtype-selective positive modulator of SK channels (SK3 > SK2 >>> SK1, IK, decreased spontaneous firing rate, increased the duration of the apamin-sensitive, medium duration afterhyperpolarization (mAHP, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using a immunohistochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior.

  10. Naringin: A Protector of the Nigrostriatal Dopaminergic Projection

    OpenAIRE

    Jung, Un Ju; Leem, Eunju; Kim, Sang Ryong

    2014-01-01

    Parkinson's disease is the second most common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons and a biochemical reduction of striatal dopamine levels. Despite the lack of fully understanding of the etiology of Parkinson's disease, accumulating evidences suggest that Parkinson's disease may be caused by the insufficient support of neurotrophic factors, and by microglial activation, resident immune cells in the brain. Naringin, a major flavonone ...

  11. Paraquat induces selective dopaminergic nigrostriatal degeneration in aging C57BL/6 mice

    Institute of Scientific and Technical Information of China (English)

    LI Xia; YIN Jun; CHENG Chun-mei; SUN Jin-lai; LI Zheng; WU Ying-liang

    2005-01-01

    Background Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPTP (1-methyl-1,2,3,6-tetrahydropyridine), has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). Aging is an accepted risk factor for idiopathic Parkinson's disease. The aim of this study was to test the hypothesis that paraquat could induce PD-like nigrostriatal dopaminergic degeneration in aging C57BL/6 mice.Methods Senile male C57BL/6 mice were intraperitoneally injected with either saline or PQ at 2-day intervals for a total of 10 doses. Locomotor activity and performance on the pole test were measured 7 days after the last injection and animals were sacrificed one day later. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and numbers of tyrosine hydroxylase (TH) positive neurons were estimated using immunohistochemistry.Results Locomotor activities were significantly decreased and the behavioral performance on the pole test were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined by 8 days after the last injection. Immunohistochemical analyses showed that PQ was associated with a reduction in numbers of tyrosine hydroxylase positive neurons.Conclusions Long-term repeated exposes to PQ can selectively impair the nigrostriatal dopaminergic system of senile mice, suggesting that PQ could play an important role in the pathogenesis of Parkinson's disease (PD). Our results also validate a novel model of PD induced by exposure to a toxic environmental agent.

  12. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease

    Science.gov (United States)

    Kustrimovic, Natasa; Rasini, Emanuela; Legnaro, Massimiliano; Bombelli, Raffaella; Aleksic, Iva; Blandini, Fabio; Comi, Cristoforo; Mauri, Marco; Minafra, Brigida; Riboldazzi, Giulio; Sanchez-Guajardo, Vanesa; Marino, Franca; Cosentino, Marco

    2016-01-01

    Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. PMID:27652978

  13. Quantification of dopaminergic neuron differentiation and neurotoxicity via a genetic reporter

    OpenAIRE

    Jun Cui; Megan Rothstein; Theo Bennett; Pengbo Zhang; Ninuo Xia; Reijo Pera, Renee A.

    2016-01-01

    Human pluripotent stem cells provide a powerful human-genome based system for modeling human diseases in vitro and for potentially identifying novel treatments. Directed differentiation of pluripotent stem cells produces many specific cell types including dopaminergic neurons. Here, we generated a genetic reporter assay in pluripotent stem cells using newly-developed genome editing technologies in order to monitor differentiation efficiency and compare dopaminergic neuron survival under diffe...

  14. Dopaminergic Differentiation of Human Embryonic Stem Cells on PA6-Derived Adipocytes.

    Science.gov (United States)

    Guloglu, M Oktar; Larsen, Anna

    2016-01-01

    Human embryonic stem cells (hESCs) are a promising source for cell replacement therapies. Parkinson's disease is one of the candidate diseases for the cell replacement therapy since the motor manifestations of the disease are associated with the loss of dopaminergic neurons in the substantia nigra pars compacta. Stromal cell-derived inducing activity (SDIA) is the most commonly used method for the dopaminergic differentiation of hESCs. This chapter describes a simple, reliable, and scalable dopaminergic induction method of hESCs using PA6-derived adipocytes. Coculturing hESCs with PA6-derived adipocytes markedly reduces the variable outcomes among experiments. Moreover, the colony differentiation step of this method can also be used for the dopaminergic induction of mouse embryonic stem cells and NTERA2 cells as well.

  15. Cellular manganese content is developmentally regulated in human dopaminergic neurons

    Science.gov (United States)

    Kumar, Kevin K.; Lowe, Edward W., Jr.; Aboud, Asad A.; Neely, M. Diana; Redha, Rey; Bauer, Joshua A.; Odak, Mihir; Weaver, C. David; Meiler, Jens; Aschner, Michael; Bowman, Aaron B.

    2014-10-01

    Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington's disease. Handling of other essential metals (e.g. iron and zinc) occurs via complex intracellular signaling networks that link metal detection and transport systems. However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content in a mouse striatal neuron cell line. Following stringent validation assays and chemical informatics, we obtained a chemical `toolbox' of 41 small molecules with diverse structure-activity relationships that can alter intracellular Mn levels under biologically relevant Mn exposures. We utilized this toolbox to test for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules. This work demonstrates cell-level regulation of Mn content across neuronal differentiation.

  16. Activation of the reward system boosts innate and adaptive immunity.

    Science.gov (United States)

    Ben-Shaanan, Tamar L; Azulay-Debby, Hilla; Dubovik, Tania; Starosvetsky, Elina; Korin, Ben; Schiller, Maya; Green, Nathaniel L; Admon, Yasmin; Hakim, Fahed; Shen-Orr, Shai S; Rolls, Asya

    2016-08-01

    Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection. PMID:27376577

  17. Effects of Selective Dopaminergic Compounds on a Delay Discounting Task

    OpenAIRE

    Koffarnus, Mikhail N.; Newman, Amy H.; Grundt, Peter; Rice, Kenner C.; Woods, James H.

    2011-01-01

    Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animals. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animals using delay discounting tasks. Here, delay discounting procedures were used to assess the effects of receptor-selective ...

  18. Early Effects of Reward Anticipation Are Modulated by Dopaminergic Stimulation

    OpenAIRE

    Thore Apitz; Nico Bunzeck

    2014-01-01

    The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predictin...

  19. Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila.

    Science.gov (United States)

    Plaçais, Pierre-Yves; Trannoy, Séverine; Isabel, Guillaume; Aso, Yoshinori; Siwanowicz, Igor; Belliart-Guérin, Ghislain; Vernier, Philippe; Birman, Serge; Tanimoto, Hiromu; Preat, Thomas

    2012-04-01

    A fundamental duty of any efficient memory system is to prevent long-lasting storage of poorly relevant information. However, little is known about dedicated mechanisms that appropriately trigger production of long-term memory (LTM). We examined the role of Drosophila dopaminergic neurons in the control of LTM formation and found that they act as a switch between two exclusive consolidation pathways leading to LTM or anesthesia-resistant memory (ARM). Blockade, after aversive olfactory conditioning, of three pairs of dopaminergic neurons projecting on mushroom bodies, the olfactory memory center, enhanced ARM, whereas their overactivation conversely impaired ARM. Notably, blockade of these neurons during the intertrial intervals of a spaced training precluded LTM formation. Two pairs of these dopaminergic neurons displayed sustained calcium oscillations in naive flies. Oscillations were weakened by ARM-inducing massed training and were enhanced during LTM formation. Our results indicate that oscillations of two pairs of dopaminergic neurons control ARM levels and gate LTM. PMID:22366756

  20. Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine.

    Directory of Open Access Journals (Sweden)

    Ginetta eCollo

    2014-11-01

    Full Text Available Mesencephalic dopaminergic neurons were suggested to be a critical physiopathology substrate for addiction disorders. Among neuroadaptive processes to addictive drugs, structural plasticity has attracted attention. While structural plasticity occurs at both pre- and post-synaptic levels in the mesolimbic dopaminergic system, the present review focuses only on dopaminergic neurons. Exposures to addictive drugs determine two opposite structural responses, hypothrophic plasticity produced by opioids and cannabinoids (in particular during the early withdrawal phase and hypertrophic plasticity, mostly driven by psychostimulants and nicotine. In vitro and in vivo studies indentified BDNF and extracellular dopamine as two critical factors in determining structural plasticity, the two molecules sharing similar intracellular pathways involved in cell soma and dendrite growth, the MEK-ERK1/2 and the PI3K-Akt-mTOR, via preferential activation of TrkB and dopamine D3 receptors, respectively. At present information regarding specific structural changes associated to the various stages of the addiction cycle is incomplete. Encouraging neuroimaging data in humans indirectly support the preclinical evidence of hypotrophic and hypertrophic effects, suggesting a possible differential engagement of dopamine neurons in parallel and partially converging circuits controlling motivation, stress and emotions.

  1. PET measurements od dopaminergic pathways in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Perlmutter, J.S. [Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Neurology and Neurological Surgery, Anatomy and Neurobiology; Moerlein, S.M. [Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Biochemistry and Molecular Biophysics, Mallinckrodt Institute of Radiology

    1999-06-01

    Position emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow of metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding 'in vivo' with PET reveals abnormalities associated with specific diseases and the actions of various drugs that effect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD.

  2. PET measurements od dopaminergic pathways in the brain

    International Nuclear Information System (INIS)

    Position emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow of metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding 'in vivo' with PET reveals abnormalities associated with specific diseases and the actions of various drugs that effect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD

  3. Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

    OpenAIRE

    Yi Pang; Lu-Tai Tien; Hobart Zhu; Juying Shen; Camilla F. Wright; Jones, Tembra K.; Mamoon, Samir A.; Bhatt, Abhay J; Zhengwei Cai; Lir-Wan Fan

    2015-01-01

    Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (I...

  4. Withania somnifera alleviates parkinsonian phenotypes by inhibiting apoptotic pathways in dopaminergic neurons.

    Science.gov (United States)

    Prakash, Jay; Chouhan, Shikha; Yadav, Satyndra Kumar; Westfall, Susan; Rai, Sachchida Nand; Singh, Surya Pratap

    2014-12-01

    Maneb (MB) and paraquat (PQ) are environmental toxins that have been experimentally used to induce selective damage of dopaminergic neurons leading to the development of Parkinson's disease (PD). Although the mechanism of this selective neuronal toxicity in not fully understood, oxidative stress has been linked to the pathogenesis of PD. The present study investigates the mechanisms of neuroprotection elicited by Withania somnifera (Ws), a herb traditionally recognized by the Indian system of medicine, Ayurveda. An ethanolic root extract of Ws was co-treated with the MB-PQ induced mouse model of PD and was shown to significantly rescue canonical indicators of PD including compromised locomotor activity, reduced dopamine in the substantia nigra and various aspects of oxidative damage. In particular, Ws reduced the expression of iNOS, a measure of oxidative stress. Ws also significantly improved the MB + PQ mediated induction of a pro-apoptotic state by reducing Bax and inducing Bcl-2 protein expression, respectively. Finally, Ws reduced expression of the pro-inflammatory marker of astrocyte activation, GFAP. Altogether, the present study suggests that Ws treatment provides nigrostriatal dopaminergic neuroprotection against MB-PQ induced Parkinsonism by the modulation of oxidative stress and apoptotic machinery possibly accounting for the behavioural effects.

  5. Early effects of reward anticipation are modulated by dopaminergic stimulation.

    Directory of Open Access Journals (Sweden)

    Thore Apitz

    Full Text Available The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2 × 2 factorial design, while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude emerged at ∼ 100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20-30 Hz and low (13-20 Hz beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine.

  6. Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms.

    Science.gov (United States)

    Perier, Celine; Bender, Andreas; García-Arumí, Elena; Melià, Ma Jesus; Bové, Jordi; Laub, Christoph; Klopstock, Thomas; Elstner, Matthias; Mounsey, Ross B; Teismann, Peter; Prolla, Tomas; Andreu, Antoni L; Vila, Miquel

    2013-08-01

    Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA

  7. Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms.

    Science.gov (United States)

    Perier, Celine; Bender, Andreas; García-Arumí, Elena; Melià, Ma Jesus; Bové, Jordi; Laub, Christoph; Klopstock, Thomas; Elstner, Matthias; Mounsey, Ross B; Teismann, Peter; Prolla, Tomas; Andreu, Antoni L; Vila, Miquel

    2013-08-01

    Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA

  8. Sweet Taste and Nutrient Value Subdivide Rewarding Dopaminergic Neurons in Drosophila

    Science.gov (United States)

    Huetteroth, Wolf; Perisse, Emmanuel; Lin, Suewei; Klappenbach, Martín; Burke, Christopher; Waddell, Scott

    2015-01-01

    Summary Dopaminergic neurons provide reward learning signals in mammals and insects [1–4]. Recent work in Drosophila has demonstrated that water-reinforcing dopaminergic neurons are different to those for nutritious sugars [5]. Here, we tested whether the sweet taste and nutrient properties of sugar reinforcement further subdivide the fly reward system. We found that dopaminergic neurons expressing the OAMB octopamine receptor [6] specifically convey the short-term reinforcing effects of sweet taste [4]. These dopaminergic neurons project to the β′2 and γ4 regions of the mushroom body lobes. In contrast, nutrient-dependent long-term memory requires different dopaminergic neurons that project to the γ5b regions, and it can be artificially reinforced by those projecting to the β lobe and adjacent α1 region. Surprisingly, whereas artificial implantation and expression of short-term memory occur in satiated flies, formation and expression of artificial long-term memory require flies to be hungry. These studies suggest that short-term and long-term sugar memories have different physiological constraints. They also demonstrate further functional heterogeneity within the rewarding dopaminergic neuron population. PMID:25728694

  9. Nicotine modulates GABAergic transmission to dopaminergic neurons in substantia nigra pars compacta

    Institute of Scientific and Technical Information of China (English)

    Cheng XIAO; Ke-chun YANG; Chun-yi ZHOU; Guo-zhang JIN; Jie WU; Jiang-hong YE

    2009-01-01

    Aim: Dopaminergic neurons in the substantia nigra pars compacta (SNc) play important roles in motor control and drug addiction. As the major afferent, GABAergic innervation controls the activity of SNc dopaminergic neurons. Although it is clear that nicotine modulates SNc dopaminergic neurons by activating subtypes of somatodendritic nicotinic acetylcholine receptors (nAChRs), the detailed mechanisms of this activation remain to be addressed.Methods: In the current study, we recorded GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIP-SCs) from dissociated SNc dopaminergic neurons that were obtained using an enzyme-free procedure. These neurons preserved some functional terminals after isolation, including those that release GABA.Results: We found that both extra- and intra-cellular calcium modulates sIPSCs in these neurons. Furthermore, both nicotine and endogenous acetylcholine enhance the frequency of sIPSCs. Moreover, endogenous acetylcholine tonically facilitates sIPSC frequency, primarily by activating the a4B2* nAChRs on the GABAergic terminals.Conclusion: Nicotine facilitates GABA release onto SNc dopaminergic neurons mainly via the activation of presynaptic a4B2* nAChRs.

  10. ADASY (Active Daylighting System)

    Science.gov (United States)

    Vázquez-Moliní, Daniel; González-Montes, Mario; Fernández-Balbuena, Antonio Á.; Bernabéu, Eusebio; García-Botella, Ángel; García-Rodríguez, Lucas; Pohl, Wilfried

    2009-08-01

    The main objective of ADASY (Active Daylighting System) work is to design a façade static daylighting system oriented to office applications, mainly. The goal of the project is to save energy by guiding daylight into a building for lighting purpose. With this approach we can reduce the electrical load for artificial lighting, completing it with sustainable energy. The collector of the system is integrated on a vertical façade and its distribution guide is always horizontal inside of the false ceiling. ADASY is designed with a specific patent pending caption system, a modular light-guide and light extractor luminaire system. Special care has been put on the final cost of the system and its building integration purpose. The current ADASY configuration is able to illuminate 40 m2 area with a 300lx-400lx level in the mid time work hours; furthermore it has a good enough spatial uniformity distribution and a controlled glare. The data presented in this study are the result of simulation models and have been confirmed by a physical scaled prototype. ADASY's main advantages over regular illumination systems are: -Low maintenance; it has not mobile pieces and therefore it lasts for a long time and require little attention once installed. - No energy consumption; solar light continue working even if there has been a power outage. - High quality of light: the colour rendering of light is very high - Psychological benefits: People working with daylight get less stress and more comfort, increasing productivity. - Health benefits

  11. Cooperatively active sensing system

    International Nuclear Information System (INIS)

    Aiming at development of a strong and flexible sensing system, a study on a sensing technology prepared with cooperativity, activity, and real time workability has been promoted. In the former period, together with preparation of plural moving robot group with real time processing capacity of a lot of sensor informations composing of platform, a parallel object direction language Eus Lisp effectively capable of describing and executing cooperative processing and action therewith was developed. And, it was also shown that capacity to adaptively act even at dynamic environment could be learnt experientially. And, on processing of individual sensor information, application of a photographing system with multiple resolution property similar to human visual sense property was attempted. In the latter period, together with intending of upgrading on adaptability of sensing function, by using moving robot group in center of a moving robot loaded with active visual sense, a cooperative active sensing prototype system was constructed to show effectiveness of this study through evaluation experiment of patrolling inspection at plant simulating environment. (G.K.)

  12. In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats

    NARCIS (Netherlands)

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

    2012-01-01

    GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GAB

  13. Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Impagnatiello Francesco

    2010-11-01

    macrophage antigen-1 (Mac-1-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX, and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons. Conclusions Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.

  14. CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate

    DEFF Research Database (Denmark)

    Herrik, Kjartan F; Redrobe, John P; Holst, Dorte;

    2012-01-01

    Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson's disease. Pharmacological...... modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca(2...... mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo...

  15. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  16. Pathological gambling: Relation of skin conductance response to dopaminergic neurotransmission and sensation-seeking

    DEFF Research Database (Denmark)

    Peterson, Ericka Ann; Møller, Arne; Doudet, Doris J.;

    2010-01-01

    Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active...... gambling, SCR differed in PG and HC subjects (P < 0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (P < 0.0001) in the baseline, compared to normal sensation-seeking (NS) PG...

  17. Perspective food addiction, caloric restriction, and dopaminergic neurotransmission

    DEFF Research Database (Denmark)

    Stankowska, Arwen Urrsula Malgorzata; Gjedde, Albert

    2013-01-01

    for a reduced cognitive reward condition. The combination of caloric restriction and food addiction imparts a high risk of relapse as a result of further reduction of dopaminergic neurotransmission and the subsequent loss of reward. As with drugs of abuse, ingestion of large quantities of sugar in circumstances......, and reduced activity in prefrontal regions of the cerebral cortex. The neurobiological characteristics suggest that obese people also have a pathological dependence in common with addicts, in the form of food addiction. Malnutrition and dieting both relate to binge eating, possibly as a compensation...

  18. Argument for a non-linear relationship between severity of human obesity and dopaminergic tone.

    Science.gov (United States)

    Horstmann, A; Fenske, W K; Hankir, M K

    2015-10-01

    Alterations in the dopaminergic system have been implicated in both animal and human obesity. However, to date, a comprehensive model on the nature and functional relevance of this relationship is missing. In particular, human data remain equivocal in that seemingly inconsistent reports exist of positive, negative or even no relationships between dopamine D2/D3 receptor availability in the striatum and measures of obesity. Further, data on receptor availability have been commonly interpreted as reflecting receptor density, despite the possibility of an alternative interpretation, namely alterations in the basal levels of endogenous dopaminergic tone. Here, we provide a unifying framework that is able to explain the seemingly contradictory findings and offer an alternative and novel perspective on existing data. In particular, we suggest (i) a quadratic relationship between alterations in the dopaminergic system and degree of obesity, and (ii) that the observed alterations are driven by shifts in the balance between general dopaminergic tone and phasic dopaminergic signalling. The proposed model consistently integrates human data on molecular and behavioural characteristics of overweight and obesity. Further, the model provides a mechanistic framework accounting not only for the consistent observation of altered (food) reward-responsivity but also for the differences in reinforcement learning, decision-making behaviour and cognitive performance associated with measures of obesity. PMID:26098597

  19. Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.

    Science.gov (United States)

    Grieder, Taryn E; Sellings, Laurie H; Vargas-Perez, Hector; Ting-A-Kee, Ryan; Siu, Eric C; Tyndale, Rachel F; van der Kooy, Derek

    2010-03-01

    The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. PMID:20032966

  20. Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.

    Science.gov (United States)

    Grieder, Taryn E; Sellings, Laurie H; Vargas-Perez, Hector; Ting-A-Kee, Ryan; Siu, Eric C; Tyndale, Rachel F; van der Kooy, Derek

    2010-03-01

    The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals.

  1. Radiopharmaceuticals for SPECT exploration of dopaminergic systems. Diagnosis and surveillance of neuro-degenerative diseases; Les radiopharmaceutiques pour l`exploration des system dopaminergique en TEMP. Interet pour le diagnostic et le suivi des maladies neurodegeneratives

    Energy Technology Data Exchange (ETDEWEB)

    Gouilloteau, D.; Prunier-Levallon, C.; Zimmer, L.; Autret, A.; Besnard, J-Cl.; Baulieu, J-L. [CHU TOURS (France)

    1997-12-31

    New radiopharmaceuticals were developed to explore the pre- or post-synaptic slopes of the dopaminergic terminations. At present, their interest is recognized for the differential diagnosis of the extra-pyramidal syndromes. Other various applications in neurology and psychiatry are in view. On the pre-synaptic slope, implied in the Parkinson`s disease, the dopamine carrier, able to be visualized due to its iodine derivatives of cocaine, is localized. The {beta}CIT, which is presently the best known specificity-free derivative, has actually an equivalent affinity for the dopamine carrier and the serotonin carrier. Besides, its kinetic does not allow its imaging in the day of injection. We have developed and validated another derivative, the PE2I: N-(3-Iodoprop-(2E)-enyl) -2{beta}-carbometoxy -3{beta}-(4`-methyl-phenyl) nortropane which displays the properties required by kinetic and specificity. On the post-synaptic slope the type-D2 dopaminergic receptors were localized, which can be explored by means of (iodolisuride) ergolenes and benzamide derivatives (IBZM). These ligands have not an AMM yet, therefore their utilization may be approached by magistral preparation. The scintigraphy of the D2 receptors and dopamine carrier could be useful for the earlier diagnosis and the therapeutic surveillance of the neuro-degenerative decease. The coupling of the pre- and post-synaptic scintigraphies may be taken into consideration to augment diagnosis potentiality

  2. Nanotechnology approach for drug addiction therapy: Gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons

    OpenAIRE

    Bonoiu, Adela C.; Mahajan, Supriya D.; Ding, Hong; Roy, Indrajit; Yong, Ken-Tye; Kumar, Rajiv; Hu, Rui; Bergey, Earl J.; Schwartz, Stanley A.; Prasad, Paras N.

    2009-01-01

    Drug abuse is a worldwide health concern in which addiction involves activation of the dopaminergic signaling pathway in the brain. Here, we introduce a nanotechnology approach that utilizes gold nanorod-DARPP-32 siRNA complexes (nanoplexes) that target this dopaminergic signaling pathway in the brain. The shift in the localized longitudinal plasmon resonance peak of gold nanorods (GNRs) was used to show their interaction with siRNA. Plasmonic enhanced dark field imaging was used to visualize...

  3. Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Haixia Ding; Meijiang Feng; Xinsheng Ding

    2008-01-01

    BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.

  4. Development of a Dual Tracer PET Method for Imaging Dopaminergic Neuromodulation

    Science.gov (United States)

    Converse, Alexander K.; Dejesus, Onofre T.; Flores, Leo G.; Holden, James E.; Kelley, Ann E.; Moirano, Jeffrey M.; Nickles, Robert J.; Oakes, Terrence R.; Roberts, Andrew D.; Ruth, Thomas J.; Vandehey, Nicholas T.; Davidson, Richard J.

    2006-04-01

    The modulatory neurotransmittor dopamine (DA) is involved in movement and reward behaviors, and malfunctions in the dopamine system are implicated in a variety of prevalent and debilitating pathologies including Parkinson's disease, attention deficit/hyperactivity disorder, schizophrenia, and addiction. Positron emission tomography (PET) has been used to separately measure changes in DA receptor occupancy and blood flow in response to various interventions. Here we describe a dual tracer PET method to simultaneously measure both responses with the aim of comparing DA release in particular areas of the brain and associated alterations in neural activity throughout the brain. Significant correlations between reductions in DA receptor occupancy and blood flow alterations would be potential signs of dopaminergic modulation, i.e. modifications in signal processing due to increased levels of extracellular DA. Methodological development has begun with rats undergoing an amphetamine challenge while being scanned with the blood flow tracer [17F]fluoromethane and the dopamine D2 receptor tracer [18F]desmethoxyfallypride.

  5. Fast transmission from the dopaminergic ventral midbrain to the sensory cortex of awake primates.

    Science.gov (United States)

    Mylius, Judith; Happel, Max F K; Gorkin, Alexander G; Huang, Ying; Scheich, Henning; Brosch, Michael

    2015-11-01

    Motivated by the increasing evidence that auditory cortex is under control of dopaminergic cell structures of the ventral midbrain, we studied how the ventral tegmental area and substantia nigra affect neuronal activity in auditory cortex. We electrically stimulated 567 deep brain sites in total within and in the vicinity of the two dopaminergic ventral midbrain structures and at the same time, recorded local field potentials and neuronal discharges in cortex. In experiments conducted on three awake macaque monkeys, we found that electrical stimulation of the dopaminergic ventral midbrain resulted in short-latency (~35 ms) phasic activations in all cortical layers of auditory cortex. We were also able to demonstrate similar activations in secondary somatosensory cortex and superior temporal polysensory cortex. The electrically evoked responses in these parts of sensory cortex were similar to those previously described for prefrontal cortex. Moreover, these phasic responses could be reversibly altered by the dopamine D1-receptor antagonist SCH23390 for several tens of minutes. Thus, we speculate that the dopaminergic ventral midbrain exerts a temporally precise, phasic influence on sensory cortex using fast-acting non-dopaminergic transmitters and that their effects are modulated by dopamine on a longer timescale. Our findings suggest that some of the information carried by the neuronal discharges in the dopaminergic ventral midbrain, such as the motivational value or the motivational salience, is transmitted to auditory cortex and other parts of sensory cortex. The mesocortical pathway may thus contribute to the representation of non-auditory events in the auditory cortex and to its associative functions.

  6. Increased Spreading Activation in Depression

    Science.gov (United States)

    Foster, Paul S.; Yung, Raegan C.; Branch, Kaylei K.; Stringer, Kristi; Ferguson, Brad J.; Sullivan, William; Drago, Valeria

    2011-01-01

    The dopaminergic system is implicated in depressive disorders and research has also shown that dopamine constricts lexical/semantic networks by reducing spreading activation. Hence, depression, which is linked to reductions of dopamine, may be associated with increased spreading activation. However, research has generally found no effects of…

  7. Alpha-synuclein promotes clathrin-mediated endocytosis of NMDA receptors in dopaminergic cells

    Institute of Scientific and Technical Information of China (English)

    Shun Yu; Furong Cheng; Xin Li; Yaohua Li; Tao Wang; Guangwei Liu; Andrius Baskys

    2012-01-01

    Loss of dopaminergic i a compensatory increase in nput to the striatum associated with Parkinson' s disease brings about glutamate release onto the dopaminergic cell bodies in the substantia nigra pars compacta (SNpc)[1] Glutamate over-activation of NMDA receptors on these cells can cause excitotoxicity and contribute to their further loss. NMDA receptor-mediated neuronal death is reduced by group I mGluR-mediated up-regulation of endocytosis protein RAB5B[2.3] Among proteins shown to interact with RAB5 proteins is a-synuclein

  8. 海胆早期多巴胺能神经系统的发育及功能研究进展%Progress on the Research of the Development and Function of the Dopaminergic Nervous System of Sea Urchin in the Early Developmental Stage

    Institute of Scientific and Technical Information of China (English)

    汝少国; 王翠翠

    2015-01-01

    Sea urchin embryo and larvae in the early developmental stages is an important model for research on marine ecological toxicology. Sea urchin dopaminergic (DA) nervous system develops earlier than the cholinergic system, and it starts to regulate the morphogenesis and swimming behaviors much earlier than the serotonergic system. Here we used sea urchin in the early developmental stages as a model and reviewed the development and the functions of the dopaminergic nervous system. The synthesis of dopamine and the receptors precedes the development of the dopaminergic nervous system. The dopaminergic neuron precursor cell period starts after the synthesis of DA and the receptors. In this period DA and DA receptor 1 (DRD1) appears in the form of granules of which the diameter is 1-2 μm (DA/DRD1-Gs), and they are also expressed on the surface of the embryo and larvae from the rotational blastula stage to the metamorphosis stage. After the aggregation of DA/DRD1-Gs, dopaminergic cells with the axon contacts begin to develop in the labial ganglion and the base of the back oral arms in the early four-wrist larval stage. The number of dopaminergic cells reached the maximum in the eight-wrist larval stage. Then the dopaminergic nervous system continues to develop until the maturity. The morphogenesis in the early developmental stage is regulated by several neurotransmitter systems together, and the swimming behaviors in different early periods can be regulated by either the dopaminergic nervous system alone or together with other systems. In the end, we assessed the prospective studies on issues, such as the factors affecting the development of the dopaminergic nervous system in the early developmental stages of sea urchin, the functions and the signaling pathway of DA receptors, the primary-secondary relationship and the mechanisms of the up-/down-regulation of the three important neurotransmitter systems in early morphogenesis and swimming behaviors, and the influences of

  9. Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner.

    Science.gov (United States)

    Cao, Xiou; Aballay, Alejandro

    2016-09-12

    The innate immune system is the front line of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects [1, 2]. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms [3-5]. Here we report that dopamine signaling controls innate immune responses through a D1-like dopamine receptor, DOP-4, in Caenorhabditis elegans. Chlorpromazine inhibition of DOP-4 in the nervous system activates a microbicidal PMK-1/p38 mitogen-activated protein kinase signaling pathway that enhances host resistance against bacterial infections. The immune inhibitory function of dopamine originates in CEP neurons and requires active DOP-4 in downstream ASG neurons. Our findings indicate that dopamine signaling from the nervous system controls immunity in a cell-non-autonomous manner and identifies the dopaminergic system as a potential therapeutic target for not only infectious diseases but also a range of conditions that arise as a consequence of malfunctioning immune responses.

  10. Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure.

    Science.gov (United States)

    Juarez, Barbara; Han, Ming-Hu

    2016-09-01

    Addictive substances are known to increase dopaminergic signaling in the mesocorticolimbic system. The origin of this dopamine (DA) signaling originates in the ventral tegmental area (VTA), which sends afferents to various targets, including the nucleus accumbens, the medial prefrontal cortex, and the basolateral amygdala. VTA DA neurons mediate stimuli saliency and goal-directed behaviors. These neurons undergo robust drug-induced intrinsic and extrinsic synaptic mechanisms following acute and chronic drug exposure, which are part of brain-wide adaptations that ultimately lead to the transition into a drug-dependent state. Interestingly, recent investigations of the differential subpopulations of VTA DA neurons have revealed projection-specific functional roles in mediating reward, aversion, and stress. It is now critical to view drug-induced neuroadaptations from a circuit-level perspective to gain insight into how differential dopaminergic adaptations and signaling to targets of the mesocorticolimbic system mediates drug reward. This review hopes to describe the projection-specific intrinsic characteristics of these subpopulations, the differential afferent inputs onto these VTA DA neuron subpopulations, and consolidate findings of drug-induced plasticity of VTA DA neurons and highlight the importance of future projection-based studies of this system. PMID:26934955

  11. Minocycline Rescues from Zinc-Induced Nigrostriatal Dopaminergic Neurodegeneration: Biochemical and Molecular Interventions.

    Science.gov (United States)

    Kumar, Vinod; Singh, Brajesh Kumar; Chauhan, Amit Kumar; Singh, Deepali; Patel, Devendra Kumar; Singh, Chetna

    2016-07-01

    Accumulation of zinc (Zn) in dopaminergic neurons is implicated in Parkinson's disease (PD), and microglial activation plays a critical role in toxin-induced Parkinsonism. Oxidative stress is accused in Zn-induced dopaminergic neurodegeneration; however, its connection with microglial activation is still not known. This study was undertaken to elucidate the role and underlying mechanism of microglial activation in Zn-induced nigrostriatal dopaminergic neurodegeneration. Male Wistar rats were treated intraperitoneally with/without zinc sulphate (20 mg/kg) in the presence/absence of minocycline (30 mg/kg), a microglial activation inhibitor, for 2-12 weeks. While neurobehavioral and biochemical indexes of PD and number of dopaminergic neurons were reduced, the number of microglial cells was increased in the substantia nigra of the Zn-exposed animals. Similarly, Zn elevated lipid peroxidation (LPO) and activities of superoxide dismutase (SOD) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; however, catalase activity was reduced. Besides, Zn increased an association of NADPH oxidase subunit p67(phox) with membrane, cytochrome c release from the mitochondria and cleavage of pro-caspase 3. Zn attenuated the expression of tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT-2) while augmented the expression of dopamine transporter (DAT) and heme oxygenase-1 (HO-1). Minocycline alleviated Zn-induced behavioural impairments, loss of TH-positive neurons, activated microglial cells and biochemical indexes and modulated the expression of studied genes/proteins towards normalcy. The results demonstrate that minocycline reduces the number of activated microglial cells and oxidative stress, which rescue from Zn-induced changes in the expression of monoamine transporter and nigrostriatal dopaminergic neurodegeneration. PMID:25764516

  12. Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Kühnel Dana

    2002-06-01

    Full Text Available Abstract Background The cockroach salivary gland consists of secretory acini with peripheral ion-transporting cells and central protein-producing cells, an extensive duct system, and a pair of reservoirs. Salivation is controled by serotonergic and dopaminergic innervation. Serotonin stimulates the secretion of a protein-rich saliva, dopamine causes the production of a saliva without proteins. These findings suggest a model in which serotonin acts on the central cells and possibly other cell types, and dopamine acts selectively on the ion-transporting cells. To examine this model, we have analyzed the spatial relationship of dopaminergic and serotonergic nerve fibers to the various cell types. Results The acinar tissue is entangled in a meshwork of serotonergic and dopaminergic varicose fibers. Dopaminergic fibers reside only at the surface of the acini next to the peripheral cells. Serotonergic fibers invade the acini and form a dense network between central cells. Salivary duct segments close to the acini are locally associated with dopaminergic and serotonergic fibers, whereas duct segments further downstream have only dopaminergic fibers on their surface and within the epithelium. In addition, the reservoirs have both a dopaminergic and a serotonergic innervation. Conclusion Our results suggest that dopamine is released on the acinar surface, close to peripheral cells, and along the entire duct system. Serotonin is probably released close to peripheral and central cells, and at initial segments of the duct system. Moreover, the presence of serotonergic and dopaminergic fiber terminals on the reservoir indicates that the functions of this structure are also regulated by dopamine and serotonin.

  13. Nimodipine enhances neurite outgrowth in dopaminergic brain slice co-cultures.

    Science.gov (United States)

    Sygnecka, Katja; Heine, Claudia; Scherf, Nico; Fasold, Mario; Binder, Hans; Scheller, Christian; Franke, Heike

    2015-02-01

    Calcium ions (Ca(2+)) play important roles in neuroplasticity and the regeneration of nerves. Intracellular Ca(2+) concentrations are regulated by Ca(2+) channels, among them L-type voltage-gated Ca(2+) channels, which are inhibited by dihydropyridines like nimodipine. The purpose of this study was to investigate the effect of nimodipine on neurite growth during development and regeneration. As an appropriate model to study neurite growth, we chose organotypic brain slice co-cultures of the mesocortical dopaminergic projection system, consisting of the ventral tegmental area/substantia nigra and the prefrontal cortex from neonatal rat brains. Quantification of the density of the newly built neurites in the border region (region between the two cultivated slices) of the co-cultures revealed a growth promoting effect of nimodipine at concentrations of 0.1μM and 1μM that was even more pronounced than the effect of the growth factor NGF. This beneficial effect was absent when 10μM nimodipine were applied. Toxicological tests revealed that the application of nimodipine at this higher concentration slightly induced caspase 3 activation in the cortical part of the co-cultures, but did neither affect the amount of lactate dehydrogenase release or propidium iodide uptake nor the ratio of bax/bcl-2. Furthermore, the expression levels of different genes were quantified after nimodipine treatment. The expression of Ca(2+) binding proteins, immediate early genes, glial fibrillary acidic protein, and myelin components did not change significantly after treatment, indicating that the regulation of their expression is not primarily involved in the observed nimodipine mediated neurite growth. In summary, this study revealed for the first time a neurite growth promoting effect of nimodipine in the mesocortical dopaminergic projection system that is highly dependent on the applied concentrations. PMID:25447789

  14. Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, D.; Tomasi, D.; Volkow, N.D.; Wang, R.; Carrillo, J.; Maloney, T.; Alia-Klein, N.; Woicik, P.A.; Telang, F.; Goldstein, R.Z.

    2010-06-01

    Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

  15. Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers.

    Directory of Open Access Journals (Sweden)

    Dardo Tomasi

    Full Text Available BACKGROUND: Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located and cortical and subcortical brain regions during the performance of a sustained attention task. METHODOLOGY/PRINCIPAL FINDINGS: We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. CONCLUSIONS/SIGNIFICANCE: These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

  16. Therapies for dopaminergic-induced dyskinesias in Parkinson disease.

    Science.gov (United States)

    Gottwald, Mildred D; Aminoff, Michael J

    2011-06-01

    Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents. PMID:21681795

  17. Dopaminergic genes predict individual differences in susceptibility to confirmation bias.

    Science.gov (United States)

    Doll, Bradley B; Hutchison, Kent E; Frank, Michael J

    2011-04-20

    The striatum is critical for the incremental learning of values associated with behavioral actions. The prefrontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics. Computational analysis found that this pattern of data is best accounted for by a confirmation bias mechanism in which prior beliefs--putatively represented in PFC--influence the learning that occurs in the striatum such that reinforcement statistics are distorted. We assessed genetic variants affecting prefrontal and striatal dopaminergic neurotransmission. A polymorphism in the COMT gene (rs4680), associated with prefrontal dopaminergic function, was predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their veracity accumulated. Polymorphisms in genes associated with striatal dopamine function (DARPP-32, rs907094, and DRD2, rs6277) were predictive of learning from positive and negative outcomes. Notably, these same variants were predictive of the degree to which such learning was overly inflated or neglected when outcomes are consistent or inconsistent with prior instructions. These findings indicate dissociable neurocomputational and genetic mechanisms by which initial biases are strengthened by experience. PMID:21508242

  18. Dopaminergic and serotonergic drug use: a nationwide register-based study of over 1,300,000 older people.

    Directory of Open Access Journals (Sweden)

    Kristina Johnell

    Full Text Available OBJECTIVE: To investigate the use of dopaminergic and serotonergic drugs in elderly people. METHODS: We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1,347,564; 81% of the total population aged ≥65 years in Sweden. Main outcome measures were dopaminergic (enhancing and/or lowering and serotonergic (enhancing and/or lowering drugs and combinations of these. RESULTS: Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%. Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern. CONCLUSION: Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.

  19. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

    Science.gov (United States)

    Sun, Xian-Chang; Ren, Xiao-Fan; Chen, Lei; Gao, Xian-Qi; Xie, Jun-Xia; Chen, Wen-Fang

    2016-01-01

    Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1. PMID:26455404

  20. Improved Active Vibration Isolation Systems

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The control force, feedback gain, and actuator stroke of several active vibration isolation systems were analyzed based on a single-layer active vibration isolation system. The analysis shows that the feedback gain and actuator stroke cannot be selected independently and the active isolation system design must make a compromise between the feedback gain and actuator stroke. The performance of active isolation systems can be improved by the joint vibration reduction using an active vibration isolation system with an adaptive dynamic vibration absorber. The results show that the joint vibration reduction method can successfully avoid the compromise between the feedback gain and actuator stroke. The control force and the object vibration amplitude are also greatly reduced.

  1. A natural compound macelignan protects midbrain dopaminergic neurons from inflammatory degeneration via microglial arginase-1 expression.

    Science.gov (United States)

    Kiyofuji, Kana; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Mishima, Satoshi; Katsuki, Hiroshi

    2015-08-01

    Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN)-γ and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 μM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-γ/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-γ/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(ω)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Overall, these results indicate that macelignan, a compound with PPARγ agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner.

  2. Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation.

    Science.gov (United States)

    Gerlai, R; McNamara, A; Choi-Lundberg, D L; Armanini, M; Ross, J; Powell-Braxton, L; Phillips, H S

    2001-10-01

    Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities. PMID:11683907

  3. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

    Directory of Open Access Journals (Sweden)

    Hatam Ahmadi

    2013-06-01

    Full Text Available Background: Nucleus accumbens (NAc and prefrontal cortex (PFC dopaminergic and glutamatergic systems are involved in regulating of locomotor activity behaviors. This study has investigated the interaction of NAc shell dopaminergic system and prelimbic glutamatergic systems in regulating locomotor activity and related parameters. Methods: The aim of this study was the effect the drugs injection interaction in the brain of male Wistar rats on locomotor activity and related parameters, in the order of this purpose, open field apparatus that automatically recorded locomotor activity was employed. Unilateral intra-cerebral injection of drugs was done. Results: Unilateral intra-prelimbic injection of D-AP7 (N-methyl-D-aspartic acid= NMDA receptor antagonist; 0.25, 0.5 and 1μg/μl did not alter locomotor activity behaviors. However, infusion of NMDA (0.9μg/μl in this region increased locomotor activity (P<0.01, whereas decreased rearing (P<0.01 and grooming (P<0.01 which was blocked by D-AP7 (0.25μg/μl (P<0.01. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1μg/μl into the left NAc shell did not alter locomotor activity. However, injection of SKF38393 (dopamine D1 receptor agonist; 4μg/μl into the left NAc shell increased locomotor activity (P<0.05 which was blocked by SCH23390 (0.25μg/μl (P<0.01. Furthermore, the subthreshold dose infusion of SCH23390 (0.25μg/μl into the left NAc shell reduced the effect of intra- prelimbic NMDA on locomotor activity (P<0.01. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1μg/μl potentiated the middle dose (P<0.05, whereas decreased the higher dose of intra-left prelimbic NMDA response (P<0.05 on locomotor activity. Conclusion: The results suggested a modulatory effect of the NAc shell dopaminergic system on increased locomotor activity by activating glutamate system in prelimbic.

  4. Physiologic activities of the contact activation system.

    Science.gov (United States)

    Schmaier, Alvin H

    2014-05-01

    The plasma contact activation (CAS) and kallikrein/kinin (KKS) systems consist of 4 proteins: factor XII, prekallikrein, high molecular weight kininogen, and the bradykinin B2 receptor. Murine genetic deletion of factor XII (F12(-/-)), prekallikrein (Klkb1(-/-)), high molecular weight kininogen (Kgn1(-/-)) and the bradykinin B2 receptor (Bdkrb2(-/-)) yield animals protected from thrombosis. With possible exception of F12(-/-) and Kgn1(-/-) mice, the mechanism(s) for thrombosis protection is not reduced contact activation. Bdkrb2(-/-) mice are best characterized and they are protected from thrombosis through over expression of components of the renin angiotensin system (RAS) leading to elevated prostacyclin with vascular and platelet inhibition. Alternatively, prolylcarboxypeptidase, a PK activator and degrader of angiotensin II, when deficient in the mouse leads to a prothrombotic state. Its mechanism for increased thrombosis also is mediated in part by components of the RAS. These observations suggest that thrombosis in mice of the CAS and KKS are mediated in part through the RAS and independent of reduced contact activation. PMID:24759141

  5. Dopaminergic and beta-adrenergic effects on gastric antral motility

    DEFF Research Database (Denmark)

    Bech, K; Hovendal, C P; Gottrup, F;

    1984-01-01

    bethanechol or pentagastrin inducing motor activity patterns as in the phase III of the MMC and the digestive state respectively. The stimulated antral motility was dose-dependently inhibited by dopamine. The effect was significantly blocked by specifically acting dopaminergic blockers, while alpha- and beta......-adrenergic blockers were without any significant effects. Dose-response experiments with bethanechol and dopamine showed inhibition of a non-competitive type. Isoprenaline was used alone and in conjunction with selective blockade of beta 1- and beta 2-receptors during infusion of bethanechol which induces a pattern...... similar to phase III in the migrating myoelectric complex. The stimulated antral motility was dose-dependently inhibited by isoprenaline. The effect could be significantly blocked by propranolol (beta 1 + beta 2-adrenoceptor blocker) and by using in conjunction the beta 1-adrenoceptor blocker practolol...

  6. The ascidian prophenoloxidase activating system

    Directory of Open Access Journals (Sweden)

    M Cammarata

    2009-03-01

    Full Text Available Phenoloxidases/tyrosinases initiate melanin synthesis in almost all organisms, and are involved in different biological activities such as the colour change of human hair and the browning or blackening of fruit skin etc. In many invertebrates, defence reactions are linked to phenoloxidase activity and/or melanization. Contacts with foreign molecules are able to trigger the prophenoloxidase (proPO system that requires serine protease cleavage for activating the zymogen to phenoloxidase (PO. It is generally accepted that the proPO system is fully expressed in arthropods, and, recently, progress in the regulation of crustacean and insect proPO activation steps have been achieved. After cells were stimulated by components of pathogen associated molecular pattern (PAMP, proPO activation takes place via zimogenic serine proteinase in turn activated by PAMPs followed by cascade, spatial and temporal control.The proPO activating system plays a defensive role in arthropods, molluscs, annelids, ascidians and the cephalochordate Branchiostoma belcheri.In the present paper, we report on ascidian proPO system and related molecules, with particular focus on the biochemical, cellular and molecular aspects of the Ciona intestinalis, proPO system of circulating hemocytes from naïve ascidians as well as of body wall following LPS inflammatory challenge.

  7. Automated activation-analysis system

    International Nuclear Information System (INIS)

    An automated delayed neutron counting and instrumental neutron activation analysis system has been developed at Los Alamos National Laboratory's Omega West Reactor (OWR) to analyze samples for uranium and 31 additional elements with a maximum throughput of 400 samples per day. The system and its mode of operation for a large reconnaissance survey are described

  8. Information system development activities and inquiring systems

    DEFF Research Database (Denmark)

    Carugati, Andrea

    2008-01-01

    This article presents a framework that maps information system development (ISD) activities on systems for the creation of knowledge. This work addresses the relevant and persisting problem of improving the chances of ISD success. The article builds upon previous research on knowledge aspects...... of ISD, abandoning the idea of a monolithic approach to knowledge and presenting a pluralistic approach based on the idea that different inquiring systems can support micro-level ISD activities. The article is divided into two parts. The first part presents the theoretical development of the framework...... based on ISD literature and on Churchman's (1971) inquiring systems. The second part presents the use of the framework in an ISD project. The case is used to show the applicability of the framework and to highlight the advantages of this approach. The main theoretical implication is that the framework...

  9. The Shh coreceptor Cdo is required for differentiation of midbrain dopaminergic neurons.

    Science.gov (United States)

    Kwon, Yu-Rim; Jeong, Myong-Ho; Leem, Young-Eun; Lee, Sang-Jin; Kim, Hyun-Jin; Bae, Gyu-Un; Kang, Jong-Sun

    2014-09-01

    Sonic hedgehog (Shh) signaling is required for numerous developmental processes including specification of ventral cell types in the central nervous system such as midbrain dopaminergic (DA) neurons. The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube. In this study, we investigated the role of Cdo in midbrain DA neurogenesis. Cdo and Shh signaling components are induced during neurogenesis of embryonic stem (ES) cells. Cdo(-/-) ES cells show reduced neuronal differentiation accompanied by increased cell death upon neuronal induction. In addition, Cdo(-/-) ES cells form fewer tyrosine hydroxylase (TH) and microtubule associated protein 2 (MAP2)-positive DA neurons correlating with the decreased expression of key regulators of DA neurogenesis, such as Shh, Neurogenin2, Mash1, Foxa2, Lmx1a, Nurr1 and Pitx3, relative to the Cdo(+/+) ES cells. Consistently, the Cdo(-/-) embryonic midbrain displays a reduction in expression of TH and Nurr1. Furthermore, activation of Shh signaling by treatment with Purmorphamine (Pur) restores the DA neurogenesis of Cdo(-/-) ES cells, suggesting that Cdo is required for the full Shh signaling activation to induce efficient DA neurogenesis.

  10. Fenpropathrin, a Widely Used Pesticide, Causes Dopaminergic Degeneration.

    Science.gov (United States)

    Xiong, Jing; Zhang, Xiaowei; Huang, Jinsha; Chen, Chunnuan; Chen, Zhenzhen; Liu, Ling; Zhang, Guoxin; Yang, Jiaolong; Zhang, Zhentao; Zhang, Zhaohui; Lin, Zhicheng; Xiong, Nian; Wang, Tao

    2016-03-01

    Fenpropathrin is one of the widely used pyrethroids in agriculture and household and also reported to have neurotoxic effects in rodent models. In our Parkinson's disease (PD) clinic, there was a unique patient with a history of daily exposure to fenpropathrin for 6 months prior to developing Parkinsonian symptoms progressively. Since whether fenpropathrin is related to any dopaminergic degeneration was unknown, we aimed in this study to evaluate the neurotoxic effects of fenpropathrin on the dopaminergic system and associated mechanisms in vitro and in vivo. In cultured SH-SY5Y cells, fenpropathrin caused cell death, reactive oxygen species generation, Lewy body-associated proteins aggregation, and Lewy body-like intracytoplasmic inclusions formation. In rodent animals, two different injections of fenpropathrin were used for administrations, intraperitoneal (i.p), or stereotaxical (ST). The rats exhibited lower number of pokes 60 days after first i.p injection, while the rats in ST group showed a significant upregulation of apomorphine-evoked rotations 60 days after first injection. Decreased tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) immunoreactivity, while increased dopamine transporter (DAT) immunoreactivity were observed in rats of either i.p or ST group 60 days after the last exposure to fenpropathrin. However, the number of TH-positive cells in the substantia nigra was more reduced 120 days after the first i.p injection than those of 60 days. Our data demonstrated that exposure to fenpropathrin could mimic the pathologic and pathogenetic features of PD especially in late onset cases. These results imply fenpropathrin as a DA neurotoxin and a possible environmental risk factor for PD. PMID:25575680

  11. MNC Headquarters as Activity Systems

    DEFF Research Database (Denmark)

    Nell, Phillip C.; Møller Larsen, Marcus

    2012-01-01

    of propositions that links headquarters unbundling and relocation to complexity and rising coordination costs. Moreover, we argue that the coordination costs are often neglected in the headquarters reconfiguration process. In sum, we provide a novel perspective on modern MNC headquarters configurations, derive......Recent literature has questioned why multinational corporations (MNC) relocate their headquarters activities overseas. In this paper, we investigate the consequences of this phenomenon. To do this, we conceptualize the MNC headquarters activities as an interdependent system, and develop a set...... consequences for MNC research, and develop a model that aims at explaining the stability of such systems....

  12. MNC Headquarters as Activity Systems

    DEFF Research Database (Denmark)

    Nell, Phillip C.; Larsen, Marcus M.

    of propositions that links headquarters unbundling and relocation to complexity and rising coordination costs. Moreover, we argue that the coordination costs are often neglected in the headquarters reconfiguration process. In sum, we provide a novel perspective on modern MNC headquarters configurations, derive......Recent literature has questioned why multinational corporations (MNC) relocate their headquarters activities overseas. In this paper, we investigate the consequences of this phenomenon. To do this, we conceptualize the MNC headquarters activities as an interdependent system, and develop a set...... consequences for MNC research, and develop a model that aims at explaining the stability of such systems....

  13. Molecular manipulation targeting regulation of dopaminergic differentiation and proliferation of neural stem cells or pluripotent stem cells.

    Science.gov (United States)

    Ding, Yin-Xiu; Wei, Li-Chun; Wang, Ya-Zhou; Cao, Rong; Wang, Xi; Chen, Liang-Wei

    2011-06-01

    Parkinson's disease (PD) is a severe deliberating neurological disease caused by progressive degenerative death of dopaminergic neurons in the substantia nigra of midbrain. While cell replacement strategy by transplantation of neural stem cells and inducement of dopaminergic neurons is recommended for the treatment of PD, understanding the differentiation mechanism and controlled proliferation of grafted stem cells remain major concerns in their clinical application. Here we review recent studies on molecular signaling pathways in regulation of dopaminergic differentiation and proliferation of stem cells, particularly Wnt/beta-catenin signaling in stimulating formation of the dopaminergic phenotype, Notch signaling in inhibiting stem cell differentiation, and Sonic hedgehog functioning in neural stem cell proliferation and neuronal cell production. Activation of oncogenes involved in uncontrolled proliferation or tumorigenicity of stem cells is also discussed. It is proposed that a selective molecular manipulation targeting strategy will greatly benefit cell replacement therapy for PD by effectively promoting dopaminergic neuronal cell generation and reducing risk of tumorigenicity of in vivo stem cell applications.

  14. Multiple value signals in dopaminergic midbrain and their role in avoidance contexts.

    Science.gov (United States)

    Rigoli, Francesco; Chew, Benjamin; Dayan, Peter; Dolan, Raymond J

    2016-07-15

    The role of dopaminergic brain regions in avoidance behaviour is unclear. Active avoidance requires motivation, and the latter is linked to increased activity in dopaminergic regions. However, avoidance is also often tethered to the prospect of punishment, a state typically characterized by below baseline levels of dopaminergic function. Avoidance has been considered from the perspective of two-factor theories where the prospect of safety is considered to act as a surrogate for reward, leading to dopamine release and enhanced motivational drive. Using fMRI we investigated predictions from two-factor theory by separating the neural representation of a conventional net expected value, which is negative in the case of avoidance, from an adjusted expected value which factors in a possibility of punishment and is larger for both big rewards and big (predictably avoidable) punishments. We show that neural responses in ventral striatum and ventral tegmental area/substantial nigra (VTA/SN) covaried with net expected value. Activity in VTA/SN also covaried with an adjusted expected value, as did activity in anterior insula. Consistent with two-factor theory models, the findings indicate that VTA/SN and insula process an adjusted expected value during avoidance behaviour.

  15. Multiple value signals in dopaminergic midbrain and their role in avoidance contexts.

    Science.gov (United States)

    Rigoli, Francesco; Chew, Benjamin; Dayan, Peter; Dolan, Raymond J

    2016-07-15

    The role of dopaminergic brain regions in avoidance behaviour is unclear. Active avoidance requires motivation, and the latter is linked to increased activity in dopaminergic regions. However, avoidance is also often tethered to the prospect of punishment, a state typically characterized by below baseline levels of dopaminergic function. Avoidance has been considered from the perspective of two-factor theories where the prospect of safety is considered to act as a surrogate for reward, leading to dopamine release and enhanced motivational drive. Using fMRI we investigated predictions from two-factor theory by separating the neural representation of a conventional net expected value, which is negative in the case of avoidance, from an adjusted expected value which factors in a possibility of punishment and is larger for both big rewards and big (predictably avoidable) punishments. We show that neural responses in ventral striatum and ventral tegmental area/substantial nigra (VTA/SN) covaried with net expected value. Activity in VTA/SN also covaried with an adjusted expected value, as did activity in anterior insula. Consistent with two-factor theory models, the findings indicate that VTA/SN and insula process an adjusted expected value during avoidance behaviour. PMID:27132047

  16. The h-current in periglomerular dopaminergic neurons of the mouse olfactory bulb.

    Directory of Open Access Journals (Sweden)

    Angela Pignatelli

    Full Text Available The properties of the hyperpolarization-activated cation current (I(h were investigated in rat periglomerular dopaminergic neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. At 37 °C and minimizing the disturbance of the intracellular milieu with perforated patches, this current shows a midpoint of activation around -82.7 mV, with a significant level of opening already at rest, thereby giving a substantial contribution to the resting potential, and ultimately playing a relevant function in the control of the cell excitability. The blockage of I(h has a profound influence on the spontaneous firing of these neurons, which result as strongly depressed. However the effect is not due to a direct role of the current in the pacemaker process, but to the I(h influence on the resting membrane potential. I(h kinetics is sensitive to the intracellular levels of cAMP, whose increase promotes a shift of the activation curve towards more positive potentials. The direct application of DA and 5-HT neurotransmitters, physiologically released onto bulbar dopaminergic neurons and known to act on metabotropic receptors coupled to the cAMP pathway, do not modifythe I(h amplitude. On the contrary, noradrenaline almost halves the I(h amplitude. Our data indicate that the HCN channels do not participate directly to the pacemaker activity of periglomerular dopaminergic neurons, but influence their resting membrane potential by controlling the excitability profile of these cells, and possibly affecting the processing of sensory information taking place at the entry of the bulbar circuitry.

  17. Histamine modulates nitric oxide release by microglia and dopaminergic neuronal survival

    OpenAIRE

    Pires, Joel Pereira

    2012-01-01

    Microglia cells, the resident immune cells in the brain, play a critical role in the development and progression of several neurodegenerative diseases. Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons (DA) in the substantia nigra (SN), striatal dopamine depletion and motor impairments. Accumulating clinical and experimental evidences suggest that neuroinflammation plays a critical role in the pathogenesis of PD through the activ...

  18. Increased dopamine D1 receptor binding in the human mesocortical system following central cholinergic activation

    International Nuclear Information System (INIS)

    Full text: The interaction between the cholinergic and dopaminergic system has been implicated in many pathological processes including, Alzheimer's disease, schizophrenia and drug addiction. Little is known about the control of dopamine (DA) release following central cholinergic activation in humans, but experimental studies suggest that endogenously released Acetylcholine (ACh) achieved by the administration of cholinesterase inhibitors, can increase dopamine efflux in different regions of the brain. This leads to the activation of different types of post-synaptic dopaminergic receptors which belong to the family of G-protein coupled receptors (GPCRs). A common paradigm of the GPCRs desensitization is that agonist-induced receptor signaling is rapidly attenuated by receptor internalisation. Several experiments have shown that the activation of Dl receptors in acute conditions leads, within minutes, to translocation of the receptor from the surface of the neurons to the endosomal compartment in the cytoplasm and increased receptor turnover. To assess changes in Dl receptor density following an intravenous infusion of the selective cholinesterase inhibitor physostigmine salicylate (PHY), we studied eleven normal subjects (10 male and 1 female, mean age 36.1 and 61617; 9.9) using [11C]-SCH23390 and PET The binding potential (BP) for SCH23390 was significantly (p0.05). There was no statistically significant difference between baseline and physostigmine Kl ratio (p>0.05) suggesting that BP changes observed were not secondary to regional blood flow changes or to an order effect of the scans. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  19. Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens.

    Science.gov (United States)

    Tobiansky, Daniel J; Will, Ryan G; Lominac, Kevin D; Turner, Jonathan M; Hattori, Tomoko; Krishnan, Krittika; Martz, Julia R; Nutsch, Victoria L; Dominguez, Juan M

    2016-06-01

    The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine-induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system. PMID:26647972

  20. Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

    Directory of Open Access Journals (Sweden)

    Yi Pang

    2015-04-01

    Full Text Available Our previous study showed that a single lipopolysaccharide (LPS treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β levels, as well as reduced tyrosine hydroxylase (TH expression in the substantia nigra (SN of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg with or without IL-1ra (0.1 mg/kg, or sterile saline was injected intracerebrally into postnatal day 5 (P5 Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure.

  1. Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats.

    Science.gov (United States)

    Pang, Yi; Tien, Lu-Tai; Zhu, Hobart; Shen, Juying; Wright, Camilla F; Jones, Tembra K; Mamoon, Samir A; Bhatt, Abhay J; Cai, Zhengwei; Fan, Lir-Wan

    2015-01-01

    Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra) protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg) with or without IL-1ra (0.1 mg/kg), or sterile saline was injected intracerebrally into postnatal day 5 (P5) Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure. PMID:25898410

  2. Active Image Authentication System (AIAS

    Directory of Open Access Journals (Sweden)

    S. B. Nikam

    2013-09-01

    Full Text Available Today’s networking age provides greater importance to the authentication mechanism for security. Authentication is the process of identification of user or client respect to service parameters. These service parameters consist of unique combination of password associated with username or userid. Graphical based authentication mechanism had provided strong alternative for knowledge based, token based {&} biometric authentication mechanism. In this paper we are going to propose new graphical based authentication mechanism. This Active Image Authentication System (AIAS provides strong solution on guessing attack using random positioning of Active Points (AP with respect to time domain

  3. Neural ablation of the PARK10 candidate Plpp3 leads to dopaminergic transmission deficits without neurodegeneration

    OpenAIRE

    Sandra Gómez-López; Ana Valeria Martínez-Silva; Teresa Montiel; Daniel Osorio-Gómez; Federico Bermúdez-Rattoni; Lourdes Massieu; Diana Escalante-Alcalde

    2016-01-01

    Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder, characterised by the progressive loss of midbrain dopaminergic neurons and a variety of motor symptoms. The gene coding for the phospholipid phosphatase 3, PLPP3 (formerly PPAP2B or LPP3), maps within the PARK10 locus, a region that has been linked with increased risk to late-onset PD. PLPP3 modulates the levels of a range of bioactive lipids controlling fundamental cellular processes within the central nervous system. H...

  4. Inverse association between dopaminergic neurotransmission and Iowa Gambling Task performance in pathological gamblers and healthy controls

    DEFF Research Database (Denmark)

    Linnet, Jakob; Møller, Arne; Peterson, Ericka;

    2010-01-01

    The dopamine system is believed to affect gambling behavior in pathological gambling. Particularly, dopamine release in the ventral striatum appears to affect decision-making in the disorder. This study investigated dopamine release in the ventral striatum in relation to gambling performance...... and maladaptive decision-making. These findings may contribute to a better understanding of dopaminergic dysfunctions in pathological gambling and substance related addictions....

  5. The Role of Spinal Dopaminergic Transmission in the Analgesic Effect of Nefopam on Rat Inflammatory Pain

    OpenAIRE

    Kim, Do Yun; Chae, Joo Wung; Lim, Chang Hun; Heo, Bong Ha; Park, Keun Suk; Lee, Hyung Gon; Choi, Jeong Il; Yoon, Myung Ha; Kim, Woong Mo

    2016-01-01

    Background Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally. Methods The effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdi...

  6. Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: a SPECT study using [123I] epidepride and [123I] beta-CIT.

    Science.gov (United States)

    Naumann, M; Pirker, W; Reiners, K; Lange, K W; Becker, G; Brücke, T

    1998-03-01

    There is increasing evidence that a dysfunction of the dopaminergic system may be involved in the pathogenesis of idiopathic dystonia. To visualize possible alterations of the pre- and postsynaptic side of striatal dopaminergic synapses, SPECT studies using the radiotracers [123I] epidepride and [123I] beta-CIT were performed in 10 patients with idiopathic cervical dystonia. Eleven age- and sex-matched subjects served as controls. [123I] Epidepride is a new highly affine marker of D2 receptors, and [123I] beta-CIT binds to dopamine transporters on dopaminergic nerve endings. [123I] Epidepride binding was significantly reduced in both striata of dystonia patients compared with controls (p < 0.05). In contrast, striatal [123I beta-CIT uptake did not differ from controls. We conclude that dopaminergic dysfunction in idiopathic focal dystonia mainly involves postsynaptic mechanisms and suggest a disturbance of the indirect pathway of the motor circuit resulting in a disinhibited thalamocortical stimulation. PMID:9539347

  7. Inducing dopaminergic differentiation of expanded rat mesencephalic neural stem cells by ascorbic acid in vitro

    Institute of Scientific and Technical Information of China (English)

    ZHENG Min; WANG Dongmei; HOU Lingling; LI Haimin; XIE Chao; JIAO Wencang; BAI Cixian; WANG Yaping; PEI Xuetao

    2004-01-01

    Ascorbic acid (AA) induced differentiation of neural stem cells (NSCs) into dopaminergic (DAergic) neurons is reported.NSCs derived from rat mesencephalon were maintained and expanded in a defined medium containing mitogens of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF).Compared with the control, ascorbic acid treatment led to more DAergic neuronal differentiation as indicated by the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT), which are specific markers of dopamine neurons.AA induction also enhanced expression of Nurr1 and Shh.PD98059, an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, could block AA-induced Nurr1, TH and DAT mRNA expression.The results might suggest a new strategy to provide enough dopaminergic cells for the therapy of Parkinson's disease (PD), and Nurr1 and ERK signaling pathway might participate in the AA-induced DAergic differentiation.

  8. In vitro study of dopaminergic central neurons radiosensitivity

    International Nuclear Information System (INIS)

    An embryonic mesencephalic neuronal culture model was used to analyze the radiosensitivity of a dopaminergic neuronal population. Several criteria have allowed to evaluate the effects of a gamma irradiation. In the order of increasing sensitivity, a reduction of the dopamine uptake, a decrease of the number of differentiated dopaminergic neurons and some modifications of the size and the degree of branching or the neurites were noted. These results are preliminary and have to be confirmed

  9. Proprioception in Parkinson's disease is acutely depressed by dopaminergic medications

    OpenAIRE

    O'Suilleabhain, P; Bullard, J; Dewey, R

    2001-01-01

    OBJECTIVES—Impaired proprioception has been previously reported in patients with Parkinson's disease. It was hypothesised that dopaminergic medications transiently depress proprioception, with amplification of adventitious movements as a result. This study tested for effects on proprioception of dopaminergic drugs, and for associations between such effects and drug induced dyskinesias.
METHODS—In 17 patients with Parkinson's disease, arm proprioception was tested in the ...

  10. Closing one's eyes to reality: evidence for a dopaminergic basis of psychoticism from spontaneous eye blink rates

    NARCIS (Netherlands)

    L.S. Colzato; H.A. Slagter; W.P.M. van den Wildenberg; B. Hommel

    2009-01-01

    We tested the idea that Psychoticism, a major personality dimension, is rooted in individual differences in dopamine functioning. To this end, we related the spontaneous eye blink rate (EBR), a marker of striatal dopaminergic activity, to scores in the Eysenck Personality Questionnaire Revised Short

  11. Endogenous Opioid-Induced Neuroplasticity of Dopaminergic Neurons in the Ventral Tegmental Area Influences Natural and Opiate Reward

    NARCIS (Netherlands)

    Pitchers, Kyle K.; Coppens, Caroline M.; Beloate, Lauren N.; Fuller, Jonathan; Van, Sandy; Frohmader, Karla S.; Laviolette, Steven R.; Lehman, Michael N.; Coolen, Lique M.

    2014-01-01

    Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance. Her

  12. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    Science.gov (United States)

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  13. Dopaminergic modulation of memory and affective processing in Parkinson depression.

    Science.gov (United States)

    Blonder, Lee X; Slevin, John T; Kryscio, Richard J; Martin, Catherine A; Andersen, Anders H; Smith, Charles D; Schmitt, Frederick A

    2013-11-30

    Depression is common in Parkinson's disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson's disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson's disease participated. Ten of these patients were depressed according to DSM IV criteria. Results revealed a statistically significant interaction between depression and medication status on three measures of verbal memory and a facial affect naming task. In all cases, depressed Parkinson's patients performed significantly more poorly while on dopaminergic medication than while off. The opposite pattern emerged for the non-depressed Parkinson's group. The administration of dopaminergic medication to depressed Parkinson patients may carry unintended risks. PMID:23838419

  14. Prostaglandin E2-Mediated Attenuation of Mesocortical Dopaminergic Pathway Is Critical for Susceptibility to Repeated Social Defeat Stress in Mice

    Science.gov (United States)

    Tanaka, Kohei; Furuyashiki, Tomoyuki; Kitaoka, Shiho; Senzai, Yuta; Imoto, Yuki; Segi-Nishida, Eri; Deguchi, Yuichi; Breyer, Richard M.; Breyer, Matthew D.; Narumiya, Shuh

    2013-01-01

    Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E2 (PGE2), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE2 level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE2-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway. PMID:22442093

  15. Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD.

    Science.gov (United States)

    Nuber, Silke; Tadros, Daniel; Fields, Jerel; Overk, Cassia Rose; Ettle, Benjamin; Kosberg, Kori; Mante, Michael; Rockenstein, Edward; Trejo, Margarita; Masliah, Eliezer

    2014-04-01

    The olfactory bulb (OB) is one of the first brain regions in Parkinson's disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD. PMID:24509835

  16. How to make a midbrain dopaminergic neuron.

    Science.gov (United States)

    Arenas, Ernest; Denham, Mark; Villaescusa, J Carlos

    2015-06-01

    Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

  17. Efficient Conversion of Spermatogonial Stem Cells to Phenotypic and Functional Dopaminergic Neurons via the PI3K/Akt and P21/Smurf2/Nolz1 Pathway.

    Science.gov (United States)

    Yang, Hao; Liu, Yang; Hai, Yanan; Guo, Ying; Yang, Shi; Li, Zheng; Gao, Wei-Qiang; He, Zuping

    2015-12-01

    Parkinson's disease (PD) is a common neurodegenerative syndrome characterized by loss of midbrain dopaminergic (DA) neurons. Generation of functional dopaminergic (DA) neurons is of unusual significance for treating Parkinson's disease (PD). However, direct conversion of spermatogonial stem cells (SSCs) to functional DA neurons without being reprogrammed to a pluripotent status has not been achieved. Here, we report an efficient approach to obtain morphological, phenotypic, and functional DA neurons from SSCs using a specific combination of olfactory ensheathing cell-conditioned medium (OECCM) and several defined growth factors (DGF). By following the current protocol, direct conversion of SSCs (both SSC line and primary SSCs) to neural cells and DA neurons was demonstrated by expression of numerous phenotypic genes and proteins for neural cells, as well as cell morphological features. More significantly, SSCs-derived DA neurons acquired neuronal functional properties such as synapse formation, electrophysiology activity, and dopamine secretion. Furthermore, PI3K/Akt pathway and p21/Nolz1 cascades were activated whereas Smurf2 was inactivated, leading to cell cycle exit during the conversion of SSCs into DA neurons. Collectively, this study could provide sufficient neural cells from SSCs for applications in the treatment of PD and offers novel insights into mechanisms underlying neural system development from the line of germ cells.

  18. Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Ana Sofia Correia

    2007-12-01

    Full Text Available In the central nervous system, fibroblast growth factor (FGF-20 has been reported to act preferentially on midbrain dopaminergic neurons. It also promotes the dopaminergic differentiation of stem cells. We have analyzed the effects of FGF-20 on human embryonic stem cells (hESCs differentiation into dopaminergic neurons. We induced neuronal differentiation of hESCs by co-culturing those with PA6 mouse stromal cells for 3 weeks. When we supplemented the culture medium with FGF-20, the number of tyrosine hydroxylase (TH- expressing neurons increased fivefold, from 3% to 15% of the hESC-derived cells. The cultured cells also expressed other midbrain dopaminergic markers (PITX3, En1, Msx1, and Aldh1, suggesting that some had differentiated into midbrain dopaminergic neurons. We observed no effect of FGF-20 on the size of the soma area or neurite length of the TH-immunopositive neurons. Regardless of whether FGF-20 had been added or not, 17% of the hESC-derived cells expressed the pan-neuronal marker b-III-Tubulin. The proportion of proliferating cells positive for Ki-67 was also not affected by FGF-20 (7% of the hESC-derived cells. By contrast, after 3 weeks in culture FGF-20 significantly reduced the proportion of cells undergoing cell death, as revealed by immunoreactivity for cleaved caspase-8, Bcl-2 associated X protein (BAX and cleaved caspase-3 (2.5% to 1.2% of cleaved caspase-3-positive cells out of the hESC-derived cells. Taken together, our results indicate that FGF-20 specifically increases the yield of dopaminergic neurons from hESCs grown on PA6 feeder cells and at least part of this effect is due to a reduction in cell death.

  19. Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Liviu Aron

    Full Text Available The mechanisms underlying the selective death of substantia nigra (SN neurons in Parkinson disease (PD remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.

  20. Dopaminergic drugs in congestive heart failure: hemodynamic and neuroendocrine responses to ibopamine, dopamine, and dihydroergotoxine.

    Science.gov (United States)

    Metra, M; Missale, C; Spano, P F; Cas, L D

    1995-05-01

    Ibopamine has hemodynamic and neurohumoral effects potentially useful for the treatment of congestive heart failure (CHF), but its mechanism of action is not completely clear. To evaluate the role of dopaminergic receptor stimulation in the hemodynamic and neurohumoral activity of ibopamine, we compared the effects of ibopamine, 100 mg orally (p.o.) with those of the dopamine 2, 4, and 6 micrograms/kg/min intravenously (i.v.) and of the DA2 agonist dihydroergotoxine 6 micrograms/kg i.v. in 13 patients with chronic CHF [left ventricular ejection fraction (LVEF) index (CI) with a 23 and 25% increase in stroke volume (SV) and stroke work indexes (SWI), respectively, and an 18% reduction in systemic vascular resistance (SVR). Similar changes were observed after DA infused at the doses of 2 and 4 micrograms/kg/min, whereas with the dose of 6 micrograms/kg/min heart rate (HR) increased by 23% and SV index (SVI) did not change further. Dihydroergotoxine administration induced only a significant 9% decrease in mean arterial pressure (MAP), with a 13% reduction in SVR.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7630152

  1. Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons

    Directory of Open Access Journals (Sweden)

    Ada eLedonne

    2011-07-01

    Full Text Available Trace amines (TAs are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as ‘false’ neurotransmitters. The discovery in 2001 of a new family of G protein-coupled receptors (GPCRs, namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA1 and trace amine receptor 2 (TA2, were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson’s disease, all of which are characterised by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA1 receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a inhibition of firing due to increased release of dopamine; (b reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to dysinhibition; and (c a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA1 receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004. Further research is needed to address this point, and to further

  2. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model.

    Science.gov (United States)

    Achour, Imène; Arel-Dubeau, Anne-Marie; Renaud, Justine; Legrand, Manon; Attard, Everaldo; Germain, Marc; Martinoli, Maria-Grazia

    2016-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE's ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model. PMID:27517912

  3. WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity

    Directory of Open Access Journals (Sweden)

    Antenor-Dorsey Jo Ann V

    2012-02-01

    Full Text Available Abstract Background The WldS mouse mutant ("Wallerian degeneration-slow" delays axonal degeneration in a variety of disorders including in vivo models of Parkinson's disease. The mechanisms underlying WldS -mediated axonal protection are unclear, although many studies have attributed WldS neuroprotection to the NAD+-synthesizing Nmnat1 portion of the fusion protein. Here, we used dissociated dopaminergic cultures to test the hypothesis that catalytically active Nmnat1 protects dopaminergic neurons from toxin-mediated axonal injury. Results Using mutant mice and lentiviral transduction of dopaminergic neurons, the present findings demonstrate that WldS but not Nmnat1, Nmnat3, or cytoplasmically-targeted Nmnat1 protects dopamine axons from the parkinsonian mimetic N-methyl-4-phenylpyridinium (MPP+. Moreover, NAD+ synthesis is not required since enzymatically-inactive WldS still protects. In addition, NAD+ by itself is axonally protective and together with WldS is additive in the MPP+ model. Conclusions Our data suggest that NAD+ and WldS act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP+ is thought to impair mitochondrial function, these results suggest that WldS might be involved in preserving mitochondrial health or maintaining cellular metabolism.

  4. Effects of cysteamine on MPTP-induced dopaminergic neurodegeneration in mice.

    Science.gov (United States)

    Sun, Linjuan; Xu, Shengli; Zhou, Ming; Wang, Chaodong; Wu, Yanchuan; Chan, Piu

    2010-06-01

    Cysteamine is a degradation product of the amino acid cysteine and a reduced form of cystamine. Cysteamine exhibits strong antioxidant activity and has been implicated in the treatment of neurodegenerative disorders such as Huntington's disease. In the present study, we investigated whether cysteamine confers protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced toxicity in the dopaminergic neurons in a mouse model for Parkinson's disease (PD). The loss of dopaminergic (DA) neurons and reduction in striatal DA concentrations induced by MPTP was ameliorated to a significant extent by pretreatment with low (20mg/kg/day), but not high (75mg/kg/day), dose of cysteamine 4days prior to and subsequently along with the MPTP treatment. Consistently, the increased production of pro-oxidants, such as reactive oxygen species (ROS) and malondialdehyde (MDA), was significantly suppressed by low dose of cysteamine. Conversely, the reduction in GSH level caused by MPTP exposure was significantly attenuated by pretreatment of cysteamine. In addition, the inhibited secretion of the brain-derived neurotrophic factor (BDNF) by neurons derived from substantia nigra pars compact (SNpc) of MPTP-treated mice was significantly restored by cysteamine administration. Our results demonstrate that cysteamine at low dose confers potent neuroprotection against MPTP-induced toxicity of dopaminergic neurons, and may become a potential therapeutic strategy for PD. PMID:20380823

  5. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

    Directory of Open Access Journals (Sweden)

    Imène Achour

    2016-08-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE, the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA. We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model.

  6. Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

    Science.gov (United States)

    Achour, Imène; Arel-Dubeau, Anne-Marie; Renaud, Justine; Legrand, Manon; Attard, Everaldo; Germain, Marc; Martinoli, Maria-Grazia

    2016-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model. PMID:27517912

  7. Complementary neural correlates of motivation in dopaminergic and noradrenergic neurons of monkeys.

    Directory of Open Access Journals (Sweden)

    Sebastien eBouret

    2012-07-01

    Full Text Available Rewards have many influences on learning, decision-making and performance. All seem to rely on complementary actions of two closely related catecholaminergic neuromodulators, dopamine and noradrenaline. We compared single unit activity of dopaminergic neurons of the substantia nigra pars compacta and noradrenergic neurons of the locus coeruleus in monkeys performing a reward schedule task. Their motivation, indexed using operant performance, increased as they progressed through schedules ending in reward delivery. The responses of dopaminergic and noradrenergic neurons around the time of major task events, visual cues predicting trial outcome and operant action to complete a trial, were similar, in that they occurred at the same time. They were also similar in that they both responded most strongly to the first cues in schedules, which are the most informative cues. The neuronal responses around the time of the monkeys’ actions were different, in that the response intensity profiles changed in opposite directions. Dopaminergic responses were stronger around predictably rewarded correct actions whereas noradrenergic responses were greater around predictably unrewarded correct actions. The complementary response profiles related to the monkeys operant actions suggest that dopamine neurons might relate to the value of the current action whereas the noradrenergic neurons relate to the psychological cost of that action.

  8. Effects of selective dopaminergic compounds on a delay-discounting task.

    Science.gov (United States)

    Koffarnus, Mikhail N; Newman, Amy H; Grundt, Peter; Rice, Kenner C; Woods, James H

    2011-08-01

    Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animal subjects. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animal subjects using delay-discounting tasks. Here, delay-discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague-Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist, SCH 23390 (0.01 mg/kg), and the D4 partial agonist, ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders. PMID:21694584

  9. Neural ablation of the PARK10 candidate Plpp3 leads to dopaminergic transmission deficits without neurodegeneration.

    Science.gov (United States)

    Gómez-López, Sandra; Martínez-Silva, Ana Valeria; Montiel, Teresa; Osorio-Gómez, Daniel; Bermúdez-Rattoni, Federico; Massieu, Lourdes; Escalante-Alcalde, Diana

    2016-01-01

    Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, characterised by the progressive loss of midbrain dopaminergic neurons and a variety of motor symptoms. The gene coding for the phospholipid phosphatase 3, PLPP3 (formerly PPAP2B or LPP3), maps within the PARK10 locus, a region that has been linked with increased risk to late-onset PD. PLPP3 modulates the levels of a range of bioactive lipids controlling fundamental cellular processes within the central nervous system. Here we show that PLPP3 is enriched in astroglial cells of the adult murine ventral midbrain. Conditional inactivation of Plpp3 using a Nestin::Cre driver results in reduced mesencephalic levels of sphingosine-1-phosphate receptor 1 (S1P1), a well-known mediator of pro-survival responses. Yet, adult PLPP3-deficient mice exhibited no alterations in the number of dopaminergic neurons or in the basal levels of striatal extracellular dopamine (DA). Potassium-evoked DA overflow in the striatum, however, was significantly decreased in mutant mice. Locomotor evaluation revealed that, although PLPP3-deficient mice exhibit motor impairment, this is not progressive or responsive to acute L-DOPA therapy. These findings suggest that disruption of Plpp3 during early neural development leads to dopaminergic transmission deficits in the absence of nigrostriatal degeneration, and without causing an age-related locomotor decline consistent with PD. PMID:27063549

  10. Neural ablation of the PARK10 candidate Plpp3 leads to dopaminergic transmission deficits without neurodegeneration.

    Science.gov (United States)

    Gómez-López, Sandra; Martínez-Silva, Ana Valeria; Montiel, Teresa; Osorio-Gómez, Daniel; Bermúdez-Rattoni, Federico; Massieu, Lourdes; Escalante-Alcalde, Diana

    2016-04-11

    Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, characterised by the progressive loss of midbrain dopaminergic neurons and a variety of motor symptoms. The gene coding for the phospholipid phosphatase 3, PLPP3 (formerly PPAP2B or LPP3), maps within the PARK10 locus, a region that has been linked with increased risk to late-onset PD. PLPP3 modulates the levels of a range of bioactive lipids controlling fundamental cellular processes within the central nervous system. Here we show that PLPP3 is enriched in astroglial cells of the adult murine ventral midbrain. Conditional inactivation of Plpp3 using a Nestin::Cre driver results in reduced mesencephalic levels of sphingosine-1-phosphate receptor 1 (S1P1), a well-known mediator of pro-survival responses. Yet, adult PLPP3-deficient mice exhibited no alterations in the number of dopaminergic neurons or in the basal levels of striatal extracellular dopamine (DA). Potassium-evoked DA overflow in the striatum, however, was significantly decreased in mutant mice. Locomotor evaluation revealed that, although PLPP3-deficient mice exhibit motor impairment, this is not progressive or responsive to acute L-DOPA therapy. These findings suggest that disruption of Plpp3 during early neural development leads to dopaminergic transmission deficits in the absence of nigrostriatal degeneration, and without causing an age-related locomotor decline consistent with PD.

  11. Dopaminergic control of motivation and reinforcement learning: a closed-circuit account for reward-oriented behavior.

    Science.gov (United States)

    Morita, Kenji; Morishima, Mieko; Sakai, Katsuyuki; Kawaguchi, Yasuo

    2013-05-15

    Humans and animals take actions quickly when they expect that the actions lead to reward, reflecting their motivation. Injection of dopamine receptor antagonists into the striatum has been shown to slow such reward-seeking behavior, suggesting that dopamine is involved in the control of motivational processes. Meanwhile, neurophysiological studies have revealed that phasic response of dopamine neurons appears to represent reward prediction error, indicating that dopamine plays central roles in reinforcement learning. However, previous attempts to elucidate the mechanisms of these dopaminergic controls have not fully explained how the motivational and learning aspects are related and whether they can be understood by the way the activity of dopamine neurons itself is controlled by their upstream circuitries. To address this issue, we constructed a closed-circuit model of the corticobasal ganglia system based on recent findings regarding intracortical and corticostriatal circuit architectures. Simulations show that the model could reproduce the observed distinct motivational effects of D1- and D2-type dopamine receptor antagonists. Simultaneously, our model successfully explains the dopaminergic representation of reward prediction error as observed in behaving animals during learning tasks and could also explain distinct choice biases induced by optogenetic stimulation of the D1 and D2 receptor-expressing striatal neurons. These results indicate that the suggested roles of dopamine in motivational control and reinforcement learning can be understood in a unified manner through a notion that the indirect pathway of the basal ganglia represents the value of states/actions at a previous time point, an empirically driven key assumption of our model.

  12. Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

    Science.gov (United States)

    Ha, Joon; Kuznetsov, Alexey

    2013-01-01

    Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is

  13. Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

    Directory of Open Access Journals (Sweden)

    Joon Ha

    Full Text Available Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR activation or applied depolarization block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG, which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations

  14. Investigating the dopaminergic synapse in vivo. I. Molecular imaging studies in humans.

    Science.gov (United States)

    Nikolaus, Susanne; Antke, Christina; Kley, Konstantin; Poeppel, Thorsten D; Hautzel, Hubertus; Schmidt, Daniela; Müller, Hans-Wilhelm

    2007-01-01

    Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. Investigations of humans in both clinical and experimental settings have yielded evidence that disturbances of dopaminergic function may be associated with numerous neurological and psychiatric conditions, among which are movement disorders, schizophrenia, attention-deficit hyperactivity disorder, depression and drug abuse. This article gives an overview of those studies, which so far have been performed on dopaminergic neurotransmission in humans using in vivo imaging methods. We focus on disease-related deficiencies within the functional entity of the dopaminergic synapse. Taken together, in vivo findings yield evidence of presynaptic dysfunctions in Parkinson's disease with decreases in striatal dopamine synthesis, dopamine storage, dopamine release and dopamine transporter binding. In contrast, 'Parkinson plus' syndromes (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies) are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis, dopamine storage, dopamine release, and dopamine transporter, as well as D, and D, receptor binding. In patients with Huntington's disease, postsynaptic dysfunctions with reductions of striatal D1 and D2 receptor binding have become apparent, whereas attention-deficit/ hyperactivity disorder is mainly characterized by presynaptic deficits with increases in dopamine transporter binding. Interestingly, findings are also consistent with respect to drug abuse: cocaine, amphetamine

  15. Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate.

    Science.gov (United States)

    Harrison, Ian F; Anis, Hiba K; Dexter, David T

    2016-02-12

    Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection. PMID:26742637

  16. Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

    Directory of Open Access Journals (Sweden)

    Teuchert-Noodt Gertraud

    2008-05-01

    Full Text Available Abstract It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD. A former study from our laboratory has shown that both methylphenidate (MP and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC of early traumatized gerbils (Meriones unguiculatus. The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model. Animals received a single early dose of methamphetamine (MA; 50 mg/kg; i.p. on postnatal day (PD 14, which is known to cause multiple changes in the subsequent development of several neurotransmitter systems including the dopaminergic systems, and were then treated with oral daily applications of MP (5 mg/kg from PD30–60. Animals treated this way were either transferred to an enriched environment after weaning (on PD30 or were kept under impoverished rearing conditions. There was no effect of an enriched environment on the dopaminergic or GABAergic fiber density neither in the PFC nor in the amygdala. With regard to former studies these results underline the particular impact of MP in the treatment of ADHD.

  17. Activity System Theory Approach to Healthcare Information System

    OpenAIRE

    Bai, Guohua

    2004-01-01

    Healthcare information system is a very complex system and has to be approached from systematic perspectives. This paper presents an Activity System Theory (ATS) approach by integrating system thinking and social psychology. First part of the paper, the activity system theory is presented, especially a recursive model of human activity system is introduced. A project ‘Integrated Mobile Information System for Diabetic Healthcare (IMIS)’ is then used to demonstrate a practical application of th...

  18. Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, Pia [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark); Department of Neurosurgery, University of Bern, CH-3010 Bern (Switzerland); Gramsbergen, Jan-Bert; Zimmer, Jens [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark); Widmer, Hans R. [Department of Neurosurgery, University of Bern, CH-3010 Bern (Switzerland); Meyer, Morten, E-mail: MMeyer@health.sdu.dk [Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21, DK-5000 Odense C (Denmark)

    2011-07-15

    Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation of rat embryonic ventral mesencephalic neuroblasts cultured at high (20%) and low (3%) oxygen tension. More cells incorporated bromodeoxyuridine in cultures expanded at low as compared to high oxygen tension, and after 6 days of differentiation there were significantly more neuronal cells in low than in high oxygen cultures. Low oxygen during FGF2-mediated expansion resulted also in a significant increase in tyrosine hydroxylase-immunoreactive (TH-ir) dopaminergic neurons as compared to high oxygen tension, but no corresponding effect was observed for dopamine release into the culture medium. However, switching FGF2-expanded cultures from low to high oxygen tension during the last two days of differentiation significantly enhanced dopamine release and intracellular dopamine levels as compared to all other treatment groups. In addition, the short-term exposure to high oxygen enhanced in situ assessed TH enzyme activity, which may explain the elevated dopamine levels. Our findings demonstrate that modulation of oxygen tension is a recognizable factor for in vitro expansion and dopaminergic differentiation of rat embryonic midbrain precursor cells.

  19. Engrailed Homeoprotein Protects Mesencephalic Dopaminergic Neurons from Oxidative Stress

    Science.gov (United States)

    Rekaik, Hocine; Blaudin de Thé, François-Xavier; Fuchs, Julia; Massiani-Beaudoin, Olivia; Prochiantz, Alain; Joshi, Rajiv L.

    2016-01-01

    Summary Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress, and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed1 heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks, and protects dopaminergic neurons against apoptosis. PMID:26411690

  20. Activity is strength: More active systems are stronger glass formers

    CERN Document Server

    Nandi, Saroj Kumar

    2016-01-01

    Interplay between activity and passive transport processes in an active system may lead to complex spatio-temporal dynamics offering a rich and fascinating phenomenology compared to their passive counterparts. Understanding the properties of an active system in the dense limit is important both from biological as well as physical point of view. Here, we extend an immensely successful microscopic theory for the glassy dynamics of passive systems in their dense low-temperature limit, namely the Random First-Order Transition (RFOT) theory, for an active system generalizing and unifying the findings of recent simulations on such systems. The qualitative picture of glassy dynamics for a passive system survives when activity is introduced, however, a number interesting properties emerge. For example, activity changes the typical length scale and relaxation times, pushes the thermodynamic and dynamic glass transition points towards higher density or lower temperature and the fragility of the system changes as a func...

  1. Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

    Directory of Open Access Journals (Sweden)

    G. Neves

    2003-05-01

    Full Text Available Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg in three experimental models: 1 blockade of amphetamine (30 mg/kg, ip-induced stereotypy in rats; 2 the catalepsy test in mice, and 3 apomorphine (1 mg/kg, ip-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip and a hypothermic response (30 mg/kg, ip which was not prevented by haloperidol (0.5 mg/kg, ip. Compound 5 (30 mg/kg, ip also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip. Only compound 4 (30 mg/kg, ip significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

  2. Dopaminergic differentiation of human neural stem cells mediated by co-cultured rat striatal brain slices

    DEFF Research Database (Denmark)

    Anwar, Mohammad Raffaqat; Andreasen, Christian Maaløv; Lippert, Solvej Kølvraa;

    2008-01-01

    Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic di...

  3. The effects of long-term dopaminergic treatment on locomotor behavior in rats

    Science.gov (United States)

    Oliveira de Almeida, Welinton Alessandro; Maculano Esteves, Andrea; Leite de Almeida-Júnior, Canuto; Lee, Kil Sun; Kannebley Frank, Miriam; Oliveira Mariano, Melise; Frussa-Filho, Roberto; Tufik, Sergio; Tulio de Mello, Marco

    2014-01-01

    Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole—PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions. PMID:26483930

  4. The Detection of Novelty Relies on Dopaminergic Signaling: Evidence from Apomorphine's Impact on the Novelty N2

    OpenAIRE

    Mauricio Rangel-Gomez; Clayton Hickey; Therese van Amelsvoort; Pierre Bet; Martijn Meeter

    2013-01-01

    Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist) and measure the change in neurological indices of novelty processing. In sepa...

  5. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease

    OpenAIRE

    Smith, Patrice D.; Crocker, Stephen J.; Jackson-Lewis, Vernice; Jordan-Sciutto, Kelly L.; Hayley, Shawn; Mount, Matthew P.; O'Hare, Michael J; Callaghan, Steven; Slack, Ruth S; Przedborski, Serge; Anisman, Hymie; Park, David S.

    2003-01-01

    Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-n...

  6. Manually controlled neutron-activation system

    Science.gov (United States)

    Johns, R. A.; Carothers, G. A.

    1982-01-01

    A manually controlled neutron activation system, the Manual Reactor Activation System, was designed and built and has been operating at one of the Savannah River Plant's production reactors. With this system, samples can be irradiated for up to 24 hours and pneumatically transferred to a shielded repository for decay until their activity is low enough for them to be handled at a radiobench. The Manual Reactor Activation System was built to provide neutron activation of solid waste forms for the Alternative Waste Forms Leach Testing Program. Neutron activation of the bulk sample prior to leaching permits sensitive multielement radiometric analyses of the leachates.

  7. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    OpenAIRE

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic int...

  8. Endogenous 17ß-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    OpenAIRE

    Alessandro eTozzi; Antonio ede Iure; Michela eTantucci; Valentina eDurante; Ana eQuiroga-Varela; Carmela eGiampà; Michela eDi Mauro; Petra eMazzocchetti; Cinzia eCosta; Massimiliano eDi Filippo; Silvarosa eGrassi; Vito Enrico Pettorossi; Paolo eCalabresi

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic int...

  9. Involvement of the monoaminergic system in the antidepressant-like activity of chromium chloride in the forced swim test.

    Science.gov (United States)

    Piotrowska, A; Siwek, A; Wolak, M; Pochwat, B; Szewczyk, B; Opoka, W; Poleszak, E; Nowak, G

    2013-08-01

    Bio-metal chromium(III) is a crucial microelement for the proper functioning of living organisms. Previous preclinical and clinical studies reported its potential antidepressant properties. The aim of the present study was to examine the effect of antidepressants and noradrenergic and dopaminergic receptor antagonists on chromium chloride (CrCl₃) activity in the forced swim test (FST) in mice and rats. Imipramine (5 mg/kg), fluoxetine (5 mg/kg) and reboxetine (5 mg/kg) but not bupropion (1 mg/kg), administered jointly with CrCl₃ at a dose of 6 mg/kg, reduced the immobility time in the FST in mice. The reduction of the immobility time induced by the active dose (12 mg/kg) of CrCl₃ was completely abolished by propranolol (2 mg/kg, β-adrenoceptor antagonist), SCH 23390 (0.5 mg/kg, a dopamine D₁ receptor antagonist), and partially by prazosin (1 mg/kg, an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, an α₂-adrenoceptor antagonist) and sulpiryd (50 mg/kg, a dopamine D₂/D₃ receptor antagonist) administration. The locomotor activity was significantly reduced by CrCl₃ + reboxetine treatment, which did not influence the reboxetine enhancement of the antidepressant-like effect of CrCl₃ in the FST. Moreover, CrCl₃ at a dose of 32 mg/kg (although not at 12 mg/kg) significantly reduced the immobility and enhanced the climbing (but not swimming) time in the FST in rats, which indicates the involvement of the noradrenergic pathway in this effect. The present study indicates that the antidepressant-like activity of chromium in the FST is dependent (although to a different extent) on the noradrenergic, dopaminergic and serotonin systems.

  10. Therapeutic Options for Continuous Dopaminergic Stimulation in Parkinson's Disease

    OpenAIRE

    Sujith, O. K.; Lane, Carol

    2009-01-01

    Treatment of Parkinson's disease aims to replace dopaminergic transmission at striatal synapses. In the normal state, nigral neurons fire continuously, exposing striatal dopamine receptors to relatively constant levels of dopamine. In the disease state, periodic dosing and the short half-life of antiparkinsonian drugs leads to more intermittent stimulation. Abnormal pulsatile sti...

  11. Basal ganglia cholinergic and dopaminergic function in progressive supranuclear palsy.

    Science.gov (United States)

    Warren, Naomi M; Piggott, Margaret A; Greally, Elizabeth; Lake, Michelle; Lees, Andrew J; Burn, David J

    2007-08-15

    Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disorder. In contrast to Parkinson's disease (PD) and dementia with Lewy bodies (DLB), replacement therapy with dopaminergic and cholinergic agents in PSP has been disappointing. The neurochemical basis for this is unclear. Our objective was to measure dopaminergic and cholinergic receptors in the basal ganglia of PSP and control brains. We measured, autoradiographically, dopaminergic (dopamine transporter, 125I PE2I and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic alpha4beta2 receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) parameters in the striatum and pallidum of pathologically confirmed PSP cases (n=15) and controls (n=32). In PSP, there was a marked loss of dopamine transporter and nicotinic alpha4beta2 binding in the striatum and pallidum, consistent with loss of nigrostriatal neurones. Striatal D2 receptors were increased in the caudate and muscarinic M1 receptors were unchanged compared with controls. These results do not account for the poor response to dopaminergic and cholinergic replacement therapies in PSP, and suggest relative preservation of postsynaptic striatal projection neurones bearing D2/M1 receptors. PMID:17534953

  12. Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease.

    Science.gov (United States)

    Cherubini, Marta; Puigdellívol, Mar; Alberch, Jordi; Ginés, Silvia

    2015-10-01

    The molecular mechanisms underlying striatal vulnerability in Huntington's disease (HD) are still unknown. However, growing evidence suggest that mitochondrial dysfunction could play a major role. In searching for a potential link between striatal neurodegeneration and mitochondrial defects we focused on cyclin-dependent kinase 5 (Cdk5). Here, we demonstrate that increased mitochondrial fission in mutant huntingtin striatal cells can be a consequence of Cdk5-mediated alterations in Drp1 subcellular distribution and activity since pharmacological or genetic inhibition of Cdk5 normalizes Drp1 function ameliorating mitochondrial fragmentation. Interestingly, mitochondrial defects in mutant huntingtin striatal cells can be worsened by D1 receptor activation a process also mediated by Cdk5 as down-regulation of Cdk5 activity abrogates the increase in mitochondrial fission, the translocation of Drp1 to the mitochondria and the raise of Drp1 activity induced by dopaminergic stimulation. In sum, we have demonstrated a new role for Cdk5 in HD pathology by mediating dopaminergic neurotoxicity through modulation of Drp1-induced mitochondrial fragmentation, which underscores the relevance for pharmacologic interference of Cdk5 signaling to prevent or ameliorate striatal neurodegeneration in HD. PMID:26143143

  13. Future testing of active safety systems

    NARCIS (Netherlands)

    Hendriks, F.M.; Pelders, H.A.A.W.

    2010-01-01

    Active safety systems are increasingly becoming available in trucks and passenger vehicles. Developments in the field of active safety are shifting from increasing driver comfort towards increasing occupant safety. Furthermore, this shift is seen within active safety systems: safety functions are ad

  14. Associations between visual perception accuracy and confidence in a dopaminergic manipulation study

    Directory of Open Access Journals (Sweden)

    Christina eAndreou

    2015-04-01

    Full Text Available Delusions are defined as fixed erroneous beliefs that are based on misinterpretation of events or perception, and cannot be corrected by argumentation to the opposite. Cognitive theories of delusions regard this symptom as resulting from specific distorted thinking styles that lead to biased integration and interpretation of perceived stimuli (i.e., reasoning biases. In previous studies, we were able to show that one of these reasoning biases, overconfidence in errors, can be modulated by drugs that act on the dopamine system, a major neurotransmitter system implicated in the pathogenesis of delusions and other psychotic symptoms. Another processing domain suggested to involve the dopamine system and to be abnormal in psychotic disorders is sensory perception. The present study aimed to investigate whether (lower-order sensory perception and (higher-order overconfidence in errors are similarly affected by dopaminergic modulation in healthy subjects. Thirty-four healthy individuals were assessed upon administration of L-dopa, placebo, or haloperidol within a randomized, double-blind, cross-over design. Variables of interest were hits and false alarms in an illusory perception paradigm requiring speeded detection of pictures over a noisy background, and subjective confidence ratings for correct and incorrect responses. There was a significant linear increase of false alarm rates from haloperidol to placebo to L-dopa, whereas hit rates were not affected by dopaminergic manipulation. As hypothesized, confidence in error responses was significantly higher with L-dopa compared to placebo. Moreover, confidence in erroneous responses significantly correlated with false alarm rates. These findings suggest that overconfidence in errors and aberrant sensory processing might be both interdependent and related to dopaminergic transmission abnormalities in patients with psychosis.

  15. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    Data.gov (United States)

    National Aeronautics and Space Administration — IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING ISAAC PERSING AND VINCENT NG Abstract. Active learning has been successfully applied to many natural language...

  16. Do CSF levels of t-Tau, p-Tau and β{sub 1-42} amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A {sup 123}I-FP-CIT study in the early stages of the disease

    Energy Technology Data Exchange (ETDEWEB)

    Chiaravalloti, Agostino; Fiorentini, Alessandro; Lacanfora, Annamaria [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); Stefani, Alessandro [University Tor Vergata, Department of Neurosciences, Rome (Italy); IRCCS Santa Lucia, Rome (Italy); Stanzione, Paolo [University Tor Vergata, Department of Neurosciences, Rome (Italy); Schillaci, Orazio [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); IRCCS Neuromed, Pozzilli (Italy)

    2014-11-15

    To investigate the relationships among cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and Aβ{sub 1-42} amyloid peptide and {sup 123}I-FP-CIT uptake. The study included 58 subjects (31 men and 27 women, age 67 ± 9 years) with a clinical diagnosis of Parkinson disease diagnosed according to the United Kingdom Parkinson Disease Society Brain Bank criteria. All subjects underwent a CSF assay 28 ± 3 days before {sup 123}I-FP-CIT SPECT scanning. The relationships were evaluated by means of linear regression analysis and Pearson correlation. Striatal {sup 123}I-FP-CIT was positively related to both t-Tau and p-Tau CSF values with low levels of t-Tau and p-Tau being related to a low uptake of {sup 123}I-FP-CIT. In particular, differences with higher statistical significance were found for the striatum between the contralateral side and the side mainly affected on clinical examination (P < 0.001). No significant relationships were found between Aβ{sub 1-42} amyloid peptide and {sup 123}I-FP-CIT binding. The results of our study suggest that the presynaptic dopaminergic system is more involved in Parkinson disease patients with lower t-Tau and p-Tau CSF values while values of Aβ{sub 1-42} amyloid peptide seems not to be related to nigrostriatal degeneration in our series. (orig.)

  17. NADPH Oxidase and the Degeneration of Dopaminergic Neurons in Parkinsonian Mice

    Directory of Open Access Journals (Sweden)

    Marina S. Hernandes

    2013-01-01

    Full Text Available Several lines of investigation have implicated oxidative stress in Parkinson’s disease (PD pathogenesis, but the mechanisms involved are still unclear. In this study, we characterized the involvement of NADPH oxidase (Nox, a multisubunit enzyme that catalyzes the reduction of oxygen, in the 6-hydroxydopamine- (6-OHDA- induced PD mice model and compared for the first time the effects of this neurotoxin in mice lacking gp91phox-/-, the catalytic subunit of Nox2, and pharmacological inhibition of Nox with apocynin. Six-OHDA induced increased protein expression of p47phox, a Nox subunit, in striatum. gp91phox-/- mice appear to be completely protected from dopaminergic cell loss, whereas the apocynin treatment conferred only a limited neuroprotection. Wt mice treated with apocynin and gp91phox-/- mice both exhibited ameliorated apomorphine-induced rotational behavior. The microglial activation observed within the striatum and the substantia nigra pars compacta (SNpc of 6-OHDA-injected Wt mice was prevented by apocynin treatment and was not detected in gp91phox-/- mice. Apocynin was not able to attenuate astrocyte activation in SN. The results support a role for Nox2 in the 6-OHDA-induced degeneration of dopaminergic neurons and glial cell activation in the nigrostriatal pathway and reveal that no comparable 6-OHDA effects were observed between apocynin-treated and gp91phox-/- mice groups.

  18. The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor.

    Science.gov (United States)

    Rigoli, Francesco; Chew, Benjamin; Dayan, Peter; Dolan, Raymond J

    2016-09-01

    Dopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor. PMID:27082045

  19. The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor.

    Science.gov (United States)

    Rigoli, Francesco; Chew, Benjamin; Dayan, Peter; Dolan, Raymond J

    2016-09-01

    Dopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor.

  20. Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Kim A Caldwell

    Full Text Available Parkinson disease (PD involves progressive neurodegeneration, including loss of dopamine (DA neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS, involved in protein degradation. The misfolding and accumulation of proteins, such as alpha-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH, the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent

  1. Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons.

    Science.gov (United States)

    Tung, Li-Wei; Lu, Guan-Ling; Lee, Yen-Hsien; Yu, Lung; Lee, Hsin-Jung; Leishman, Emma; Bradshaw, Heather; Hwang, Ling-Ling; Hung, Ming-Shiu; Mackie, Ken; Zimmer, Andreas; Chiou, Lih-Chu

    2016-01-01

    Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP. PMID:27448020

  2. Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons

    Science.gov (United States)

    Tung, Li-Wei; Lu, Guan-Ling; Lee, Yen-Hsien; Yu, Lung; Lee, Hsin-Jung; Leishman, Emma; Bradshaw, Heather; Hwang, Ling-Ling; Hung, Ming-Shiu; Mackie, Ken; Zimmer, Andreas; Chiou, Lih-Chu

    2016-01-01

    Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP. PMID:27448020

  3. Ganoderma Lucidum polysaccharides protect against MPP+ and rotenone-induced apoptosis in primary dopaminergic cell cultures through inhibiting oxidative stress

    Science.gov (United States)

    Guo, Shan-Shan; Cui, Xiao-Lan; Rausch, Wolf-Dieter

    2016-01-01

    Oxidative stress plays a pivotal role in the progressive neurodegeneration in Parkinson’s disease (PD) which is responsible for disabling motor abnormalities in more than 6.5 million people worldwide. Polysaccharides are the main active constituents from Ganoderma lucidum which is characterized with anti-oxidant, antitumor and immunostimulant properties. In the present study, primary dopaminergic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effects and the potential mechanisms of Ganoderma lucidum polysaccharides (GLP) on the degeneration of dopaminergic neurons induced by the neurotoxins methyl-4-phenylpyridine (MPP+) and rotenone. Results revealed that GLP can protect dopamine neurons against MPP+ and rotenone at the concentrations of 100, 50 and 25 μg/ml in primary mesencephalic cultures in a dose-dependent manner. Interestingly, either with or without neurotoxin treatment, GLP treatment elevated the survival of THir neurons, and increased the length of neurites of dopaminergic neurons. The Trolox equivalent anti-oxidant capacity (TEAC) of GLP was determined to be 199.53 μmol Trolox/g extract, and the decrease of mitochondrial complex I activity induced by MPP+ and rotenone was elevated by GLP treatment (100, 50, 25 and 12.5 μg/ml) in a dose dependent manner. Furthermore, GLP dramatically decreased the relative number of apoptotic cells and increased the declining mitochondrial membrane potential (ΔΨm) induced by MPP+ and rotenone in a dose-dependent manner. In addition, GLP treatment reduced the ROS formation induced by MPP+ and rotenone at the concentrations of 100, 50 and 25 μg/ml in a dose-dependent manner. Our study indicates that GLP possesses neuroprotective properties against MPP+ and rotenone neurotoxicity through suppressing oxidative stress in primary mesencephalic dopaminergic cell culture owning to its antioxidant activities. PMID:27335703

  4. Ganoderma Lucidum polysaccharides protect against MPP(+) and rotenone-induced apoptosis in primary dopaminergic cell cultures through inhibiting oxidative stress.

    Science.gov (United States)

    Guo, Shan-Shan; Cui, Xiao-Lan; Rausch, Wolf-Dieter

    2016-01-01

    Oxidative stress plays a pivotal role in the progressive neurodegeneration in Parkinson's disease (PD) which is responsible for disabling motor abnormalities in more than 6.5 million people worldwide. Polysaccharides are the main active constituents from Ganoderma lucidum which is characterized with anti-oxidant, antitumor and immunostimulant properties. In the present study, primary dopaminergic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effects and the potential mechanisms of Ganoderma lucidum polysaccharides (GLP) on the degeneration of dopaminergic neurons induced by the neurotoxins methyl-4-phenylpyridine (MPP(+)) and rotenone. Results revealed that GLP can protect dopamine neurons against MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in primary mesencephalic cultures in a dose-dependent manner. Interestingly, either with or without neurotoxin treatment, GLP treatment elevated the survival of THir neurons, and increased the length of neurites of dopaminergic neurons. The Trolox equivalent anti-oxidant capacity (TEAC) of GLP was determined to be 199.53 μmol Trolox/g extract, and the decrease of mitochondrial complex I activity induced by MPP(+) and rotenone was elevated by GLP treatment (100, 50, 25 and 12.5 μg/ml) in a dose dependent manner. Furthermore, GLP dramatically decreased the relative number of apoptotic cells and increased the declining mitochondrial membrane potential (ΔΨm) induced by MPP(+) and rotenone in a dose-dependent manner. In addition, GLP treatment reduced the ROS formation induced by MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in a dose-dependent manner. Our study indicates that GLP possesses neuroprotective properties against MPP(+) and rotenone neurotoxicity through suppressing oxidative stress in primary mesencephalic dopaminergic cell culture owning to its antioxidant activities.

  5. Ganoderma Lucidum polysaccharides protect against MPP(+) and rotenone-induced apoptosis in primary dopaminergic cell cultures through inhibiting oxidative stress.

    Science.gov (United States)

    Guo, Shan-Shan; Cui, Xiao-Lan; Rausch, Wolf-Dieter

    2016-01-01

    Oxidative stress plays a pivotal role in the progressive neurodegeneration in Parkinson's disease (PD) which is responsible for disabling motor abnormalities in more than 6.5 million people worldwide. Polysaccharides are the main active constituents from Ganoderma lucidum which is characterized with anti-oxidant, antitumor and immunostimulant properties. In the present study, primary dopaminergic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effects and the potential mechanisms of Ganoderma lucidum polysaccharides (GLP) on the degeneration of dopaminergic neurons induced by the neurotoxins methyl-4-phenylpyridine (MPP(+)) and rotenone. Results revealed that GLP can protect dopamine neurons against MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in primary mesencephalic cultures in a dose-dependent manner. Interestingly, either with or without neurotoxin treatment, GLP treatment elevated the survival of THir neurons, and increased the length of neurites of dopaminergic neurons. The Trolox equivalent anti-oxidant capacity (TEAC) of GLP was determined to be 199.53 μmol Trolox/g extract, and the decrease of mitochondrial complex I activity induced by MPP(+) and rotenone was elevated by GLP treatment (100, 50, 25 and 12.5 μg/ml) in a dose dependent manner. Furthermore, GLP dramatically decreased the relative number of apoptotic cells and increased the declining mitochondrial membrane potential (ΔΨm) induced by MPP(+) and rotenone in a dose-dependent manner. In addition, GLP treatment reduced the ROS formation induced by MPP(+) and rotenone at the concentrations of 100, 50 and 25 μg/ml in a dose-dependent manner. Our study indicates that GLP possesses neuroprotective properties against MPP(+) and rotenone neurotoxicity through suppressing oxidative stress in primary mesencephalic dopaminergic cell culture owning to its antioxidant activities. PMID:27335703

  6. Behavioral effects of lesions in the A10 dopaminergic area of the rat.

    Science.gov (United States)

    Galey, D; Simon, H; Le Moal, M

    1977-03-18

    Experiments have been carried out with 150 rats in order to study some psychophysiological functions of the mesencephalocortico limbic dopaminergic A10 group. Lesions in the A10 area were made by using 6-hydroxydopamine (6-OHDA) local injections; 2 small volumes of injections were used at the same concentration (2 mug/1 mul or 1 mug/0.5 mul). In a first experiment the effects of these two injections were tested on locomotor activity measured in a circular corridor, 10 and 30 days after surgery. Injections provoked hyperactivity, mainly during nocturnal basal activity periods, but not during initial exploratory activity periods. The larger the injection, the more important the hyperactivity was. The larger injections induced important food spillage evidence through the wire floor of the home cage and perturbation in a passive avoidance learning. There was no change in body weight or in amount of ingested food. In a second experiment, the effects of local injection of 6-OHDA in the other CA structures or bundles situated in or near the ventral tegmental area were tested. Injections in the substantia nigra compacta, in the noradrenergic ventral bundle, in the dorsal periventricular system-tegmental radiations did not provoke locomotor hyperactivity. In a third experiment, a possible role of the median raphe (MR) nucleus in the A10-lesion induced hyperactivity was tested: first, radiofrequency MR lesions were made and no durable significant hyperactivity was recorded; secondly, 6-OHDA (1 mug/0.5 mul) was injected into the A10 area and activity was measured 10 days later: these injections provoked significant hyperactivity during the nocturnal basal and the diurnal basal activity periods. It might be concluded that neither the neighboring CA fibers nor the MR were directly involved in the ventral tegmental -- 6-OHDA lesions syndrome. Anatomical controls by using the Fink-Heimer silver impregnating method have demonstrated, first, that the 6-OHDA injections did not

  7. Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons.

    Science.gov (United States)

    Jo, Junghyun; Xiao, Yixin; Sun, Alfred Xuyang; Cukuroglu, Engin; Tran, Hoang-Dai; Göke, Jonathan; Tan, Zi Ying; Saw, Tzuen Yih; Tan, Cheng-Peow; Lokman, Hidayat; Lee, Younghwan; Kim, Donghoon; Ko, Han Seok; Kim, Seong-Oh; Park, Jae Hyeon; Cho, Nam-Joon; Hyde, Thomas M; Kleinman, Joel E; Shin, Joo Heon; Weinberger, Daniel R; Tan, Eng King; Je, Hyunsoo Shawn; Ng, Huck-Hui

    2016-08-01

    Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases. PMID:27476966

  8. A DJ-1 Based Peptide Attenuates Dopaminergic Degeneration in Mice Models of Parkinson's Disease via Enhancing Nrf2.

    Directory of Open Access Journals (Sweden)

    Nirit Lev

    Full Text Available Drugs currently used for treating Parkinson's disease patients provide symptomatic relief without altering the neurodegenerative process. Our aim was to examine the possibility of using DJ-1 (PARK7, as a novel therapeutic target for Parkinson's disease. We designed a short peptide, named ND-13. This peptide consists of a 13 amino acids segment of the DJ-1-protein attached to 7 amino acids derived from TAT, a cell penetrating protein. We examined the effects of ND-13 using in vitro and in vivo experimental models of Parkinson's disease. We demonstrated that ND-13 protects cultured cells against oxidative and neurotoxic insults, reduced reactive oxygen species accumulation, activated the protective erythroid-2 related factor 2 system and increased cell survival. ND-13 robustly attenuated dopaminergic system dysfunction and in improved the behavioral outcome in the 6-hydroxydopamine mouse model of Parkinson's disease, both in wild type and in DJ-1 knockout mice. Moreover, ND-13 restored dopamine content in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. These findings validate DJ-1 as a promising therapeutic target in Parkinson's disease and identify a novel peptide with clinical potential, which may be significant for a broader range of neurological diseases, possibly with an important impact for the neurosciences.

  9. Essential Roles of Enteric Neuronal Serotonin in Gastrointestinal Motility and the Development/Survival of Enteric Dopaminergic Neurons

    OpenAIRE

    Li, Zhishan; Chalazonitis, Alcmène; Huang, Yung-Yu; Mann, J. John; Margolis, Kara Gross; Yang, Qi Melissa; Kim, Dolly O.; Côté, Francine; Mallet, Jacques; Gershon, Michael D.

    2011-01-01

    The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (...

  10. Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

    OpenAIRE

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

    2014-01-01

    Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 rece...

  11. Tryptamine-derived alkaloids from Annonaceae exerting neurotrophin-like properties on primary dopaminergic neurons.

    Science.gov (United States)

    Schmidt, Fanny; Le Douaron, Gael; Champy, Pierre; Amar, Majid; Séon-Méniel, Blandine; Raisman-Vozari, Rita; Figadère, Bruno

    2010-07-15

    N-fatty acyl tryptamines constitute a scarce group of natural compounds mainly encountered in Annonaceous plants. No biological activity was reported so far for these rare molecules. This study investigated the neurotrophic properties of these natural tryptaminic derivatives on dopaminergic (DA) neurons in primary mesencephalic cultures. A structure-activity relationships study led us to precise the role of a nitrogen atom into the aliphatic chain conferring to the compounds a combined neuroprotective and neuritogenic activity in the nanomolar range. The potent antioxidant activity of these natural products seems to be involved in part of their mechanism of action. This study provides the first description of natural neurotrophin mimetics present in Annonaceae extracts, and led to the biological characterization of compounds, which present a potential interest in neurodegenerative diseases such as Parkinson's disease.

  12. An active tactile perception system

    Science.gov (United States)

    Petriu, E.; Greenspan, M.; Gelinas, F.; McMath, W. S.; Yeung, S. K.

    System development and application aspects are described for an experimental robotic system for the tactile perception of the global geometric profile of object surfaces which are larger than the dimensions of the tactile sensor. Local cutaneous information provided by a tactile sensor is integrated with the kinesthetic position parameters of a robot arm, resulting in a 3D geometric model of the tactile sensor pose on the explored object surface. Currently available tactile sensors provide poor information on the geometric profile of 3D object surfaces. In order to maximize the information available for 3D analysis, an instrumented passive compliant wrist was used to attach a pressure measuring tactile probe to the robot arm carrier. Data was collected by a noncompliant planar sensing array in direct contact with an object surface. Information recorded includes the following: positional and orientation data on the robot arm manipulator, passive compliance kinesthetic data as measured by the kinematics of the wrist, and cutaneous tactile data represented by the binary image of the sensors pose on the object. The dimensions of the sensor array were found to be a critical factor in system performance. Use of a large array results in fewer touch poses being required to explore an object's surface, on the other hand a large planar array will touch fewer and higher peaks thus missing surface detail. To improve performance, there is a need to design tactile sensors specifically for geometric profile measuring.

  13. Gender differences in nigrostriatal dopaminergic innervation are present at young-to-middle but not at older age in normal adults.

    NARCIS (Netherlands)

    Wong, K.K.; Muller, M.L.; Kuwabara, H.; Studenski, S.A.; Bohnen, N.I.

    2012-01-01

    Gender differences in brain dopaminergic activity have been variably reported in the literature. We performed an evaluation for gender effects on striatal dopamine transporter (DAT) binding in a group of normal subjects. Community-dwelling adults (n = 85, 50F/35M, mean age 62.7 +/- 16.2 SD, range 20

  14. Performance of Active Wave Absorption Systems

    DEFF Research Database (Denmark)

    Hald, Tue; Frigaard, Peter

    A comparison of wave gauge based on velocity meter based active absorption systems is presented discussing advantages and disadvantages of the systems. In detail one system based on two surface elevations, one system based on a surface elevation and a horisontal velocity and one system based...... on a horisontal and vertical velocity are treated. All three systems are based on digital FIR-filters. For numerical comparison a performance function combining the frequency response of the set of filters for each system is derived enabling discussion on optimal filter design and system setup. Irregular wave...

  15. GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease.

    Science.gov (United States)

    Kramer, Edgar R; Liss, Birgit

    2015-12-21

    Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD.

  16. Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

    Science.gov (United States)

    Vieira-Brock, Paula L; McFadden, Lisa M; Nielsen, Shannon M; Ellis, Jonathan D; Walters, Elliot T; Stout, Kristen A; McIntosh, J Michael; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2015-12-01

    Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection. PMID:26391161

  17. Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease

    Science.gov (United States)

    Isaias, Ioannis U.; Trujillo, Paula; Summers, Paul; Marotta, Giorgio; Mainardi, Luca; Pezzoli, Gianni; Zecca, Luigi; Costa, Antonella

    2016-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease. PMID:27597825

  18. Implementation of Business Game Activity Support System

    Institute of Scientific and Technical Information of China (English)

    TANABU Motonari

    2004-01-01

    Business game can be used not only as an educational tool for the development of decision making ability, but also can be used for supporting the knowledge creation activity in organizations. In this paper, some conceptual considerations to meanings of the business game in the knowledge creation activity by using the knowledge creation theory and other related theories are given,and business game activity concept which refers to game play and development is proposed. Then focusing on the business game activity as an instantiation of the knowledge creation activity, and a Web based gaming activity support system based on the former system called YBG that enables us to play and develop many business games through the standard web browser is proposed. This system also provides us a lot of opportunities to play and develop the business games over business game communities.

  19. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    Science.gov (United States)

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-01

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD. PMID:27313094

  20. Neuroprotective effects of tadalafil on gerbil dopaminergic neurons following cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Kwang Taek Kim; Kyung Jin Chung; Han Sae Lee; Il Gyu Ko; Chang Ju Kim; Yong Gil Na; Khae Hawn Kim

    2013-01-01

    Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine D2 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury.

  1. Neuroprotective effects of tadalafil on gerbil dopaminergic neurons following cerebral ischemia.

    Science.gov (United States)

    Kim, Kwang Taek; Chung, Kyung Jin; Lee, Han Sae; Ko, Il Gyu; Kim, Chang Ju; Na, Yong Gil; Kim, Khae Hawn

    2013-03-15

    Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine D2 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury. PMID:25206715

  2. Automobile active suspension system with fuzzy control

    Institute of Scientific and Technical Information of China (English)

    刘少军; 黄中华; 陈毅章

    2004-01-01

    A quarter-automobile active suspension model was proposed. High speed on/off solenoid valves were used as control valves and fuzzy control was chosen as control method . Based on force analyses of system parts, a mathematical model of the active suspension system was established and simplified by linearization method. Simulation study was conducted with Matlab and three scale coefficients of fuzzy controller (ke, kec, ku) were acquired. And an experimental device was designed and produced. The results indicate that the active suspension system can achieve better vibration isolation performance than passive suspension system, the displacement amplitude of automobile body can be reduced to 55%. Fuzzy control is an effective control method for active suspension system.

  3. 多巴胺受体激动药治疗帕金森病的新进展%New Advances of Dopaminergic Agonists for Treatment of Parkinsons Disease

    Institute of Scientific and Technical Information of China (English)

    孙斌

    2001-01-01

    Parkinson's disease (PD) caused by the deficiency of DA in the substantial nigra-striatum system in the brain is a chronically progressive disease. Early diagnosis and prompt treatment PD can prolong work time and improve life quality of the patient. There are three primary approaches to increase activity of dopaminergic system:vicarious treatment to compensate DA; promote releasing DA in nerve endings of dopamine neurons and to prevent decreasing DA metabolism,as well as application of agonists that stimulate dopamine receptors. Some specialists suggest that application of dopaminergic agonists in the initial stage can not only delay the occurrence of syndrome on side effects with long-term use of levodopa,but also prevent the damage of dopaminergic cell caused by levodopa or its metabolite,and delay the development of PD. There are positive and adverse effects with DA agonists. This paper discussed the usage and side effects of classic and new dopaminergic agonists.%由于脑内黑质-纹状体系统中缺少多巴胺(DA)所致的帕金森病(PD)为慢性进展性疾病。对帕金森病尽早诊断和及时治疗的意义,在于能够延长患者的可工作时间和提高生存质量。增加DA能系统的活性,有三种途径:即DA替代疗法;促进DA神经元末端释放DA和阻止DA的降解代谢;应用DA受体激动药。一些作者主张在PD的早期先用DA能受体激动药,不但使“左旋多巴长期综合征”的出现延迟,并且可防止左旋多巴或其代谢产物损害DA能细胞和迟滞病情发展。应用DA受体激动药有利也有弊。介绍了常用和新型的DA能受体激动药的特点、用法和副作用等。

  4. Illumination controls dopaminergic differentiation regulating behavior

    OpenAIRE

    Dulcis, Davide; Spitzer, Nicholas C.

    2008-01-01

    Specification of the appropriate neurotransmitter is a crucial step in neuronal differentiation because it enables signaling among populations of neurons. Experimental manipulations demonstrate that both autonomous and activity-dependent genetic programs contribute to this process during development, but whether natural environmental stimuli specify transmitter expression in a neuronal population is unknown. We investigated neurons of the ventral suprachiasmatic nucleus that regulate neuroend...

  5. Neuropathologic Implication of Peripheral Neuregulin-1 and EGF Signals in Dopaminergic Dysfunction and Behavioral Deficits Relevant to Schizophrenia: Their Target Cells and Time Window

    Directory of Open Access Journals (Sweden)

    Hiroyuki Nawa

    2014-01-01

    Full Text Available Neuregulin-1 and epidermal growth factor (EGF are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages.

  6. Dopaminergic mesocortical projections to M1: role in motor learning and motor cortex plasticity

    Directory of Open Access Journals (Sweden)

    Jonas Aurel Hosp

    2013-10-01

    Full Text Available Although the architecture of a dopaminergic (DA system within the primary motorcortex (M1 was well characterized anatomically, its functional significance remainedobscure for a long time. Recent studies in rats revealed that the integrity ofdopaminergic fibers in M1 is a prerequisite for successful acquisition of motor skills.This essential contribution of DA for motor learning is plausible as it modulates M1circuitry at multiple levels thereby promoting plastic changes that are required forinformation storage: at the network level, DA increases cortical excitability andenhances the stability of motor maps. At the cellular level, DA induces the expressionof learning related genes via the transcription factor c-fos. At the level of synapses,DA is required for the formation of long-term potentiation (LTP, a mechanism thatlikely is a fingerprint of a motor memory trace within M1. Dopaminergic fibersinnervating M1 originate within the midbrain, precisely the ventral tegmental area(VTA and the medial portion of substantia nigra (SN. Thus, they could be part of themeso-cortico-limibic pathway – a network that provides information about saliencyand motivational value of an external stimulus and is commonly referred as

  7. Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

    Directory of Open Access Journals (Sweden)

    Sylvia Navailles

    2012-01-01

    Full Text Available L-DOPA-induced dyskinesias (LIDs are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs.

  8. On the physiology of jouissance: interpreting the mesolimbic dopaminergic reward functions from a psychoanalytic perspective

    Directory of Open Access Journals (Sweden)

    Ariane eBazan

    2013-11-01

    Full Text Available Jouissance is a Lacanian concept, infamous for being impervious to understanding and which expresses the paradoxical satisfaction that a subject may derive from his symptom. On the basis of Freud’s experience of satisfaction we have proposed a first working definition of jouissance as the (benefit gained from the motor tension underlying the action which was [once] adequate in bringing relief to the drive and, on the basis of their striking reciprocal resonances, we have proposed that central dopaminergic systems could embody the physiological architecture of Freud’s concept of the drive. We have then distinguished two constitutive axes to jouissance: one concerns the subject’s body and the other the subject’s history. Four distinctive aspects of these axes are discussed both from a metapsychological and from a neuroscience point of view. We conclude that jouissance could be described as an accumulation of body tension, fuelling for action, but continuously balancing between reward and anxiety, and both marking the physiology of the body with the history of its commemoration and arising from this inscription as a constant push to act and to repeat. Moroever, it seems that the mesolimbic accumbens dopaminergic pathway is a reasonable candidate for its underlying physiological architecture.

  9. A shift of paradigm: from noradrenergic to dopaminergic modulation of learning?

    Science.gov (United States)

    Breitenstein, Caterina; Flöel, Agnes; Korsukewitz, Catharina; Wailke, Stefanie; Bushuven, Stefan; Knecht, Stefan

    2006-10-25

    d-Amphetamine coupled with behavioral training has been effective for improving functional recovery after stroke. d-amphetamine acts on multiple brain transmitter systems, but the recovery enhancing effect has been attributed to its noradrenergic actions. Another potent modulator of learning is dopamine, which may also enhance stroke recovery in humans. Based on data from previous studies of our group, we compared the learning enhancing effects of d-amphetamine with a more selective dopaminergic substance (levodopa) in identical protocols. Using a prospective, randomized, double-blind, placebo-controlled design, we had taught 60 male healthy subjects a miniature lexicon of 50 concrete nouns over the course of five consecutive training days using an associative learning principle. Subjects had received either d-amphetamine (0.25 mg/kg), levodopa/carbidopa (fixed dose of 100/25 mg), or placebo 90 min prior to training on each of the 5 days. Novel word learning was significantly enhanced in both the d-amphetamine and levodopa groups as compared to the placebo group. The learning superiority was maintained at the two re-assessments (1 week and 1 month post training). Both d-amphetamine and levodopa are thus potent drugs in enhancing learning in humans. We here discuss why the efficiency of both d-amphetamine and levodopa may be related to dopaminergic rather than noradrenergic actions. PMID:16815467

  10. Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

    Institute of Scientific and Technical Information of China (English)

    Jian-Hong Wang; Joshua Dominie Rizak; Yan-Mei Chen; Liang Li; Xin-Tian Hu; Yuan-Ye Ma

    2013-01-01

    Opiates and dopamine (DA) play key roles in learning and memory in humans and animals.Although interactions between these neurotransmitters have been found,their functional roles remain to be fully elucidated,and their dysfunction may contribute to human diseases and addiction.Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task.Morphine and DA agonists (SKF-38393,apomorphine and bromocriptine) or DA antagonists (SKF-83566,haloperidol and sulpiride) were co-administered to the monkeys 30 min prior to the task.We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone.For example,morphine at 0.01 mg/kg impaired spatial working memory,while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect.Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys.A better understanding of these interactive relationships may provide insights into human addiction.

  11. Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons.

    Science.gov (United States)

    Caudal, D; Alvarsson, A; Björklund, A; Svenningsson, P

    2015-11-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-synuclein called Lewy bodies. Viral vector-induced overexpression of α-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague-Dawley rats received bilateral injections of a recombinant adeno-associated virus (AAV) vector expressing human α-synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8 weeks post-injection. We report that nigral α-synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-α-synuclein group exhibited modest, but significant motor impairments 8 weeks after vector administration. The AAV-α-synuclein group displayed depressive-like behavior in the forced swim test after 3 weeks, and reduced sucrose preference at week 8. At both timepoints, overexpression of α-synuclein was linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone. The depressive-like phenotype was also correlated with decreased nigral brain-derived neurotrophic factor and spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated protein. This study demonstrates that AAV-mediated α-synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in experimental Parkinsonism is correlated to dysregulation of the HPA axis and to

  12. Circumpolar Active-Layer Permafrost System (CAPS)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Circumpolar Active-Layer Permafrost System (CAPS) contains over 100 data sets pertaining to permafrost and frozen ground topics. It also contains detailed...

  13. Dopaminergic therapy affects learning and impulsivity in Parkinson’s disease

    OpenAIRE

    Nole M. Hiebert; Seergobin, Ken N.; Vo, Andrew; Ganjavi, Hooman; MacDonald, Penny A

    2014-01-01

    Objective The aim was to examine the effect of dopaminergic medication on stimulus-response learning versus performing decisions based on learning. Method To see the effect of dopaminergic therapy on stimulus-response learning and response selection, participants with Parkinson’s disease (PD) were either tested on and/or off their prescribed dose of dopaminergic therapy during different testing days. Forty participants with PD and 34 healthy controls completed the experiment on consecutive da...

  14. Active impedance matching of complex structural systems

    Science.gov (United States)

    Macmartin, Douglas G.; Miller, David W.; Hall, Steven R.

    1991-01-01

    Viewgraphs on active impedance matching of complex structural systems are presented. Topics covered include: traveling wave model; dereverberated mobility model; computation of dereverberated mobility; control problem: optimal impedance matching; H2 optimal solution; statistical energy analysis (SEA) solution; experimental transfer functions; interferometer actuator and sensor locations; active strut configurations; power dual variables; dereverberation of complex structure; dereverberated transfer function; compensators; and relative power flow.

  15. SYSTEMIC BLOOD ACTIVATION DURING AND AFTER AUTOTRANSFUSION

    NARCIS (Netherlands)

    SCHONBERGER, JPAM; VANOEVEREN, W; BREDEE, JJ; EVERTS, PAM; DEHAAN, J; WILDEVUUR, CRH

    1994-01-01

    To evaluate the extent of shed blood activation in two autotransfusion systems and the effect of circulating blood activation upon autotransfusion, we performed a prospective study in 18 patients undergoing internal mammary artery bypass operation and a control group of 10 patients. The autotransfus

  16. Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease.

    Science.gov (United States)

    Gordon, Richard; Singh, Neeraj; Lawana, Vivek; Ghosh, Anamitra; Harischandra, Dilshan S; Jin, Huajun; Hogan, Colleen; Sarkar, Souvarish; Rokad, Dharmin; Panicker, Nikhil; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2016-09-01

    Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCδ activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCδ contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including α-synuclein, tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCδ with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKCδ in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCδ in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCδ in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKCδ activated NFκB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFκB led to translocation of the p65 subunit to the nucleus, IκBα degradation and phosphorylation of p65

  17. Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words.

    Science.gov (United States)

    Lou, Hans C; Skewes, Joshua C; Thomsen, Kristine Rømer; Overgaard, Morten; Lau, Hakwan C; Mouridsen, Kim; Roepstorff, Andreas

    2011-02-23

    Liberal acceptance, overconfidence, and increased activity of the neurotransmitter dopamine have been proposed to account for abnormal sensory experiences, for instance, hallucinations in schizophrenia. In normal subjects, increased sensory experience in Yoga Nidra meditation is linked to striatal dopamine release. We therefore hypothesize that the neurotransmitter dopamine may function as a regulator of subjective confidence of visual perception in the normal brain. Although much is known about the effect of stimulation by neurotransmitters on cognitive functions, their effect on subjective confidence of perception has never been recorded experimentally before. In a controlled study of 24 normal, healthy female university students with the dopamine agonist pergolide given orally, we show that dopaminergic activation increases confidence in seeing rapidly presented words. It also improves performance in a forced-choice word recognition task. These results demonstrate neurotransmitter regulation of subjective conscious experience of perception and provide evidence for a crucial role of dopamine.

  18. Effects of 6-OHDA lesion of hippocampal CA3 dopaminergic system on conditioned fear memory in rats%损毁海马CA3区多巴胺能系统对大鼠条件性恐惧记忆的影响

    Institute of Scientific and Technical Information of China (English)

    文加玲; 时燕薇; 赵虎

    2012-01-01

    目的 研究大鼠海马CA3区多巴胺(DA)能系统在条件性恐惧记忆形成与保持中的作用.方法 条件性恐惧训练前2周向双侧海马CA3区注入6-羟基多巴胺(6-OHDA)进行损毁,训练后用Western blotting检测前额叶皮层、CA1、杏仁体GluR1及NR2B的表达变化.结果 (1)与生理盐水组[(66.44±16.58)%,(73.43±23.57)%,(55.27±20.57)%]比较,6-OHDA损毁组恐惧记忆获得的僵住反应[ (65.58±5.33)%]差异无统计学意义(P>0.05),短时恐惧记忆的僵住反应[(39.24±12.83)%]与长时恐惧记忆的僵住反应[(31.15±6.51)%]明显减少(P<0.05).(2)与生理盐水组比较,6-OHDA损毁组大鼠前额叶皮层,海马CA1区的GluR1蛋白表达差异无统计学意义(P>0.05),杏仁体BLA区的GluR1蛋白表达升高(P<0.01).与生理盐水组比较,6-OHDA损毁组大鼠前额叶皮层的NR2B蛋白表达升高(P<0.01),海马CA1区的NR2B蛋白表达差异无统计学意义(P>0.05),杏仁体BLA区的NR2B蛋白表达降低(P<0.01).结论 大鼠海马CA3区多巴胺能系统功能下调能损害恐惧记忆的巩固但不影响其获得,还可以调节其他脑区记忆相关蛋白的表达.%Objective To investigate the effects of hippocampal CA3 dopaminergic system in acquisition and consolidation of Pavlovian fear conditioning,and expression of GluR1 and NR2B in medial prefrontal cortex (mPFC),CA1 and basolateral amygdala (BLA) after fear conditioning training.Methods Bilateral injection 6-OHDA into hippocampal CA3 to lesion dopaminergic fibers 2 weeks before fear conditioning training.The change of GluR1 and NR2B were analyzed by western blot after training.Results Compared with the saline group ( (66.44 ± 16.58)% ),there were significant decreases ( (39.24 ± 12.83)%,(31.15 ±6.51 )% ) in the consolidation of short- and long- term fear memory (P < 0.05 ) but not the acquisition ( ( 65.58 ± 5.33 ) %,P > 0.05).The expression of GluR1 protein was significantly increased in BLA

  19. Gamma band activity in the reticular activating system (RAS

    Directory of Open Access Journals (Sweden)

    Francisco J Urbano

    2012-01-01

    Full Text Available This review considers recent evidence showing that cells in three regions of the reticular activating system (RAS exhibit gamma band activity, and describes the mechanisms behind such manifestation. Specifically, we discuss how cells in the mesopontine pedunculopontine nucleus (PPN, intralaminar parafascicular nucleus (Pf, and pontine Subcoeruleus nucleus dorsalis (SubCD all fire in the beta/gamma band range when maximally activated, but no higher. The mechanisms behind this ceiling effect have been recently elucidated. We describe recent findings showing that every cell in the PPN have high threshold, voltage-dependent P/Q-type calcium channels that are essential, while N-type calcium channels are permissive, to gamma band activity. Every cell in the Pf also showed that P/Q-type and N-type calcium channels are responsible for this activity. On the other hand, every SubCD cell exhibited sodium-dependent subthreshold oscillations. A novel mechanism for sleep-wake control based on well-known transmitter interactions, electrical coupling, and gamma band activity is described. The data presented here on inherent gamma band activity demonstrates the global nature of sleep-wake oscillation that is orchestrated by brainstem-thalamic mechanism, and questions the undue importance given to the hypothalamus for regulation of sleep-wakefulness. The discovery of gamma band activity in the RAS follows recent reports of such activity in other subcortical regions like the hippocampus and cerebellum. We hypothesize that, rather than participating in the temporal binding of sensory events as seen in the cortex, gamma band activity manifested in the RAS may help stabilize coherence related to arousal, providing a stable activation state during waking and paradoxical sleep. Most of our thoughts and actions are driven by preconscious processes. We speculate that continuous sensory input will induce gamma band activity in the RAS that could participate in the

  20. Phase Transitions in Model Active Systems

    Science.gov (United States)

    Redner, Gabriel S.

    The amazing collective behaviors of active systems such as bird flocks, schools of fish, and colonies of microorganisms have long amazed scientists and laypeople alike. Understanding the physics of such systems is challenging due to their far-from-equilibrium dynamics, as well as the extreme diversity in their ingredients, relevant time- and length-scales, and emergent phenomenology. To make progress, one can categorize active systems by the symmetries of their constituent particles, as well as how activity is expressed. In this work, we examine two categories of active systems, and explore their phase behavior in detail. First, we study systems of self-propelled spherical particles moving in two dimensions. Despite the absence of an aligning interaction, this system displays complex emergent dynamics, including phase separation into a dense active solid and dilute gas. Using simulations and analytic modeling, we quantify the phase diagram and separation kinetics. We show that this nonequilibrium phase transition is analogous to an equilibrium vapor-liquid system, with binodal and spinodal curves and a critical point. We also characterize the dense active solid phase, a unique material which exhibits the structural signatures of a crystalline solid near the crystal-hexatic transition point, as well as anomalous dynamics including superdiffusive motion on intermediate timescales. We also explore the role of interparticle attraction in this system. We demonstrate that attraction drastically changes the phase diagram, which contains two distinct phase-separated regions and is reentrant as a function of propulsion speed. We interpret this complex situation with a simple kinetic model, which builds from the observed microdynamics of individual particles to a full description of the macroscopic phase behavior. We also study active nematics, liquid crystals driven out of equilibrium by energy-dissipating active stresses. The equilibrium nematic state is unstable in these

  1. A neural population model incorporating dopaminergic neurotransmission during complex voluntary behaviors.

    Directory of Open Access Journals (Sweden)

    Stefan Fürtinger

    2014-11-01

    Full Text Available Assessing brain activity during complex voluntary motor behaviors that require the recruitment of multiple neural sites is a field of active research. Our current knowledge is primarily based on human brain imaging studies that have clear limitations in terms of temporal and spatial resolution. We developed a physiologically informed non-linear multi-compartment stochastic neural model to simulate functional brain activity coupled with neurotransmitter release during complex voluntary behavior, such as speech production. Due to its state-dependent modulation of neural firing, dopaminergic neurotransmission plays a key role in the organization of functional brain circuits controlling speech and language and thus has been incorporated in our neural population model. A rigorous mathematical proof establishing existence and uniqueness of solutions to the proposed model as well as a computationally efficient strategy to numerically approximate these solutions are presented. Simulated brain activity during the resting state and sentence production was analyzed using functional network connectivity, and graph theoretical techniques were employed to highlight differences between the two conditions. We demonstrate that our model successfully reproduces characteristic changes seen in empirical data between the resting state and speech production, and dopaminergic neurotransmission evokes pronounced changes in modeled functional connectivity by acting on the underlying biological stochastic neural model. Specifically, model and data networks in both speech and rest conditions share task-specific network features: both the simulated and empirical functional connectivity networks show an increase in nodal influence and segregation in speech over the resting state. These commonalities confirm that dopamine is a key neuromodulator of the functional connectome of speech control. Based on reproducible characteristic aspects of empirical data, we suggest a number

  2. Modeling dopamine system dysfunction in experimental animals

    International Nuclear Information System (INIS)

    Quite a substantial number of human disorders have been associated with a primary or a secondary impairment of one or several of the dopaminergic pathways. Among disorders associated with a primary impairment of dopaminergic transmission are Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, and possibly schizophrenia. Diseases of secondary dopamine dysfunction are chiefly represented by Huntington's disease in which dopaminergic transmission is being interrupted by progressive loss of the striatal neurons bearing the postsynaptic D1- and D2-dopamine receptors. Central dopaminergic systems have anatomical as well as organizational properties that render them unique by comparison to other neurotransmission systems, making them able to play a pivotal role in the modulation of various important brain functions such as locomotor activity, attention, and some cognitive abilities. These properties of dopamine neurons have obviously several implications in the clinical expression of human disorders involving dopamine neuron dysfunction. In addition, they can greatly influence the clinical/behavioral consequences of experimental lesions in animal models of dopamine dysfunctions

  3. Active containment systems incorporating modified pillared clays

    Energy Technology Data Exchange (ETDEWEB)

    Lundie, P. [Envirotech (Scotland) Ltd., Aberdeen (United Kingdom)]|[Environmental Resource Industries Disposal Pty Ltd., Perth (Australia); McLeod, N. [Envirotreat Ltd., Kingswinford (United Kingdom)

    1997-12-31

    The application of treatment technologies in active containment systems provides a more advanced and effective method for the remediation of contaminated sites. These treatment technologies can be applied in permeable reactive walls and/or funnel and gate systems. The application of modified pillared clays in active containment systems provides a mechanism for producing permeable reactive walls with versatile properties. These pillared clays are suitably modified to incorporate reactive intercalatants capable of reacting with both a broad range of organic pollutants of varying molecular size, polarity and reactivity. Heavy metals can be removed from contaminated water by conventional ion-exchange and other reactive processes within the clay structure. Complex contamination problems can be addressed by the application of more than one modified clay on a site specific basis. This paper briefly describes the active containment system and the structure/chemistry of the modified pillared clay technology, illustrating potential applications of the in-situ treatment process for contaminated site remediation.

  4. Electric Current Systems in Solar Active Regions

    Science.gov (United States)

    LaBonte, B. J.; Mickey, D. L.

    2000-05-01

    The first study to show the persistence of local field-aligned current systems in active regions was reported by Pevtsov, Canfield, and Metcalf (Astrophys. J., 425, L117, 1994). Their work was limited to a sample of complex, flare-productive regions because of the sensitivity limit of the data from the Haleakala Stokes Polarimeter. I report here on a new survey of active regions with the Imaging Vector Magnetograph (IVM) at Mees Solar Observatory. The IVM data permit a look at current systems in simpler, more typical active regions, because of better sensitivity, temporal sampling, spatial resolution and field-of-view. Small scale current systems are commonly seen. Transport of current systems by advective processes is commonly seen over times of hours. This work was supported by NASA grant NAG5-4941 and by a subcontract with LMSAL in support of NASA contract NAS8-40801 for YOHKOH SXT.

  5. Performance improvement clarification for refrigeration system using active system monitoring

    DEFF Research Database (Denmark)

    Green, Torben; Niemann, Hans Henrik; Izadi-Zamanabadi, Roozbeh

    2011-01-01

    This paper addresses the problem of determining whether a refrigeration plant has the possibility of delivering a better performance of the operation. The controllers are wellknown but detailed knowledge about the underlying dynamics of the refrigeration plant is not available. Thus, the question...... is if it is possible to achieve a better performance by changing the controller parameter. An approach to active system monitoring, based on active fault diagnosis techniques, is employed in order to evaluate changes in the system performance under operation....

  6. Brain areas activated by uncertain reward-based decision-making in healthy volunteers

    OpenAIRE

    Guo, Zongjun; Chen, Juan; Liu, Shien; Li, Yuhuan; Sun, Bo; Gao, Zhenbo

    2013-01-01

    Reward-based decision-making has been found to activate several brain areas, including the ventrolateral prefrontal lobe, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and mesolimbic dopaminergic system. In this study, we observed brain areas activated under three degrees of uncertainty in a reward-based decision-making task (certain, risky, and ambiguous). The tasks were presented using a brain function audiovisual stimulation system. We conducted brain scans of 15 healt...

  7. The problem of activity in systemic scleroderma

    Directory of Open Access Journals (Sweden)

    N G Guseva

    2013-06-01

    Full Text Available The problem of systemic scleroderma (SSD activity enters into the view of standardized patient examination and it is important for choosing a therapeutic complex, for determining the dose of drugs, and for monitoring therapy. Great difficulties in the determination of activity in SSD are caused by the pathogenetic and morphogenetic features of the disease. It should be emphasized that there are no clearly defined exacerbation and remission periods. It is difficult to differentiate the potentially reversible inflammatory changes determining the activity of SSD from the irreversible fibrous changes characterizing the severity of the disease. The laboratory parameters of inflammatory activity are also of little informative value. The complicated problem of activity in SSD is to be further investigated both to improve and modify existing indices and to search for a common specific marker and/or key pathogenetically and clinically relevant markers of disease activity.

  8. Active system monitoring applied on wind turbines

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik; Poulsen, Niels Kjølstad; Parbo, Henrik;

    2009-01-01

    A concept for active system monitoring (ASM) applied on wind turbines is presented in this paper. The concept is based on an injection of a small periodic auxiliary signal in the system. An investigation of the signature from the auxiliary input in residual (error) signals can then be applied for...... for an online monitoring of central parameters/elements of the system. Statistical tests are applied on the residual signals for obtaining a correct monitoring.......A concept for active system monitoring (ASM) applied on wind turbines is presented in this paper. The concept is based on an injection of a small periodic auxiliary signal in the system. An investigation of the signature from the auxiliary input in residual (error) signals can then be applied...

  9. Modulation of post-coital dopaminergic tone by prior parity

    OpenAIRE

    Lucia Helena Sider; Erica Engelberg Teixeira da Silva Hucke; Luciano Freitas Felicio

    2010-01-01

    The aim of this study was to investigate the possible effects of reproductive experience on dopaminergic profile in three different brain tissues, hypothalamus, striatum and cortex in rats on 7th-8th day of pregnancy during the light-dark shift (between 1700-1900h). Results showed that in hypothalamus, dopamine levels increased and DOPAC/DA decreased as a function of parity. In cortex, no differences were observed. In striata, the haloperidol-induced HVA and HVA/DA increases were less intense...

  10. Transcriptional comparison of human induced and primary midbrain dopaminergic neurons

    OpenAIRE

    Ninuo Xia; Pengbo Zhang; Fang Fang; Zhengyuan Wang; Megan Rothstein; Benjamin Angulo; Rosaria Chiang; James Taylor; Reijo Pera, Renee A.

    2016-01-01

    Generation of induced dopaminergic (iDA) neurons may provide a significant step forward towards cell replacement therapy for Parkinson’s disease (PD). To study and compare transcriptional programs of induced cells versus primary DA neurons is a preliminary step towards characterizing human iDA neurons. We have optimized a protocol to efficiently generate iDA neurons from human pluripotent stem cells (hPSCs). We then sequenced the transcriptomes of iDA neurons derived from 6 different hPSC lin...

  11. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease

    DEFF Research Database (Denmark)

    Callesen, Mette Buhl; Hansen, K V; Gjedde, A;

    2013-01-01

    Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision...... decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG....

  12. A robust activity marking system for exploring active neuronal ensembles

    Science.gov (United States)

    Sørensen, Andreas T; Cooper, Yonatan A; Baratta, Michael V; Weng, Feng-Ju; Zhang, Yuxiang; Ramamoorthi, Kartik; Fropf, Robin; LaVerriere, Emily; Xue, Jian; Young, Andrew; Schneider, Colleen; Gøtzsche, Casper René; Hemberg, Martin; Yin, Jerry CP; Maier, Steven F; Lin, Yingxi

    2016-01-01

    Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system’s versatility. DOI: http://dx.doi.org/10.7554/eLife.13918.001 PMID:27661450

  13. Involvement of dopaminergic and cholinergic pathways in the induction of yawning and genital grooming by the aqueous extract of Saccharum officinarum L. (sugarcane) in rats.

    Science.gov (United States)

    Gamberini, Maria T; Gamberini, Maria C; Nasello, Antonia G

    2015-01-01

    Yawning, associated with genital grooming, is a physiological response that may be used for elucidating the mechanism of action of drugs. Preliminary analysis showed that aqueous extract (AE) of Saccharum induced yawns in rats. So, we aimed to quantify these behavioral responses and investigate the pharmacological mechanisms involved in these actions. During 120 min, after AE administration, the yawns and the genital grooming were quantified at 10 min intervals. Since dopaminergic and cholinergic pathways are implied in these responses, AE were evaluated in the presence of haloperidol 0.5 mg/kg and atropine 2 mg/kg. AE 0.5 g/kg increased the yawns, effect that was blocked both by haloperidol and atropine. Genital grooming could only be stimulated by AE 0.5 g/kg when dopaminergic receptors were blocked by haloperidol. However, it was inhibited when atropine was previously administered. So, we demonstrated a central action of Saccharum and it was postulated that neural circuits with the participation of dopaminergic and cholinergic pathways are involved. The fact that AE is comprised of innumerous compounds could justify the extract's distinct responses. Also, we cannot disregard the presence of different neural circuits that count on the participation of dopaminergic and cholinergic pathways and could be activated by the same induction agent.

  14. Study on cooperative active sensing system

    International Nuclear Information System (INIS)

    This study aims to develop a dispersed cooperative intellectualized system technique and a sensing system required for construction of a robot group inspectable in patrol and maintainable in selfish in a plant with large scale and complex variety. In particular, in order to establish a system with flexibility response to environment and soundness durable to abnormal accident, a cooperative active sensing technique and real-time active vision sensing technique were started. On the base of last two years results, in 1996 fiscal year, important and expansion of each element technique was conducted to start a study on movement of focussing point which was an important function of the active vision sensing. (G.K.)

  15. Active Displacement Control of Active Magnetic Bearing System

    Directory of Open Access Journals (Sweden)

    Kertész Milan

    2014-12-01

    Full Text Available The worldwide energy production nowadays is over 3400 GW while storage systems have a capacity of only 90 GW [1]. There is a good solution for additional storage capacity in flywheel energy storage systems (FES. The main advantage of FES is its relatively high efficiency especially with using the active magnetic bearing system. Therefore there exist good reasons for appropriate simulations and for creating a suitable magneto-structural control system. The magnetic bearing, including actuation, is simulated in the ANSYS parametric design language (APDL. APDL is used to create the loops of transient simulations where boundary conditions (BC are updated based upon a “gap sensor” which controls the nodal position values of the centroid of the shaft and the current density inputs onto the copper windings.

  16. ECOLOGICAL ACTIVITY IN THE ACCOUNTING SYSTEM

    OpenAIRE

    Лень, В. С.; Коливешко, А. М.

    2016-01-01

    The place of accounting of ecological activity in the accounting system is considered in the article. It is proved that accounting of ecological activity is a subsystem of accounting and is carried out within financial and management accounting. It is also proved that the concept of “environmental accounting” is a concept of higher level in comparison with the concept of “accounting of ecological activity”. Environmental accounting refers to the process of recognition, assessment and transfer...

  17. Study on Active Drive System for Colonoscope

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The paper deals with active drive system for colonoscope. The system is mainly composed of soft mobile mechanism for earthworm locomotion and turning mechanism based on shape memory effect. The soft mobile mechanism contacts colon wall with airin inflatable balloons, so the robot has better soft and non invasive properties. The turning mechanism can be actively bent by shape memory alloy components. It ensures the colonoscope to adapt to the tortuous shape of colon. Some experiment results are given in the paper.

  18. Pseudo energy wells in active systems

    CERN Document Server

    Sheshka, Raman; Truskinovsky, Lev

    2015-01-01

    Active stabilization in systems with zero or negative stiffness is an essential element of a wide variety of biological processes. We study a prototypical example of this phenomenon at a micro-scale and show how active rigidity, interpreted as a formation of a pseudo-well in the effective energy landscape, can be generated in an overdamped ratchet-type stochastic system. We link the transition from negative to positive rigidity with correlations in the noise and show that subtle differences in out-of-equilibrium driving may compromise the emergence of a pseudo-well.

  19. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism

    Directory of Open Access Journals (Sweden)

    Mireia Rabella

    2016-01-01

    Conclusions: These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

  20. Harmonic Reduction System Using Active Filter

    Directory of Open Access Journals (Sweden)

    Pallavi B.Endait

    2016-06-01

    Full Text Available This paper presents the harmonics analysis and compensation which occurred in the electrical system. We use the electrical signal analysis based on FFT technique in order to calculate harmonics that occurred in the electrical system. The harmonics are compensated by using active harmonic filters. This system consists of a computer which works as controller, processor, analysis, monitor and database unit together with a microcontroller which has A/D converter is used for sampling the electrical signals via a parallel port of the computer. The active harmonic filters (IGBT Module are controlled by PWM (Pulse Width Modulation signal from the microcontroller. The PWM data (Switching angle is programmed by computer. The data such as voltages, currents, the total harmonic distortion etc., can be saved as database for analysis. The harmonics compensation increase high efficiency of the electrical system and decrease the damage and incorrect operation that may happen with electrical devices.

  1. Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions

    International Nuclear Information System (INIS)

    Uranium is an environmental ubiquitous metal-trace element. It has both chemical and radiological toxicity. After chronic ingestion, uranium can distribute in any part of the body and accumulate in the brain. The aims of this study was 1) to determine and estimate the effects of uranium on dopaminergic, serotoninergic and cholinergic systems and 2) to measure the uranium amount in the brain, after chronic exposure by ingestion of depleted (D.U.) or enriched (E.U.) uranium during 1.5 to 18 months at 40 mg.L-1 (40 ppm) in different rat brain areas. At any time of exposure, the results show that both the neurotransmission alterations and the uranium brain accumulation were moderate, area specific, time-evolutive and depended on uranium specific activity. After D.U. exposure, monoamine perturbations are chronic and progressive. On the contrary, monoamine alterations occurred only after long term of E.U. exposure. These mono-aminergic modifications are not always dependent on uranium accumulation in brain areas. Moreover, although the cholinergic system was not affected at both 1.5 and 9 months of D.U. exposure, the alteration of ChE activity after E.U. exposure are both dependent on uranium accumulation in brain areas and on uranium specific activity. After E.U. exposure, cholinergic modification and uranium accumulation in hippocampus could partially explain the short-term memory disturbances which have been previously reported. (author)

  2. The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons

    Science.gov (United States)

    Chung, Chee Yeun; Licznerski, Pawel; Alavian, Kambiz N.; Simeone, Antonio; Lin, Zhicheng; Martin, Eden; Vance, Jeffery; Isacson, Ole

    2010-01-01

    Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson's disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease.…

  3. Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats.

    Science.gov (United States)

    Manduca, Antonia; Servadio, Michela; Damsteegt, Ruth; Campolongo, Patrizia; Vanderschuren, Louk Jmj; Trezza, Viviana

    2016-08-01

    Social play behavior is a highly rewarding form of social interaction displayed by young mammals. Social play is important for neurobehavioral development and it has been found to be impaired in several developmental psychiatric disorders. In line with the rewarding properties of social play, we have previously identified the nucleus accumbens (NAc) as an important site of action for endocannabinoid and opioid modulation of this behavior. NAc dopamine has a well-known role in certain components of reward processes, such as incentive motivation. However, its contribution to the positive emotional aspects of social interactions is less clear. Therefore, we investigated the role of dopaminergic neurotransmission in the NAc in social play behavior in rats. We found that intra-NAc infusion of the dopamine releaser/reuptake inhibitor amphetamine increased social play behavior that was dependent on activation of both D1 and D2 dopamine receptors. This increase in social play behavior was mimicked by intra-NAc infusion of the dopamine receptor agonist apomorphine, but not of the dopamine reuptake inhibitor GBR-12909. Blockade of either D1 or D2 NAc dopamine receptors reduced social play in animals highly motivated to play as a result of longer social isolation before testing. Last, blockade of NAc dopamine receptors prevented the play-enhancing effects of endocannabinoid and opioid receptor stimulation. These findings demonstrate an important modulatory role of NAc dopaminergic neurotransmission in social play. Thus, functional activity in the mesolimbic dopamine pathway plays an important role in adaptive social development, whereas abnormal NAc dopamine function may underlie the social impairments observed in developmental psychiatric disorders such as autism, attention deficit hyperactivity disorder or early-onset schizophrenia. PMID:26860202

  4. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Eric J Benner

    Full Text Available BACKGROUND: The neuropathology of Parkinson's disease (PD includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration. METHODS AND FINDINGS: Nitrotyrosine (NT-modified alpha-Syn was detected readily in cervical lymph nodes (CLN from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. CONCLUSIONS: These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and

  5. An effective inducer of dopaminergic neuron-like differentiation

    Institute of Scientific and Technical Information of China (English)

    Wenyu Fu; Cui Lv; Wenxin Zhuang; Dandan Chen; E Lv; Fengjie Li; Xiaocui Wang

    2013-01-01

    Rat bone marrow-derived mesenchymal stem cells were cultured and passaged in vitro. After induction with basic fibroblast growth factor for 24 hours, passage 3 bone marrow-derived mesenchymal stem cells were additionally induced into dopaminergic neurons using three different combinations with basic fibroblast growth factor as follows: 20% Xiangdan injection; all-trans retinoic acid + glial-derived neurotrophic factor; or sonic hedgehog + fibroblast growth factor 8. Results suggest that the bone marrow-derived mesenchymal stem cells showed typical neuronal morphological characteristics after induction. In particular, after treatment with sonic hedgehog + fibroblast growth factor 8, the expressions of nestin, neuron-specific enolase, microtubuleassociated protein 2, tyrosine hydroxylase and vesicular monoamine transporter-2 in cells were significantly increased. Moreover, the levels of catecholamines in the culture supernatant were significantly increased. These findings indicate that Xiangdan injection, all-trans retinoic acid + glial-derived neurotrophic factor, and sonic hedgehog + fibroblast growth factor 8 can all induce dopaminergic neuronal differentiation from bone marrow-derived mesenchymal stem cells. In particular, the efficiency of sonic hedgehog + fibroblast growth factor 8 was highest.

  6. Dopaminergic Genetic Polymorphisms Predict Rule-based Category Learning.

    Science.gov (United States)

    Byrne, Kaileigh A; Davis, Tyler; Worthy, Darrell A

    2016-07-01

    Dopaminergic genes play an important role in cognitive function. DRD2 and DARPP-32 dopamine receptor gene polymorphisms affect striatal dopamine binding potential, and the Val158Met single-nucleotide polymorphism of the COMT gene moderates dopamine availability in the pFC. Our study assesses the role of these gene polymorphisms on performance in two rule-based category learning tasks. Participants completed unidimensional and conjunctive rule-based tasks. In the unidimensional task, a rule along a single stimulus dimension can be used to distinguish category members. In contrast, a conjunctive rule utilizes a combination of two dimensions to distinguish category members. DRD2 C957T TT homozygotes outperformed C allele carriers on both tasks, and DARPP-32 AA homozygotes outperformed G allele carriers on both tasks. However, we found an interaction between COMT and task type where Met allele carriers outperformed Val homozygotes in the conjunctive rule task, but both groups performed equally well in the unidimensional task. Thus, striatal dopamine binding may play a critical role in both types of rule-based tasks, whereas prefrontal dopamine binding is important for learning more complex conjunctive rule tasks. Modeling results suggest that striatal dopaminergic genes influence selective attention processes whereas cortical genes mediate the ability to update complex rule representations. PMID:26918585

  7. Orosensory self-stimulation by sucrose involves brain dopaminergic mechanisms.

    Science.gov (United States)

    Schneider, L H

    1989-01-01

    The most convincing body of evidence supporting a role for brain dopaminergic mechanisms in sweet taste reward has been obtained using the sham-feeding rat. In rats prepared with a chronic gastric fistula and tested with the cannula open, intake is a direct function of the palatability of the solution offered as well as of the state of food deprivation. Because essentially none of the ingested fluid passes on to the intestine, negative postingestive feedback is eliminated. Thus, the relative orosensory/hedonic potency of the food determines and sustains the rate of sham intake; long periods of food deprivation are not required. In this way, the sham feeding of sweet solutions may be considered a form of oral self-stimulation behavior and afford a preparation through which the neurochemical and neuranatomical substrates of sweet taste reward may be identified. The results obtained in the series of experiments summarized in this paper clearly indicate that central D-1 and D-2 receptor mechanisms are critical for the orosensory self-stimulation by sucrose in the rat. In conclusion, I suggest that such investigations of the roles of brain dopaminergic mechanisms in the sucrose sham-feeding rat preparation may further our understanding of normal and aberrant attractions to sweet fluids in humans (see Cabanac, Drewnowski, and Halmi, this volume), as an innate, positive affective response of human neonates to sucrose and the sustained positive hedonic ratings for glucose when tasted but not when consumed have demonstrated. PMID:2699194

  8. Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro.

    Science.gov (United States)

    Giacomelli, S; Palmery, M; Romanelli, L; Cheng, C Y; Silvestrini, B

    1998-01-01

    The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

  9. CPB-K mice a mouse model of schizophrenia? Differences in dopaminergic, serotonergic and behavioral markers compared to BALB/cJ mice.

    Science.gov (United States)

    Panther, P; Nullmeier, S; Dobrowolny, H; Schwegler, H; Wolf, R

    2012-04-21

    Schizophrenia is characterized by disturbances in social behavior, sensorimotor gating and cognitive function, that are discussed to be caused by a termination of different transmitter systems. Beside morphological alterations in cortical and subcortical areas reduced AMPA- NMDA-, 5-HT2-receptor densities and increased 5-HT1-receptor densities are found in the hippocampus.The two inbred mouse strains CPB-K and BALB/cJ are known to display considerable differences in cognitive function and prepulse inhibition, a stable marker of sensorimotor gating. Furthermore, CPB-K mice exhibit lower NMDA-, AMPA- and increased 5-HT-receptor densities in the hippocampus as compared to BALB/cJ mice. We investigated both mouse strains in social interaction test for differences in social behavior and with immuncytochemical approaches for alterations of dopaminergic and serotonergic parameters. Our results can be summarized as follows: compared to BALB/cJ, CPB-K mice showed:(1) significantly reduced traveling distance and number of contacts in social interaction test, (2) differences in the number of serotonin transporter-immunoreactive neurons and volume of raphe nuclei and a lower serotonergic fiber density in the ventral and dorsal hippocampal subfields CA1 and CA3, (3) no alterations of dopaminergic markers like neuron number, neuron density and volume in subregions of substantia nigra and ventral tegmental area, but a significantly higher dopaminergic fiber density in the dorsal hippocampus, the ventral hippocampus of CA1 and gyrus dentatus, (4) no significant differences in serotonergic and dopaminergic fiber densities in the amygdala.Based on our results and previous studies, CPB-K mice compared to BALB/cJ may serve as an important model to understand the interaction of the serotonergic and dopaminergic system and their impact on sensorimotor gating and cognitive function as related to neuropsychiatric disorders like schizophrenia.

  10. Communication Systems and Study Method for Active Distribution Power systems

    DEFF Research Database (Denmark)

    Wei, Mu; Chen, Zhe

    Due to the involvement and evolvement of communication technologies in contemporary power systems, the applications of modern communication technologies in distribution power system are becoming increasingly important. In this paper, the International Organization for Standardization (ISO......) reference seven-layer model of communication systems, and the main communication technologies and protocols on each corresponding layer are introduced. Some newly developed communication techniques, like Ethernet, are discussed with reference to the possible applications in distributed power system....... The suitability of the communication technology to the distribution power system with active renewable energy based generation units is discussed. Subsequently the typical possible communication systems are studied by simulation. In this paper, a novel method of integrating communication system impact into power...

  11. System of strategic planning of enterprises activity

    OpenAIRE

    Тригоб’юк, Сергій Сергійович

    2012-01-01

    The review of researches of strategic management is resulted in the article, especially features of strategic administrative decisions, strategic diagnostics, in the system of the strategic planning of activity of enterprises, and the problems of leadership, development of strategic thinking and social aspects of business conduct in a modern variable environment also.

  12. Supporting Classroom Activities with the BSUL System

    Science.gov (United States)

    Ogata, Hiroaki; Saito, Nobuji A.; Paredes J., Rosa G.; San Martin, Gerardo Ayala; Yano, Yoneo

    2008-01-01

    This paper presents the integration of ubiquitous computing systems into classroom settings, in order to provide basic support for classrooms and field activities. We have developed web application components using Java technology and configured a classroom with wireless network access and a web camera for our purposes. In this classroom, the…

  13. Active Fault Isolation in MIMO Systems

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik; Poulsen, Niels Kjølstad

    2014-01-01

    isolation is based directly on the input/output s ignals applied for the fault detection. It is guaranteed that the fault group includes the fault that had occurred in the system. The second step is individual fault isolation in the fault group . Both types of isolation are obtained by applying dedicated......Active fault isolation of parametric faults in closed-loop MIMO system s are considered in this paper. The fault isolation consists of two steps. T he first step is group- wise fault isolation. Here, a group of faults is isolated from other pos sible faults in the system. The group-wise fault...

  14. A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

    International Nuclear Information System (INIS)

    In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2

  15. Positron emission tomography in degenerative disorders of the dopaminergic system

    International Nuclear Information System (INIS)

    21 patients who had Parkinson's disease (PD), PD plus dementia of Alzheimer type (PDAT) or progressive supranuclear palsy (PSP), were studied with positron emission tomography (PET) using (18F)-2-fluoro-2-deoxy-D-glucose (FDG). In one patient with strictly unilateral PD side differences in striatal dopa uptake were studied with 6-(18F)fluoro-L-dopa (F-dopa). In patients with PD PET with FDG did not show any significant change in regional cerebral metabolic rates for glucose (rCMR(Glu)). In PDAT glucose metabolism was generally reduced, the most severe decrease was found in parietal cortex. The metabolic pattern was similar to that typically found in patients with Alzheimer's disease (AD). In the patient with strictly unilateral PD rCMR(Glu) was normal, F-dopa PET, however, revealed a distinct reduction of dopa uptake in the contralateral putamen. In PSP glucose metabolism was significantly decreased in subcortical regions (caudatum, putamen and brainstem) and in frontal cortex. Thus PET demonstrated a clear difference of metabolic pattern between PDAT and PSP. (authors)

  16. Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo.

    Science.gov (United States)

    Nam, Jin Han; Leem, Eunju; Jeon, Min-Tae; Kim, Young-Je; Jung, Un Ju; Choi, Myung-Sook; Maeng, Sungho; Jin, Byung Kwan; Kim, Sang Ryong

    2014-05-01

    Prothrombin kringle-2 (pKr-2), a domain of prothrombin, can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation. However, the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known. The present study investigated whether minocycline, a semisynthetic tetracycline derivative, could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic (DA) neurons in vivo. To address this question, rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline. Our results show that pKr-2 induces the production of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inducible nitric oxide synthase from the activated microglia. In parallel, 7 days after pKr-2 injection, tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons. This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase. These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation. PMID:24488033

  17. Expert system aided operator's mental activities training

    International Nuclear Information System (INIS)

    The operator's mental activity is the most important part of his work. A processing of a large amount of the information by the operator is possible only if he/she possesses appropriate cognitive skills. To facilitate the novice's acquisition of the experienced operator's cognitive skills of the decision-making process a special type of the expert system was developed. The cognitive engineering's models and problem-solving methodology constitutes the basis of this expert system. The article gives an account of the prototype of the mentioned expert system developed to aid the whole mental activity of the nuclear power plant operator during his decision-making process. (author). 6 refs, 6 figs

  18. Active gated imaging in driver assistance system

    Science.gov (United States)

    Grauer, Yoav

    2014-04-01

    In this paper, we shall present the active gated imaging system (AGIS) in relation to the automotive field. AGIS is based on a fast-gated camera and pulsed illuminator, synchronized in the time domain to record images of a certain range of interest. A dedicated gated CMOS imager sensor and near infra-red (NIR) pulsed laser illuminator, is presented in this paper to provide active gated technology. In recent years, we have developed these key components and learned the system parameters, which are most beneficial to nighttime (in all weather conditions) driving in terms of field of view, illumination profile, resolution, and processing power. We shall present our approach of a camera-based advanced driver assistance systems (ADAS) named BrightEye™, which makes use of the AGIS technology in the automotive field.

  19. Study on cooperative active sensing system

    International Nuclear Information System (INIS)

    Electrotechnical Laboratory is involved in the development and the improvement of three dimensional geometrical modeling for the work environment including various kinds of robots. Here, the research on the system which allows to materialize an active sensing by the cooperation of robots and the construction of an experimental system for the assessment of such modeling were reviewed. In the second stage of this project, the development of cooperative active sensory system with small size mobile robots as an operation platform was attempted. Thus, studies on the sensing techniques for robot operation and the real-time sensing techniques were started. An electric binocular head was prepared after consideration of size, cost and convenience and attached to the commercially available mobile robot base (Mouse 89, Japan System Design Co., Ltd.). The small mobile robot capable of binocular visual tracing thus obtained was confirmed to be highly efficient by various cooperative control experiments although the head was prepared at the sacrifice of control characteristics. Next, a real-time sensing system which allows to trace a moving object was constructed on the basis of Zero Disparity Filter (ZDF) produced by Kaenel et al. and further improved in the respect of the difficulty in real time processing and an expanded type ZDF was obtained. This system is routinely used as an basic vision unit for a mobile robot in the presence. (M.N.)

  20. Modular System to Enable Extravehicular Activity

    Science.gov (United States)

    Sargusingh, Miriam J.

    2012-01-01

    The ability to perform extravehicular activity (EVA), both human and robotic, has been identified as a key component to space missions to support such operations as assembly and maintenance of space systems (e.g. construction and maintenance of the International Space Station), and unscheduled activities to repair an element of the transportation and habitation systems that can only be accessed externally and via unpressurized areas. In order to make human transportation beyond lower Earth orbit (LEO) practical, efficiencies must be incorporated into the integrated transportation systems to reduce system mass and operational complexity. Affordability is also a key aspect to be considered in space system development; this could be achieved through commonality, modularity and component reuse. Another key aspect identified for the EVA system was the ability to produce flight worthy hardware quickly to support early missions and near Earth technology demonstrations. This paper details a conceptual architecture for a modular EVA system that would meet these stated needs for EVA capability that is affordable, and that could be produced relatively quickly. Operational concepts were developed to elaborate on the defined needs, and to define the key capabilities, operational and design constraints, and general timelines. The operational concept lead to a high level design concept for a module that interfaces with various space transportation elements and contains the hardware and systems required to support human and telerobotic EVA; the module would not be self-propelled and would rely on an interfacing element for consumable resources. The conceptual architecture was then compared to EVA Systems used in the Space Shuttle Orbiter, on the International Space Station to develop high level design concepts that incorporate opportunities for cost savings through hardware reuse, and quick production through the use of existing technologies and hardware designs. An upgrade option

  1. Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study.

    Science.gov (United States)

    Zakharov, Denis; Lapish, Christopher; Gutkin, Boris; Kuznetsov, Alexey

    2016-01-01

    Dopaminergic (DA) neurons display two modes of firing: low-frequency tonic and high-frequency bursts. The high frequency firing within the bursts is attributed to NMDA, but not AMPA receptor activation. In our models of the DA neuron, both biophysical and abstract, the NMDA receptor current can significantly increase their firing frequency, whereas the AMPA receptor current is not able to evoke high-frequency activity and usually suppresses firing. However, both currents are produced by glutamate receptors and, consequently, are often co-activated. Here we consider combined influence of AMPA and NMDA synaptic input in the models of the DA neuron. Different types of neuronal activity (resting state, low frequency, or high frequency firing) are observed depending on the conductance of the AMPAR and NMDAR currents. In two models, biophysical and reduced, we show that the firing frequency increases more effectively if both receptors are co-activated for certain parameter values. In particular, in the more quantitative biophysical model, the maximal frequency is 40% greater than that with NMDAR alone. The dynamical mechanism of such frequency growth is explained in the framework of phase space evolution using the reduced model. In short, both the AMPAR and NMDAR currents flatten the voltage nullcline, providing the frequency increase, whereas only NMDA prevents complete unfolding of the nullcline, providing robust firing. Thus, we confirm a major role of the NMDAR in generating high-frequency firing and conclude that AMPAR activation further significantly increases the frequency. PMID:27252643

  2. Control Systems Cyber Security Standards Support Activities

    Energy Technology Data Exchange (ETDEWEB)

    Robert Evans

    2009-01-01

    The Department of Homeland Security’s Control Systems Security Program (CSSP) is working with industry to secure critical infrastructure sectors from cyber intrusions that could compromise control systems. This document describes CSSP’s current activities with industry organizations in developing cyber security standards for control systems. In addition, it summarizes the standards work being conducted by organizations within the sector and provides a brief listing of sector meetings and conferences that might be of interest for each sector. Control systems cyber security standards are part of a rapidly changing environment. The participation of CSSP in the development effort for these standards has provided consistency in the technical content of the standards while ensuring that information developed by CSSP is included.

  3. Preparation of 99Tcm-Annexin V and in vitro study of its binding characteristics in dopaminergic apoptotic neurons

    International Nuclear Information System (INIS)

    Objective: The aims of this study were two. One was to find out an optimal method for 99Tcm-Annexin V preparation and the other was to investigate the binding characteristics of 99Tcm-Annexin V in dopaminergic apoptotic neurons in vitro. Methods: For 99Tcm-Annexin V preparation, hydrazine nicotinamide (HYNIC), a bifunctional chelating agent was used. Product was purified by Sephadex G-25 column chromatography and analyzed with instant thin layer chromatography (ITLC). To test the binding characteristics in dopaminergic apoptotic neurons in vitro, a rat pheoehromocytoma cell line (PC12) treated with l-methyl-4-phenylpyridinium (MPP+) was used. Tests including time-temperature binding, saturable bind- ing, competition binding between dopaminergic apoptotic neurons and 99Tcm-HYNIC-Annexin V and dose- dependent MPP+ studies were performed and evaluated. Results: The labeling rate of 99Tcm was (64.56 ± 6.23)%. The specific activity of 99Tcm-HYNIC-Annexin V was (3.7-74)xl05 kBq/mg protein. The radiochemical purity was (93.6±2.48)% and was >90% after 4 hours storage at room temperature. Seat- chard plotting suggested that the concentrations of Kd was (7.16±1.78) nmol/L, and Bmax was (178.73± 32.62) fmoL/106 ceils. Conclusions: The preliminary results show that an optimal 99Tcm-HYNIC-Annexin V preparation method can be provided. The 99Tcm-HYNIC-Annexin V prepared in our laboratory has good receptor-binding activity and may possibly be a potential drug in studying the apoptotic phenomenon in Parkin- son's disease at early stage in an animal model. (authors)

  4. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    Science.gov (United States)

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

    2016-01-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  5. Active State Model for Autonomous Systems

    Science.gov (United States)

    Park, Han; Chien, Steve; Zak, Michail; James, Mark; Mackey, Ryan; Fisher, Forest

    2003-01-01

    The concept of the active state model (ASM) is an architecture for the development of advanced integrated fault-detection-and-isolation (FDI) systems for robotic land vehicles, pilotless aircraft, exploratory spacecraft, or other complex engineering systems that will be capable of autonomous operation. An FDI system based on the ASM concept would not only provide traditional diagnostic capabilities, but also integrate the FDI system under a unified framework and provide mechanism for sharing of information between FDI subsystems to fully assess the overall health of the system. The ASM concept begins with definitions borrowed from psychology, wherein a system is regarded as active when it possesses self-image, self-awareness, and an ability to make decisions itself, such that it is able to perform purposeful motions and other transitions with some degree of autonomy from the environment. For an engineering system, self-image would manifest itself as the ability to determine nominal values of sensor data by use of a mathematical model of itself, and selfawareness would manifest itself as the ability to relate sensor data to their nominal values. The ASM for such a system may start with the closed-loop control dynamics that describe the evolution of state variables. As soon as this model was supplemented with nominal values of sensor data, it would possess self-image. The ability to process the current sensor data and compare them with the nominal values would represent self-awareness. On the basis of self-image and self-awareness, the ASM provides the capability for self-identification, detection of abnormalities, and self-diagnosis.

  6. Peripheral neural activity recording and stimulation system.

    Science.gov (United States)

    Loi, D; Carboni, C; Angius, G; Angotzi, G N; Barbaro, M; Raffo, L; Raspopovic, S; Navarro, X

    2011-08-01

    This paper presents a portable, embedded, microcontroller-based system for bidirectional communication (recording and stimulation) between an electrode, implanted in the peripheral nervous system, and a host computer. The device is able to record and digitize spontaneous and/or evoked neural activities and store them in data files on a PC. In addition, the system has the capability of providing electrical stimulation of peripheral nerves, injecting biphasic current pulses with programmable duration, intensity, and frequency. The recording system provides a highly selective band-pass filter from 800 Hz to 3 kHz, with a gain of 56 dB. The amplification range can be further extended to 96 dB with a variable gain amplifier. The proposed acquisition/stimulation circuitry has been successfully tested through in vivo measurements, implanting a tf-LIFE electrode in the sciatic nerve of a rat. Once implanted, the device showed an input referred noise of 0.83 μVrms, was capable of recording signals below 10 μ V, and generated muscle responses to injected stimuli. The results demonstrate the capability of processing and transmitting neural signals with very low distortion and with a power consumption lower than 1 W. A graphic, user-friendly interface has been developed to facilitate the configuration of the entire system, providing the possibility to activate stimulation and monitor recordings in real time.

  7. Active fault detection in MIMO systems

    DEFF Research Database (Denmark)

    Niemann, Hans Henrik; Poulsen, Niels Kjølstad

    2014-01-01

    The focus in this paper is on active fault detection (AFD) for MIMO systems with parametric faults. The problem of design of auxiliary inputs with respect to detection of parametric faults is investigated. An analysis of the design of auxiliary inputs is given based on analytic transfer functions...... from auxiliary input to residual outputs. The analysis is based on a singular value decomposition of these transfer functions Based on this analysis, it is possible to design auxiliary input as well as design of the associated residual vector with respect to every single parametric fault in the system...

  8. Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model.

    Science.gov (United States)

    Qi, Xin; Davis, Brandon; Chiang, Yung-Hsiao; Filichia, Emily; Barnett, Austin; Greig, Nigel H; Hoffer, Barry; Luo, Yu

    2016-09-01

    p53, a stress response gene, is involved in diverse cell death pathways and its activation has been implicated in the pathogenesis of Parkinson's disease (PD). However, whether the neuronal p53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 knock-out (KO) mice, we examined the effect of DA specific p53 gene deletion in DAT-p53KO mice. These DAT-p53KO mice did not exhibit apparent changes in the general structure and neuronal density of DA neurons during late development and in aging. However, in DA-p53KO mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that the induction of Bax and p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein levels by MPTP were diminished in both striatum and substantia nigra of these mice. Notably, deletion of the p53 gene in DA neurons significantly reduced dopaminergic neuronal loss in substantia nigra, dopaminergic neuronal terminal loss at striatum and, additionally, decreased motor deficits in mice challenged with MPTP. In contrast, there was no difference in astrogliosis between WT and DAT-p53KO mice in response to MPTP treatment. These findings demonstrate a specific contribution of p53 activation in DA neuronal cell death by MPTP challenge. Our results further support the role of programmed cell death mediated by p53 in this animal model of PD and identify Bax, BAD and PUMA genes as downstream targets of p53 in modulating DA neuronal death in the in vivo MPTP-induced PD model. We deleted p53 gene in dopaminergic neurons in late developmental stages and found that DA specific p53 deletion is protective in acute MPTP animal model possibly through blocking MPTP-induced BAX and PUMA up-regulation. Astrocyte activation measured by GFAP positive cells and GFAP gene up-regulation in the striatum shows no difference

  9. Dopaminergic control of cognitive flexibility in humans and animals

    Directory of Open Access Journals (Sweden)

    Marianne eKlanker

    2013-11-01

    Full Text Available Striatal dopamine is thought to code for learned associations between cues and reinforcers and to mediate approach behavior towards a reward. Less is known about the contribution of dopamine to cognitive flexibility – the ability to adapt behavior in response to changes in the environment. Altered reward processing and impairments in cognitive flexibility are observed in psychiatric disorders such as obsessive compulsive disorder. Patients with this disorder show a disruption of functioning in the frontostriatal circuit and alterations in dopamine signaling. In this review we summarize findings from animal and human studies that have investigated the involvement of striatal dopamine in cognitive flexibility. These findings may provide a better understanding of the role of dopaminergic dysfunction in cognitive inflexibility in psychiatric disorders, such as OCD.

  10. Activation of microglia and dopaminergic neurons degeneration following intraventricular injection of LPS in the substantia nigra of rats%经侧脑室注射脂多糖诱导大鼠黑质部位小胶质细胞激活及多巴胺能神经元损伤的研究

    Institute of Scientific and Technical Information of China (English)

    赵咏梅; 李军泉; 吕风月; 闫颖; 徐群渊

    2012-01-01

    目的 观察经脑室注射脂多糖(LPS)后大鼠的黑质部小胶质细胞激活及多巴胺(DA)能神经元的变化,探讨脑内炎性反应在黑质DA能神经元慢性变性过程中的作用.方法 健康雄性SD大鼠30只,随机分为生理盐水(NS)对照组和LPS组,分别向大鼠右侧脑室注射20μLNS或50 μg LPS,40周后用免疫组织化学方法检测大鼠黑质小胶质细胞是否激活、激活的程度(OX-42及OX-6抗体水平),以及酪氨酸羟化酶(TH)阳性神经元的形态和数量.以Fluoro-Jade B(FJB)染色法检测黑质部位神经元变性情况.结果 (1)NS对照组大鼠黑质部位OX-42阳性小胶质细胞呈静息状态,染色浅.LPS组大鼠黑质部OX-42阳性小胶质细胞呈部分激活状态,染色深.两组大鼠黑质部位均未发现OX-6阳性小胶质细胞.(2)NS对照组大鼠黑质部位有大量深染的TH阳性神经元.LPS组大鼠黑质部位TH阳性染色神经元数目(99.11±20.31)比NS对照组(189.52±12.12)减少47.7% (P<0.01).(3)两组大鼠黑质部位均未见FJB阳性染色神经元.结论 经侧脑室单次注射LPS可能造成大鼠黑质部位小胶质细胞长期慢性激活及DA能神经元慢性迟发性功能性损伤.%Objective To investigate the effect of intraventricular injection of lipoplysaccharide (LPS) on microglia activation and dopaminergic (DA) neurons in the substantia nigra of rats and to explore the role of intracephalic inflammation on DA neurons chronic degeneration. Methods 30 healthy male SD rats were randomly assigned into normal saline (NS) control group and 50 jig LPS group. The rats were treated with intraventricularl injection of 20 jiL NS or 50 fig LPS on right side. 40 weeks later, OX-42 and OX-6 antibodies were used to detect whether the microglia were activated in the substantia nigra of rats. The morphology and numbers of DA neurons were observed by tyrosine hydroxylase (TH) immunohistochemical staining. The degenerated neurons were detected by using Fluoro

  11. Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study

    International Nuclear Information System (INIS)

    We analyzed 18F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced 18F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60 % of subjects with abnormal 18F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal 18F-dopa uptake in susceptible relatives may predict later clinical disease. (author)

  12. Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

    OpenAIRE

    Qi Xu; Kanthasamy, Anumantha G.; Reddy, Manju B.

    2011-01-01

    Iron may play an important role in Parkinson's disease (PD) since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6) can protect against 6-hydroxydopamine- (6-OHDA-) induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; < . 0 0 1 ) and 30 μmol/L I...

  13. Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy.

    Science.gov (United States)

    Dhanda, Saurabh; Sandhir, Rajat

    2015-06-01

    The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE. PMID:25639545

  14. Noninvasive ambulatory measurement system of cardiac activity.

    Science.gov (United States)

    Pino, Esteban J; Chavez, Javier A P; Aqueveque, Pablo

    2015-08-01

    This work implements a noninvasive system that measures the movements caused by cardiac activity. It uses unobtrusive Electro-Mechanical Films (EMFi) on the seat and on the backrest of a regular chair. The system detects ballistocardiogram (BCG) and respiration movements. Real data was obtained from 54 volunteers. 19 of them were measured in the laboratory and 35 in a hospital waiting room. Using a BIOPAC acquisition system, the ECG was measured simultaneously to the BCG for comparison. Wavelet Transform (WT) is a better option than Empirical Mode Decomposition (EMD) for signal extraction and produces higher effective measurement time. In the laboratory, the best results are obtained on the seat. The correlation index was 0.9800 and the Bland-Altman limits of agreement were 0.7136 ± 4.3673 [BPM]. In the hospital waiting room, the best results are also from the seat sensor. The correlation index was 0.9840, and the limits of agreement were 0.4386 ± 3.5884 [BPM]. The system is able to measure BCG in an unobtrusive way and determine the cardiac frequency with high precision. It is simple to use, which means the system can easily be used in non-standard settings: resting in a chair or couch, at the gym, schools or in a hospital waiting room, as shown. PMID:26738057

  15. Active Sensor Configuration Validation for Refrigeration Systems

    DEFF Research Database (Denmark)

    Hovgaard, Tobias Gybel; Blanke, Mogens; Niemann, Hans Henrik;

    2010-01-01

    Major faults in the commissioning phase of refrigeration systems are caused by defects related to sensors. With a number of similar sensors available that do not differ by type but only by spatial location in the plant, interchange of sensors is a common defect. With sensors being used quite...... differently by the control system, fault-finding is difficult in practice and defects are regularly causing commissioning delays at considerable expense. Validation and handling of faults in the sensor configuration are therefore essential to cut costs during commissioning. With passive fault......-diagnosis methods falling short on this problem, this paper suggests an active diagnosis procedure to isolate sensor faults at the commissioning stage, before normal operation has started. Using statistical methods, residuals are evaluated versus multiple hypothesis models in a minimization process to uniquely...

  16. Actively controlled vibration welding system and method

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Wayne W.; Kang, Bongsu; Tan, Chin-An

    2013-04-02

    A vibration welding system includes a controller, welding horn, an active material element, and anvil assembly. The assembly may include an anvil body connected to a back plate and support member. The element, e.g., a piezoelectric stack or shape memory alloy, is positioned with respect to the assembly. The horn vibrates in a desirable first direction to form a weld on a work piece. The element controls any vibrations in a second direction by applying calibrated response to the anvil body in the second direction. A method for controlling undesirable vibrations in the system includes positioning the element with respect to the anvil assembly, connecting the anvil body to the support member through the back plate, vibrating the horn in a desirable first direction, and transmitting an input signal to the element to control vibration in an undesirable second direction.

  17. Spontaneous Oscillations in an Active Matter System

    Science.gov (United States)

    Hayes, Robert; Tsang, Boyce; Granick, Steve

    Active matter (which consumes energy to move about) can organize into dynamic structures more interesting than those possible at steady-state. Here we show spontaneous periodic self-assembly in a simple three-component system of water, oil phase, and surfactant at constant room temperature, with emphasis on one model system. Benchtop experiments show that liquid crystal oil droplets spontaneously and collectively oscillate like a `beating heart' for several hours; contract, relax, and subsequently re-contract in a petri dish at a rate of a few `beats' per minute. These oscillations, emergent from the cooperative interaction of the three components, are driven by the competition between positive and negative feedback processes. This illustration of feedback in action reveals a new way to program self-assembled structures to vary with time.

  18. Brief dopaminergic stimulations produce transient physiological changes in prefrontal pyramidal neurons.

    Science.gov (United States)

    Moore, Anna R; Zhou, Wen-Liang; Potapenko, Evgeniy S; Kim, Eun-Ji; Antic, Srdjan D

    2011-01-25

    In response to food reward and other pertinent events, midbrain dopaminergic neurons fire short bursts of action potentials causing a phasic release of dopamine in the prefrontal cortex (rapid and transient increases in cortical dopamine concentration). Here we apply short (2s) iontophoretic pulses of glutamate, GABA, dopamine and dopaminergic agonists locally, onto layer 5 pyramidal neurons in brain slices of the rat medial prefrontal cortex (PFC). Unlike glutamate and GABA, brief dopaminergic pulses had negligible effects on the resting membrane potential. However, dopamine altered action potential firing in an extremely rapid (iontophoresis current artifact. Our present data imply that one population of PFC pyramidal neurons receiving direct synaptic contacts from midbrain dopaminergic neurons would stall during the 0.5s of the phasic dopamine burst. The spillover dopamine, on the other hand, would act as a positive stimulator of cortical excitability (30% increase) to all D2-receptor carrying pyramidal cells, for the next 40s.

  19. Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

    Science.gov (United States)

    Blum, Kenneth; Simpatico, Thomas; Badgaiyan, Rajendra D.; Demetrovics, Zsolt; Fratantonio, James; Agan, Gozde; Febo, Marcelo; Gold, Mark S.

    2016-01-01

    Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of “Personalized Medicine” in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term “Reward Deficiency Syndrome (RDS)” to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score” (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior

  20. Coupling Neurogenetics (GARS™ and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS: Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

    Directory of Open Access Journals (Sweden)

    Kenneth Blum

    2015-06-01

    Full Text Available Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2] to associate with severe alcoholism serves as a blue-print for the development of "Personalized Medicine" in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term "Reward Deficiency Syndrome (RDS" to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as "Genetic Addiction Risk Score" (GARSpDX™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASIMedia Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior

  1. 偏侧帕金森大鼠模型各个发病时期多巴胺能系统的动态监测%The unilateral 6-hydroxydopamine lesion rats' dynamic supervision about the nigrostriatal dopaminergic system in various stages of its pathogenesis

    Institute of Scientific and Technical Information of China (English)

    曹非; 陈涵; 张潇潇; 孙圣刚

    2012-01-01

    Objective To dynamically supervise the changes of the nigrostriatal dopaminergic system of rats with unilateral 6-hydroxydopamine(6-OHDA) lesion in various stages of its pathogenesis and to find out the rules of the changes ,and to build up a model of treatment for the further research. Methods The unilateral lesioned rat models of Parkinsons Disease with 6-0HDA were treated with levodopa for 14 days after the successful models were made. Each 7 days during the course, we measure the behavioral rotations, count the numbers of the tyrosine hydroxylase(TH)positive cells ,the dopamine(DA) contents, and make the Nissle stain. Results At the first and the second time points, the concentration of DA collapsed by 16.7% and 80% , the numbers of TH positive cells decreased by 47. 97% and 93. 28% , besides the Nissl's bodies were cut by 31. 4% and 46. 4% . After the treatment with low dose of levodopa, the rotational behaviour and the number of the TH positive cells and the Nissl's bodies didn t change obviously. Only the concentration of DA increased to 58. 3% of that of the control group . Conclusion These items all positively related to each other during the pathogenesis. The low-dose administration of levodopa for a short time only had some effect on the ascending of the concentration of dopamine for in advanced Parkinsons disease.%目的 动态监测帕金森大鼠不同发病阶段多巴胺能系统的改变,掌握其变化规律和各指标间的量化关系,为进一步实验提供动物治疗模型.方法 偏侧两点注射法制作帕金森病大鼠模型,模型成功两周后给予小剂量左旋多巴治疗一周.每周检测纹状体多巴胺(DA)含量,黑质酪氨酸羟化酶(TH)染色和尼氏染色,观察行为学改变.结果 一周后即发病的代偿期,行为学开始出现向健侧的旋转;两周后即失代偿期,旋转次数加重至最高峰.前两周多巴胺含量分别较正常对照侧减少16.7%和80%,TH阳性细胞分别下降47.97

  2. Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.

    Directory of Open Access Journals (Sweden)

    Adam W Oaks

    Full Text Available Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.

  3. Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

    DEFF Research Database (Denmark)

    Herz, Damian M.; Haagensen, Brian N.; Christensen, Mark S.;

    2015-01-01

    Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy......-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements....

  4. Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function

    OpenAIRE

    van Schouwenburg, Martine R.; Zwiers, Marcel P.; van der Schaaf, Marieke E.; Geurts, Dirk E M; Arnt F.A. Schellekens; Buitelaar, Jan K; Verkes, Robbert J.; Cools, Roshan

    2013-01-01

    Rationale The neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals. Objectives We investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts. ...

  5. The detection of novelty relies on dopaminergic signaling: evidence from apomorphine's impact on the novelty N2.

    Directory of Open Access Journals (Sweden)

    Mauricio Rangel-Gomez

    Full Text Available Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist and measure the change in neurological indices of novelty processing. In separate drug and placebo sessions, participants completed a von Restorff task. Apomorphine speeded and potentiated the novelty-elicited N2, an Event-Related Potential (ERP component thought to index early aspects of novelty detection, and caused novel-font words to be better recalled. Apomorphine also decreased the amplitude of the novelty-P3a. An increase in D1/D2 receptor activation thus appears to potentiate neural sensitivity to novel stimuli, causing this content to be better encoded.

  6. Effects of Nano-MnO2 on Dopaminergic Neurons and the Spatial Learning Capability of Rats

    Directory of Open Access Journals (Sweden)

    Tao Li

    2014-08-01

    Full Text Available This study aimed to observe the effect of intracerebrally injected nano-MnO2 on neurobehavior and the functions of dopaminergic neurons and astrocytes. Nano-MnO2, 6-OHDA, and saline (control were injected in the substantia nigra and the ventral tegmental area of Sprague-Dawley rat brains. The neurobehavior of rats was evaluated by Morris water maze test. Tyrosine hydroxylase (TH, inducible nitric oxide synthase (iNOS and glial fibrillary acidic protein (GFAP expressions in rat brain were detected by immunohistochemistry. Results showed that the escape latencies of nano-MnO2 treated rat increased significantly compared with control. The number of TH-positive cells decreased, GFAP- and iNOS-positive cells increased significantly in the lesion side of the rat brains compared with the contralateral area in nano-MnO2 group. The same tendencies were observed in nano-MnO2-injected rat brains compared with control. However, in the the positive control, 6-OHDA group, escape latencies increased, TH-positive cell number decreased significantly compared with nano-MnO2 group. The alteration of spatial learning abilities of rats induced by nano-MnO2 may be associated with dopaminergic neuronal dysfunction and astrocyte activation.

  7. Child maltreatment, impulsivity, and antisocial behavior in African American children: Moderation effects from a cumulative dopaminergic gene index.

    Science.gov (United States)

    Thibodeau, Eric L; Cicchetti, Dante; Rogosch, Fred A

    2015-11-01

    A model examining the effects of an increasing number of maltreatment subtypes experienced on antisocial behavior, as mediated by impulsivity and moderated by a polygenic index of dopaminergic genotypes, was investigated. An African American sample of children (N = 1,012, M age = 10.07) with and without maltreatment histories participated. Indicators of aggression, delinquency, and disruptive peer behavior were obtained from peer- and counselor-rated measures to form a latent variable of antisocial behavior; impulsivity was assessed by counselor report. Five genotypes in four dopaminergic genes (dopamine receptors D4, D2, known as DRD4, DRD2; dopamine active transporter 1, known as DAT1; and catechol-O-methyltransferase, known as COMT) conferring heightened environmental sensitivity were combined into one polygenic index. Using structural equation modeling, a first-stage, moderated-mediation model was evaluated. Age and sex were entered as covariates, both as main effects and in interaction with maltreatment and the gene index. The model had excellent fit: χ2 (32, N = 1,012) = 86.51, p effect of maltreatment subtypes on antisocial behavior was partially mediated by impulsivity (β = 0.173, p maltreatment and impulsivity was stronger as children evinced more differentiating genotypes, thereby strengthening the mediational effect of impulsivity on antisocial behavior. These findings elucidate the manner by which maltreated children develop early signs of antisocial behavior, and the genetic mechanisms involved in greater vulnerability for maladaptation in impulse control within the context of child maltreatment. PMID:26535948

  8. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.

    Science.gov (United States)

    Pristerà, Alessandro; Lin, Wei; Kaufmann, Anna-Kristin; Brimblecombe, Katherine R; Threlfell, Sarah; Dodson, Paul D; Magill, Peter J; Fernandes, Cathy; Cragg, Stephanie J; Ang, Siew-Lan

    2015-09-01

    Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice. PMID:26283356

  9. Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Xi-Xun Du; Hua-Min Xu; Hong Jiang; Ning Song; Jun Wang; Jun-Xia Xie

    2012-01-01

    [Objective] Curcumin is a plant polyphenolic compound and a major component of spice turmeric (Curcuma longa).It has been reported to possess free radical-scavenging,iron-chelating,and anti-inflammatory properties in different tissues.Our previous study showed that curcumin protects MES23.5 dopaminergic cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro.The present study aimed to explore this neuroprotective effect in the 6-OHDAlesioned rat model of Parkinson's disease in vivo.[Methods] Rats were given intragastric curcumin for 24 days.6-OHDA lesioning was conducted on day 4 of curcumin treatment.Dopamine content was assessed by high-performance liquid chromatography with electrochemical detection,tyrosine hydroxylase (TH)-containing neurons by immunohistochemistry,and iron-containing cells by Perls' iron staining.[Results] The dopamine content in the striatum and the number of THimmunoreactive neurons decreased after 6-OHDA treatment.Curcumin pretreatment reversed these changes.Further studies demonstrated that 6-OHDA treatment increased the number of iron-staining cells,which was dramatically decreased by curcumin pretreatment.[Conclusion]The protective effects of curcumin against 6-OHDA may be attributable to the ironchelating activity of curcumin to suppress the iron-induced degeneration of nigral dopaminergic neurons.

  10. Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date.

    Science.gov (United States)

    Sami, Musa Basser; Rabiner, Eugenii A; Bhattacharyya, Sagnik

    2015-08-01

    A significant body of epidemiological evidence has linked psychotic symptoms with both acute and chronic use of cannabis. Precisely how these effects of THC are mediated at the neurochemical level is unclear. While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in dopamine neurotransmission is considered to be the final common abnormality. One would thus expect cannabis use to be associated with dopamine signaling alterations. This is the first systematic review of all studies, both observational as well as experimental, examining the acute as well as chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man. We aimed to review all studies conducted in man, with any reported neurochemical outcomes related to the dopamine system after cannabis, cannabinoid or endocannabinoid administration or use. We identified 25 studies reporting outcomes on over 568 participants, of which 244 participants belonged to the cannabis/cannabinoid exposure group. In man, there is as yet little direct evidence to suggest that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status in healthy human volunteers. However some work has suggested that acute cannabis exposure increases dopamine release in striatal and pre-frontal areas in those genetically predisposed for, or at clinical high risk of psychosis. Furthermore, recent studies are suggesting that chronic cannabis use blunts dopamine synthesis and dopamine release capacity. Further well-designed studies are required to definitively delineate the effects of cannabis use on the dopaminergic system in man. PMID:26068702

  11. Neurokinin receptor 3 peptide exacerbates 6-hydroxydopamine-induced dopaminergic degeneration in rats through JNK pathway.

    Science.gov (United States)

    Chu, John Man Tak; Chan, Ying Shing; Chen, Liang Wei; Yung, Ken Kin Lam

    2012-11-01

    Neurokinin 3 (NK3) receptor is predominantly expressed in striatum and substantia nigra (SN). Evidences have indicated the roles of NK3 receptor in the pathogenesis of Parkinson's disease. By administrating NK3 receptor agonist senktide into 6-hydroxydopamine (6-OHDA)-lesioned rats, exacerbation of dopaminergic degeneration was found in striatum and substantia nigra pars compacta. From apomorphine rotation test, significant increase of contralateral rotation number was detected in 6-OHDA-lesioned rats with senktide injection. Furthermore, tyrosine hydroxylase expression in striatum and substantia nigra pars compacta were examined by immunohistochemistry and Western blotting. Further reduction of tyrosine hydroxylase immunoreactivities was found in 6-OHDA-lesioned rats that received senktide treatment. Also, phosphorylation of N-methyl-D-aspartate receptor 1 subunit was investigated in SN region and significant up-regulation was revealed in senktide-treated 6-OHDA-lesioned rats. Finally, phosphorylation of mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) and c-Jun were examined in nigral region. Up-regulation of phosphorylated JNK molecules was shown in SN region after senktide injection. In line with this evidence, phosphorylation of c-Jun at Ser 63 and Ser 73 was also up-regulated by senktide treatment, thus presenting new aspects that NK3 peptide could exacerbate 6-OHDA toxicity in in vivo models and the possible mechanism may be contributed by the modulation of N-methyl-D-aspartate receptor 1 subunit and JNK pathway activities.

  12. A microfluidic method for dopamine uptake measurements in dopaminergic neurons.

    Science.gov (United States)

    Yu, Yue; Shamsi, Mohtashim H; Krastev, Dimitar L; Dryden, Michael D M; Leung, Yen; Wheeler, Aaron R

    2016-02-01

    Dopamine (DA) is a classical neurotransmitter and dysfunction in its synaptic handling underlies many neurological disorders, including addiction, depression, and neurodegeneration. A key to understanding DA dysfunction is the accurate measurement of dopamine uptake by dopaminergic neurons. Current methods that allow for the analysis of dopamine uptake rely on standard multiwell-plate based ELISA, or on carbon-fibre microelectrodes used in in vivo recording techniques. The former suffers from challenges associated with automation and analyte degradation, while the latter has low throughput and is not ideal for laboratory screening. In response to these challenges, we introduce a digital microfluidic platform to evaluate dopamine homeostasis in in vitro neuron culture. The method features voltammetric dopamine sensors with limit of detection of 30 nM integrated with cell culture sites for multi-day neuron culture and differentiation. We demonstrate the utility of the new technique for DA uptake assays featuring in-line culture and analysis, with a determination of uptake of approximately ∼32 fmol in 10 min per virtual microwell (each containing ∼200 differentiated SH-SY5Y cells). We propose that future generations of this technique will be useful for drug discovery for neurodegenerative disease as well as for a wide range of applications that would benefit from integrated cell culture and electroanalysis. PMID:26725686

  13. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

    Energy Technology Data Exchange (ETDEWEB)

    Kugaya, Akira; Fujita, Masahiro; Innis, R.B. [Yale Univ., New Haven, CT (United States). School of Medicine

    2000-02-01

    Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [{sup 123}I]{beta}-CIT ((1R)-2{beta}-Carbomethoxy-3{beta}-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [{sup 123}I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [{sup 123}I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders. (author)

  14. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

    International Nuclear Information System (INIS)

    Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [123I]β-CIT ((1R)-2β-Carbomethoxy-3β-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [123I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [123I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders. (author)

  15. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders.

    Science.gov (United States)

    Kugaya, A; Fujita, M; Innis, R B

    2000-02-01

    Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [123I]beta-CIT ((1R)-2beta-Carbomethoxy-3beta-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [123I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [123I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders. PMID:10770574

  16. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

    Directory of Open Access Journals (Sweden)

    Lyte Mark

    2007-01-01

    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  17. Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

    Science.gov (United States)

    Khani, Abbas; Kermani, Mojtaba; Hesam, Soghra; Haghparast, Abbas; Argandoña, Enrike G; Rainer, Gregor

    2015-06-01

    Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions. PMID:25529106

  18. Activity systems in the inquiry classroom

    Science.gov (United States)

    Wortham, Donald William

    Inquiry science, as called for by reform-minded organizations such as the National Research Council (1996), offers a platform with the potential for introducing all students to the practice of science while maintaining focus on key concepts and theories. This project followed two small groups as they completed an inquiry unit on genetics at a Midwestern high school. I investigated whether levels of student-to-teacher, student-to-student, student-apparatus, and student-concept connections were approximately equal across all students in each of the two groups. I found differences among students in levels of student-to-teacher, student-to-student, and student-concept connections. From a situated idiopathic perspective, these differences may indicate different levels of opportunity-to-learn. At a more abstract (nomothetic) level, these differences may be due to emergent divisions of labor (roles) within the two groups. From the perspective of Activity Theory (Leont'ev, 1978; Engestrom, 1987), roles serve as important mediators that simultaneously allow the social unit to accomplish its objectives, while shaping the development of participants. I describe three roles that capture modes of participation for students interacting in the small groups, and that may contribute to what Engestrom (2001) calls subject-producing activity systems: networked contributor, social member, and isolate. This paper also describes tools for teachers and researchers to use in identifying levels of mediation and roles as they occur in small groups.

  19. Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+ treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade

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    Das Mita

    2011-10-01

    Full Text Available Abstract Background Reactive oxygen species (ROS, superoxide and hydrogen peroxide (H2O2, are necessary for appropriate responses to immune challenges. In the brain, excess superoxide production predicts neuronal cell loss, suggesting that Parkinson's disease (PD with its wholesale death of dopaminergic neurons in substantia nigra pars compacta (nigra may be a case in point. Although microglial NADPH oxidase-produced superoxide contributes to dopaminergic neuron death in an MPTP mouse model of PD, this is secondary to an initial die off of such neurons, suggesting that the initial MPTP-induced death of neurons may be via activation of NADPH oxidase in neurons themselves, thus providing an early therapeutic target. Methods NADPH oxidase subunits were visualized in adult mouse nigra neurons and in N27 rat dopaminergic cells by immunofluorescence. NADPH oxidase subunits in N27 cell cultures were detected by immunoblots and RT-PCR. Superoxide was measured by flow cytometric detection of H2O2-induced carboxy-H2-DCFDA fluorescence. Cells were treated with MPP+ (MPTP metabolite following siRNA silencing of the Nox2-stabilizing subunit p22phox, or simultaneously with NADPH oxidase pharmacological inhibitors or with losartan to antagonize angiotensin II type 1 receptor-induced NADPH oxidase activation. Results Nigral dopaminergic neurons in situ expressed three subunits necessary for NADPH oxidase activation, and these as well as several other NADPH oxidase subunits and their encoding mRNAs were detected in unstimulated N27 cells. Overnight MPP+ treatment of N27 cells induced Nox2 protein and superoxide generation, which was counteracted by NADPH oxidase inhibitors, by siRNA silencing of p22phox, or losartan. A two-wave ROS cascade was identified: 1 as a first wave, mitochondrial H2O2 production was first noted at three hours of MPP+ treatment; and 2 as a second wave, H2O2 levels were further increased by 24 hours. This second wave was eliminated by

  20. Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice

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    Dhingra Dinesh

    2008-01-01

    Full Text Available Objectives: The present study was undertaken to investigate the effect of the ethanolic extract of Allium sativum L. (Family: Lilliaceae, commonly known as garlic, on depression in mice. Materials and Methods: Ethanolic extract of garlic (25, 50 and 100 mg/kg was administered orally for 14 successive days to young Swiss albino mice of either sex and antidepressant-like activity was evaluated employing tail suspension test (TST and forced swim test (FST. The efficacy of the extract was compared with standard antidepressant drugs like fluoxetine and imipramine. The mechanism of action of the extract was investigated by co-administration of prazosin (α1-adrenoceptor antagonist, sulpiride (selective D2-receptor antagonist, baclofen (GABA B agonist and p-CPA (serotonin antagonist separately with the extract and by studying the effect of the extract on brain MAO-A and MAO-B levels. Results: Garlic extract (25, 50 and 100 mg/kg significantly decreased immobility time in a dose-dependent manner in both TST and FST, indicating significant antidepressant-like activity. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg p.o. and imipramine (15 mg/kg p.o. in both TST and FST. The extract did not show any significant effect on the locomotor activity of the mice. Prazosin, sulpiride, baclofen and p-CPA significantly attenuated the extract-induced antidepressant-like effect in TST. Garlic extract (100 mg/kg administered orally for 14 successive days significantly decreased brain MAO-A and MAO-B levels, as compared to the control group. Conclusion: Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems.

  1. Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

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    Jordi Riba; Krämer, Ulrike M.; Marcus Heldmann; Sylvia Richter; Münte, Thomas F.

    2008-01-01

    The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefo...

  2. Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPET study using {sup 123}I-{beta}-CIT and {sup 123}I-IBZM

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    Donnemiller, E.; Riccabona, G. [Innsbruck Univ. (Austria). Dept. of Nuclear Medicine; Brenneis, C.; Wissel, J.; Scherfler, C.; Poewe, W.; Wenning, G.K. [Dept. of Neurology, Univ. of Innsbruck (Austria)

    2000-09-01

    Structural imaging suggests that traumatic brain injury (TBI) may be associated with disruption of neuronal networks, including the nigrostriatal dopaminergic pathway. However, to date deficits in pre- and/or postsynaptic dopaminergic neurotransmission have not been demonstrated in TBI using functional imaging. We therefore assessed dopaminergic function in ten TBI patients using [{sup 123}I]2-{beta}-carbomethoxy-3-{beta}-(4-iodophenyl)tropane ({beta}-CIT) and [{sup 123}I]iodobenzamide (IBZM) single-photon emission tomography (SPET). Average Glasgow Coma Scale score ({+-}SD) at the time of head trauma was 5.8{+-}4.2. SPET was performed on average 141 days (SD {+-}92) after TBI. The SPET images were compared with structural images using cranial computerised tomography (CCT) and magnetic resonance imaging (MRI). SPET was performed with an ADAC Vertex dual-head camera. The activity ratios of striatal to cerebellar uptake were used as a semiquantitative parameter of striatal dopamine transporter (DAT) and D2 receptor (D2R) binding. Compared with age-matched controls, patients with TBI had significantly lower striatal/cerebellar {beta}-CIT and IBZM binding ratios (P{<=}0.01). Overall, the DAT deficit was more marked than the D2R loss. CCT and MRI studies revealed varying cortical and subcortical lesions, with the frontal lobe being most frequently affected whereas the striatum appeared structurally normal in all but one patient. Our findings suggest that nigrostriatal dysfunction may be detected using SPET following TBI despite relative structural preservation of the striatum. Further investigations of possible clinical correlates and efficacy of dopaminergic therapy in patients with TBI seem justified. (orig.)

  3. N-Acetyl Cysteine Protects against Methamphetamine-Induced Dopaminergic Neurodegeneration via Modulation of Redox Status and Autophagy in Dopaminergic Cells

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    Prashanth Chandramani Shivalingappa

    2012-01-01

    Full Text Available Methamphetamine- (MA- induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. Our previous study demonstrated that MA induces autophagy in a dopaminergic neuronal cell model (N27 cells. The cellular mechanisms underlying MA-induced autophagy and apoptosis remain poorly characterized. In the present study we sought to investigate the importance of GSH redox status in MA-induced neurotoxicity using a thiol antioxidant, N-acetylcysteine (NAC. Morphological and biochemical analysis revealed that MA-induced autophagy in N27 dopaminergic cells was associated with pronounced depletion of GSH levels. Moreover, pretreatment with NAC reduced MA-induced GSH depletion and autophagy, while depletion of GSH using L-buthionine sulfoximine (L-BSO enhanced autophagy. Furthermore, treatment with NAC significantly attenuated MA-induced apoptotic cell death as well as oxidative stress markers, namely, 3-nitrotyrosine (3-NT and 4-hydroxynonenal (4-HNE. Together, these results suggest that NAC exhibits significant protective effects against MA-induced dopaminergic cell death, presumably via modulation of the GSH level and autophagy. Collectively, our data provide mechanistic insights into the role of cellular GSH redox status in MA-induced autophagy and apoptotic cell death, and additional studies are needed to determine the therapeutic effectiveness of cellular redox modifiers in attenuating dopaminergic neurodegeneration in vivo.

  4. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

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    Rachele eSalvi

    2016-03-01

    Full Text Available While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG and the subventricular zone (SVZ, recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g. the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX and Ropinirole (ROP, on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU a proliferation paradigm was performed in which two BrdU injections (100 mg/kg were applied intraperitoneally within 12 hours after a 14-day-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and NeuN 32 days after the last of five BrdU injections (50 mg/kg applied at the beginning of 14-day DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and

  5. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice.

    Science.gov (United States)

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C M; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX(+) neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  6. In vitro induced dopaminergic differentiation of expanded rat mesencephalic neural stem cell

    Institute of Scientific and Technical Information of China (English)

    ZHENG Min; WANG Dongmei; JIAO Wenchang; LI Haiming; ZHAO Lianxu; BAI Chixian; WANG Yaping; PEI Xuetao

    2003-01-01

    Neural stem cell (NSC) is the progenitor of the neural system with the character of self-renew and having the potential to differentiate into all the phenotypes in the central nervous system (CNS). NSC may serve as a source of cell transplantation for the treatment of neurodegenerative diseases to replace degenerative neurons. In this study, NSCs derived from E12.5 rat mesencephalon were maintained and expanded using a serum-free defined medium containing basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). While proliferating, the cells were immunoreactive for nestin and remained multipotent to generate neurons, astrocytes, and oligodendrocytes. After 15 times passage the total number of the cell expanded about 2.4×104 fold. Compared with untreated cultures, ascorbic acid (AA) treatment led to more dopaminergic (DAergic) differentitiation as indicated by the expression of tyrosine hydroxylase (TH). With the concentration increasing, more TH+ neurons were obtained. 100 μmol/L AA could lead to a increase more than 20-fold, and a concentration of 10 μmol/L could lead to nearly 5-fold increase in TH+ cells. However, the ratio of TH+ cells was not improved any longer with the AA increasing above the concentration of 100 μmol/L. The results demonstrate that expanded NSCs can be induced to differentiate into dopamine neurons in vitro, which can provide enough cell population for the cell transplantation, as a main intervention for the neurodegenerative diseases such as Parkinson's disease.

  7. Novel Method To Differentiate Human Embryonic Stem Cells Into Dopaminergic Nerve Cells | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Institute on Drug Abuse's Development and Plasticity Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize novel methods to differentiate human embryonic stem cells into dopaminergic nerve cells. The invention described here is a novel method of differentiating human embryonic stem cells (hESCs) into dopaminergic nerve cells, which is preferable to the currently available dopaminergic differentiation techniques.

  8. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

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    Dirk Taubert

    Full Text Available BACKGROUND: The etiology of neurodegenerative disorders, such as the accelerated loss of dopaminergic neurons in Parkinson's disease, is unclear. Current hypotheses suggest an abnormal function of the neuronal sodium-dependent dopamine transporter DAT to contribute to cell death in the dopaminergic system, but it has not been investigated whether sodium-independent amine transporters are implicated in the pathogenesis of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: By the use of a novel tandem-mass spectrometry-based substrate search technique, we have shown that the dopaminergic neuromodulators histidyl-proline diketopiperazine (cyclo(his-pro and salsolinol were the endogenous key substrates of the sodium-independent organic cation transporter OCT2. Quantitative real-time mRNA expression analysis revealed that OCT2 in contrast to its related transporters was preferentially expressed in the dopaminergic regions of the substantia nigra where it colocalized with DAT and tyrosine hydroxylase. By assessing cell viability with the MTT reduction assay, we found that salsolinol exhibited a selective toxicity toward OCT2-expressing cells that was prevented by cyclo(his-pro. A frequent genetic variant of OCT2 with the amino acid substitution R400C reduced the transport efficiency for the cytoprotective cyclo(his-pro and thereby increased the susceptibility to salsolinol-induced cell death. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the OCT2-regulated interplay between cyclo(his-pro and salsolinol is crucial for nigral cell integrity and that a shift in transport efficiency may impact the risk of Parkinson's disease.

  9. Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence

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    Edouard ePearlstein

    2015-05-01

    Full Text Available The spontaneous activity pattern of adult dopaminergic (DA neurons of the substantia nigra pars compacta (SNc results from interactions between intrinsic membrane conductances and afferent inputs. In adult SNc DA neurons, low-frequency tonic background activity is generated by intrinsic pacemaker mechanisms, whereas burst generation depends on intact synaptic inputs in particular the glutamatergic ones. Tonic DA release in the striatum during pacemaking is required to maintain motor activity, and burst firing evokes phasic DA release, necessary for cue-dependent learning tasks. However, it is still unknown how the firing properties of SNc DA neurons mature during postnatal development before reaching the adult state. We studied the postnatal developmental profile of spontaneous and evoked AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs in SNc DA neurons in brain slices from immature (postnatal days P4-10 and young adult (P30-50 tyrosine hydroxylase (TH-GFP mice. We found that somato-dendritic fields of SNc DA neurons are already mature at P4-10. In contrast, spontaneous glutamatergic EPSCs show a developmental sequence. Spontaneous NMDA EPSCs in particular are larger and more frequent in immature SNc DA neurons than in young adult ones and have a bursty pattern. They are mediated by GluN2B and GluN2D subunit-containing NMDA receptors. The latter generate long-lasting, DQP1105-sensitive, spontaneous EPSCs, which are transiently recorded during this early period. Due to high NMDA activity, immature SNc DA neurons generate large and long lasting NMDA receptor-dependent (APV-sensitive bursts in response to the stimulation of the subthalamic nucleus. We conclude that the transient high NMDA activity allows calcium influx into the dendrites of developing SNc DA neurons.

  10. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence.

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    Andrea Vereczkei

    Full Text Available BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2, ANKK1 (ankyrin repeat and kinase domain containing 1, dopamine D4 receptor (DRD4, catechol-O-methyl transferase (COMT and dopamine transporter (SLC6A3 genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA. FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497 and TaqIB (rs1079597 variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955 of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462 of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955 polymorphism in the promoter.

  11. Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats.

    Science.gov (United States)

    Fujii, Hiromi; Matsubara, Kohki; Sakai, Kiyoshi; Ito, Mikako; Ohno, Kinji; Ueda, Minoru; Yamamoto, Akihito

    2015-07-10

    Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of nigrostriatal dopaminergic (DAergic) neurons and the depletion of striatal dopamine. Here we show that DAergic-neuron-like cells could be efficiently induced from stem cells derived from human exfoliated deciduous teeth (SHEDs), and that these induced cells had therapeutic benefits in a 6-OHDA-induced Parkinsonian rat model. In our protocol, EGF and bFGF signaling activated the SHED's expression of proneural genes, Ngn2 and Mash1, and subsequent treatment with brain-derived neurotrophic factor (BDNF) promoted their maturation into DAergic neuron-like SHEDs (dSHEDs). A hypoxic DAergic differentiation protocol improved cell viability and enhanced the expression of multiple neurotrophic factors, including BDNF, GDNF, NT-3, and HGF. Engrafted dSHEDs survived in the striatum of Parkinsonian rats, improved the DA level more efficiently than engrafted undifferentiated SHEDs, and promoted the recovery from neurological deficits. Our findings further suggested that paracrine effects of dSHEDs contributed to neuroprotection against 6-OHDA-induced neurodegeneration and to nigrostriatal tract restoration. In addition, we found that the conditioned medium derived from dSHEDs protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth in vitro. Thus, our data suggest that stem cells derived from dental pulp may have therapeutic benefits for PD.

  12. Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

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    Yaping Sun

    Full Text Available Parkinson's disease is a neurodegenerative disorder characterized by the prominent degeneration of dopaminergic (DA neurons among other cell types. Here we report a first chemical screen of over 5,000 compounds in zebrafish, aimed at identifying small molecule modulators of DA neuron development or survival. We find that Neriifolin, a member of the cardiac glycoside family of compounds, impairs survival but not differentiation of both zebrafish and mammalian DA neurons. Cardiac glycosides are inhibitors of Na(+/K(+ ATPase activity and widely used for treating heart disorders. Our data suggest that Neriifolin impairs DA neuronal survival by targeting the neuronal enriched Na(+/K(+ ATPase α3 subunit (ATP1A3. Modulation of ionic homeostasis, knockdown of p53, or treatment with antioxidants protects DA neurons from Neriifolin-induced death. These results reveal a previously unknown effect of cardiac glycosides on DA neuronal survival and suggest that it is mediated through ATP1A3 inhibition, oxidative stress, and p53. They also elucidate potential approaches for counteracting the neurotoxicity of this valuable class of medications.

  13. Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival.

    Science.gov (United States)

    Pang, Xueyan; Hogan, Eric M; Casserly, Alison; Gao, Guangping; Gardner, Paul D; Tapper, Andrew R

    2014-01-01

    The type III RNAse, Dicer, is responsible for the processing of microRNA (miRNA) precursors into functional miRNA molecules, non-coding RNAs that bind to and target messenger RNAs for repression. Dicer expression is essential for mouse midbrain development and dopaminergic (DAergic) neuron maintenance and survival during the early post-natal period. However, the role of Dicer in adult mouse DAergic neuron maintenance and survival is unknown. To bridge this gap in knowledge, we selectively knocked-down Dicer expression in individual DAergic midbrain areas, including the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) via viral-mediated expression of Cre in adult floxed Dicer knock-in mice (Dicer(flox/flox)). Bilateral Dicer loss in the VTA resulted in progressive hyperactivity that was significantly reduced by the dopamine agonist, amphetamine. In contrast, decreased Dicer expression in the SNpc did not affect locomotor activity but did induce motor-learning impairment on an accelerating rotarod. Knock-down of Dicer in both midbrain regions of adult Dicer(flox/flox) mice resulted in preferential, progressive loss of DAergic neurons likely explaining motor behavior phenotypes. In addition, knock-down of Dicer in midbrain areas triggered neuronal death via apoptosis. Together, these data indicate that Dicer expression and, as a consequence, miRNA function, are essential for DAergic neuronal maintenance and survival in adult midbrain DAergic neuron brain areas.

  14. Screening for dopa-responsive dystonia in patients with Scans Without Evidence of Dopaminergic Deficiency (SWEDD).

    Science.gov (United States)

    De Rosa, Anna; Carducci, Claudia; Carducci, Carla; Peluso, Silvio; Lieto, Maria; Mazzella, Andrea; Saccà, Francesco; Brescia Morra, Vincenzo; Pappatà, Sabina; Leuzzi, Vincenzo; De Michele, Giuseppe

    2014-11-01

    The clinical diagnosis of Parkinson's Disease (PD) is not supported by Single Photon Emission Computed Tomography (SPECT) using dopamine transporter radioligand in 4-15 % of patients. It has been hypothesized that this phenomenon, named "Scans Without Evidence of Dopaminergic Deficiency" (SWEDD), may be an adult-onset dystonia. We investigated the hypothesis that these patients might be affected by Dopa-Responsive Dystonia (DRD). We enrolled eleven unrelated patients (8 F and 3 M) with clinical parkinsonism and normal [(123)I]FP-CIT SPECT. The GTP-cyclohydrolase1 (GCH1) gene was sequenced in all patients; urine biopterin and neopterin analysis was carried out in nine and oral phenylalanine (Phe) loading in seven. Neurological examination showed bradykinesia and resting/postural tremor in all patients, and rigidity in ten, suggesting a clinical diagnosis of PD. We detected mild dystonic signs in eight cases. In particular, five of them presented cranial dyskinesias. No mutation of the GCH1 gene was found. The results of the urine biopterin and neopterin analysis and the oral Phe loading did not reveal biochemical abnormalities suggestive of reduced GCH1 activity. We confirm that some clinical features, namely the presence of focal or segmental dystonia, suggest an adult-onset dystonia in SWEDD cases. However, we exclude DRD caused by GCH1 gene mutations in the present series. PMID:25182701

  15. Alterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders.

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    Eva C Schulte

    Full Text Available Serum metabolite profiling can be used to identify pathways involved in the pathogenesis of and potential biomarkers for a given disease. Both restless legs syndrome (RLS and Parkinson`s disease (PD represent movement disorders for which currently no blood-based biomarkers are available and whose pathogenesis has not been uncovered conclusively. We performed unbiased serum metabolite profiling in search of signature metabolic changes for both diseases.456 metabolites were quantified in serum samples of 1272 general population controls belonging to the KORA cohort, 82 PD cases and 95 RLS cases by liquid-phase chromatography and gas chromatography separation coupled with tandem mass spectrometry. Genetically determined metabotypes were calculated using genome-wide genotyping data for the 1272 general population controls.After stringent quality control, we identified decreased levels of long-chain (polyunsaturated fatty acids of individuals with PD compared to both RLS (PD vs. RLS: p = 0.0001 to 5.80x10-9 and general population controls (PD vs. KORA: p = 6.09x10-5 to 3.45x10-32. In RLS, inositol metabolites were increased specifically (RLS vs. KORA: p = 1.35x10-6 to 3.96x10-7. The impact of dopaminergic drugs was reflected in changes in the phenylalanine/tyrosine/dopamine metabolism observed in both individuals with RLS and PD.A first discovery approach using serum metabolite profiling in two dopamine-related movement disorders compared to a large general population sample identified significant alterations in the polyunsaturated fatty acid metabolism in PD and implicated the inositol metabolism in RLS. These results provide a starting point for further studies investigating new perspectives on factors involved in the pathogenesis of the two diseases as well as possible points of therapeutic intervention.

  16. Dopaminergic Modulation of Phase Reversal in Desert Locusts

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    Ahmad M Alessi

    2014-11-01

    Full Text Available Phenotypic plasticity allows animals to modify their behaviour, physiology and morphology to adapt to environmental change. The global pest, the desert locust, shows two extreme phenotypes; a solitarious phase that is relatively harmless and a gregarious phase that forms swarms and causes extensive agricultural and economic damage. In the field, environmental conditions can drive isolated animals into crowded populations and previous studies have identified the biogenic amine serotonin as a key determinant of this transition. Here we take an integrated approach to investigate the neurochemical, physiological and behavioural correlates defined by a laboratory based paradigm that mimics facets of swarm break down as gregarious locusts become isolated. Following isolation there was an increased propensity of locusts to avoid conspecifics, and show a reduced locomotion. Changes in choice behavior occurred within 1hr of isolation although isolation-related changes progressed with increased isolation time. Isolation was accompanied by changes in the levels of the biogenic amines dopamine, octopamine and serotonin within the CNS within 1hr. Dopamine levels were higher in isolated animals and focused on the role played by this transmitter in synaptic changes that may underpin solitarization. Dopamine reduced synaptic efficacy at a key central synapse between campaniform sensilla and a fast extensor tibiae motor neuron that is involved in limb movement. We also show that dopamine injection into the haemocoel was sufficient to induce solitarious-like behaviour in otherwise gregarious locusts. Further, injection of a dopamine antagonist, fluphenazine, into isolated locusts induced gregarious-like behaviour. This highlights that dopaminergic modulation plays an important role in the plasticity underpinning phase transition and sets a context to deepen the understanding of the complementary role that distinct neuromodulatory play in polyphenism in locusts.

  17. Wnt5a regulates midbrain dopaminergic axon growth and guidance.

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    Brette D Blakely

    Full Text Available During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM the cues that guide dopaminergic (DA axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway. Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a-/- mice, where fasciculation of the medial forebrain bundle (MFB as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.

  18. Extravehicular Activity Suit/Portable Life Support System Project

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    National Aeronautics and Space Administration — The objective of this project is to mature technologies and systems that will enable future Extravehicular Activity (EVA) systems. Advanced EVA systems have...

  19. Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons

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    Parinya Noisa

    2015-01-01

    Full Text Available Human embryonic stem cells (hESCs are able to proliferate in vitro indefinitely without losing their ability to differentiate into multiple cell types upon exposure to appropriate signals. Particularly, the ability of hESCs to differentiate into neuronal subtypes is fundamental to develop cell-based therapies for several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. In this study, we differentiated hESCs to dopaminergic neurons via an intermediate stage, neural progenitor cells (NPCs. hESCs were induced to neural progenitor cells by Dorsomorphin, a small molecule that inhibits BMP signalling. The resulting neural progenitor cells exhibited neural bipolarity with high expression of neural progenitor genes and possessed multipotential differentiation ability. CBF1 and bFGF responsiveness of these hES-NP cells suggested their similarity to embryonic neural progenitor cells. A substantial number of dopaminergic neurons were derived from hES-NP cells upon supplementation of FGF8 and SHH, key dopaminergic neuron inducers. Importantly, multiple markers of midbrain neurons were detected, including NURR1, PITX3, and EN1, suggesting that hESC-derived dopaminergic neurons attained the midbrain identity. Altogether, this work underscored the generation of neural progenitor cells that retain the properties of embryonic neural progenitor cells. These cells will serve as an unlimited source for the derivation of dopaminergic neurons, which might be applicable for treating patients with Parkinson’s disease.

  20. Kinematic analysis of dopaminergic effects on skilled handwriting movements in Parkinson's disease.

    Science.gov (United States)

    Tucha, O; Mecklinger, L; Thome, J; Reiter, A; Alders, G L; Sartor, H; Naumann, M; Lange, K W

    2006-05-01

    Patients with Parkinson's disease (PD) exhibit impairments in the execution of highly practiced and skilled motor actions such as handwriting. The analysis of kinematic aspects of handwriting movements has demonstrated that size, speed, acceleration and stroke duration are affected in PD. Although beneficial effects of dopaminergic therapy in regard to execution of movements have been reported, the effects of pharmacological therapy on these measures have not been examined in detail. The present study has compared kinematic aspects of handwriting movements of 27 healthy subjects and 27 patients with PD both on their usual dopaminergic treatment and following withdrawal of dopaminergic medication. Healthy subjects were matched with PD patients according to age, sex, handedness and education level. A digitising tablet was used for the assessment of handwriting movements. Subjects were asked to perform a simple writing task. Movement time, distance, velocity, acceleration and measures of fluency of handwriting movements were measured. Compared with healthy subjects, the kinematics of handwriting movements in PD patients were markedly disturbed following withdrawal of dopaminergic medication. Although dopaminergic treatment in PD patients resulted in marked improvements in the kinematics of handwriting movements, PD patients did not reach an undisturbed level of performance. The results suggest that dopamine medication results in partial restoration of automatic movement execution. PMID:16082511

  1. Roles for the TGFβ superfamily in the development and survival of midbrain dopaminergic neurons.

    Science.gov (United States)

    Hegarty, Shane V; Sullivan, Aideen M; O'Keeffe, Gerard W

    2014-10-01

    The adult midbrain contains 75% of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct clusters termed A8, A9 and A10. The A9 group plays a functionally non-redundant role in the control of voluntary movement, which is highlighted by the motor syndrome that results from their progressive degeneration in the neurodegenerative disorder, Parkinson's disease. Despite 50 years of investigation, treatment for Parkinson's disease remains symptomatic, but an intensive research effort has proposed delivering neurotrophic factors to the brain to protect the remaining dopaminergic neurons, or using these neurotrophic factors to differentiate dopaminergic neurons from stem cell sources for cell transplantation. Most neurotrophic factors studied in this context have been members of the transforming growth factor β (TGFβ) superfamily. In recent years, an intensive research effort has focused on understanding the function of these proteins in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region, with the goal of applying this knowledge to develop novel therapies for Parkinson's disease. In this review, the current evidence showing that TGFβ superfamily members play critical roles in the regulation of midbrain dopaminergic neuron induction, differentiation, target innervation and survival during embryonic and postnatal development is analysed, and the implications of these findings are discussed.

  2. Optogenetic measurement of presynaptic calcium transients using conditional genetically encoded calcium indicator expression in dopaminergic neurons.

    Directory of Open Access Journals (Sweden)

    Carmelo Sgobio

    Full Text Available Calcium triggers dopamine release from presynaptic terminals of midbrain dopaminergic (mDA neurons in the striatum. However, calcium transients within mDA axons and axon terminals are difficult to study and little is known about how they are regulated. Here we use a newly-developed method to measure presynaptic calcium transients (PreCaTs in axons and terminals of mDA neurons with a genetically encoded calcium indicator (GECI GCaMP3 expressed in transgenic mice. Using a photomultiplier tube-based system, we measured electrical stimulation-induced PreCaTs of mDA neurons in dorsolateral striatum slices from these mice. Single-pulse stimulation produced a transient increase in fluorescence that was completely blocked by a combination of N- and P/Q-type calcium channel blockers. DA and cholinergic, but not serotoninergic, signaling pathways modulated the PreCaTs in mDA fibers. These findings reveal heretofore unexplored dynamic modulation of presynaptic calcium in nigrostriatal terminals.

  3. Music improves dopaminergic neurotransmission: demonstration based on the effect of music on blood pressure regulation.

    Science.gov (United States)

    Sutoo, Den'etsu; Akiyama, Kayo

    2004-08-01

    The mechanism by which music modifies brain function is not clear. Clinical findings indicate that music reduces blood pressure in various patients. We investigated the effect of music on blood pressure in spontaneously hypertensive rats (SHR). Previous studies indicated that calcium increases brain dopamine (DA) synthesis through a calmodulin (CaM)-dependent system. Increased DA levels reduce blood pressure in SHR. In this study, we examined the effects of music on this pathway. Systolic blood pressure in SHR was reduced by exposure to Mozart's music (K.205), and the effect vanished when this pathway was inhibited. Exposure to music also significantly increased serum calcium levels and neostriatal DA levels. These results suggest that music leads to increased calcium/CaM-dependent DA synthesis in the brain, thus causing a reduction in blood pressure. Music might regulate and/or affect various brain functions through dopaminergic neurotransmission, and might therefore be effective for rectification of symptoms in various diseases that involve DA dysfunction. PMID:15246862

  4. Diverse roles for Wnt7a in ventral midbrain neurogenesis and dopaminergic axon morphogenesis.

    Science.gov (United States)

    Fernando, Chathurini V; Kele, Julianna; Bye, Christopher R; Niclis, Jonathan C; Alsanie, Walaa; Blakely, Brette D; Stenman, Jan; Turner, Brad J; Parish, Clare L

    2014-09-01

    During development of the central nervous system, trophic, together with genetic, cues dictate the balance between cellular proliferation and differentiation. Subsequent to the birth of new neurons, additional intrinsic and extrinsic signals regulate the connectivity of these cells. While a number of regulators of ventral midbrain (VM) neurogenesis and dopaminergic (DA) axon guidance are known, we identify a number of novel roles for the secreted glycoprotein, Wnt7a, in this context. We demonstrate a temporal and spatial expression of Wnt7a in the VM, indicative of roles in neurogenesis, differentiation, and axonal growth and guidance. In primary VM cultures, and validated in Wnt7a-deficient mice, we show that the early expression within the VM is important for regulating VM progenitor proliferation, cell cycle progression, and cell survival, thereby dictating the number of midbrain Nurr1 precursors and DA neurons. During early development of the midbrain DA pathways, Wnt7a promotes axonal elongation and repels DA neurites out of the midbrain. Later, Wnt7a expression in the VM midline suggests a role in preventing axonal crossing while expression in regions flanking the medial forebrain bundle (thalamus and hypothalamus) ensured appropriate trajectory of DA axons en route to their forebrain targets. We show that the effects of Wnt7a in VM development are mediated, at least in part, by the β-catenin/canonical pathways. Together, these findings identify Wnt7a as a new regulator of VM neurogenesis and DA axon growth and guidance.

  5. Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine.

    Science.gov (United States)

    Siciliano, Cody A; Ferris, Mark J; Jones, Sara R

    2015-08-01

    Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine-induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self-administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self-administration (fixed-ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self-administration, there was a marked reduction in ventral tegmental area-stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug-taking and drug-seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse. PMID:26037018

  6. Conceptualization and Integration of Information Systems in Educational Business Activities

    OpenAIRE

    Salah Alkhafaji; B. Sriram

    2013-01-01

    The business activities are highly incorporated with the technology development and need to be updated periodically. Business activities have made the technology to be more creative and innovative. The organizations need to integrate their business activities into a single system to achieve their aims and objectives successfully. Various studies are already conducted in integrating such business activities as Business Process Management System. In particular, various management systems are av...

  7. Dopaminergic basis of the psychosis-prone personality investigated with functional magnetic resonance imaging of procedural learning

    Directory of Open Access Journals (Sweden)

    Ulrich eEttinger

    2013-04-01

    Full Text Available Previous evidence shows a reliable association between psychosis-prone (especially schizotypal personality traits and performance on dopamine (DA-sensitive tasks (e.g., prepulse inhibition and antisaccade. Here, we used blood oxygen level dependent (BOLD fMRI and an established procedural learning task to examine the dopaminergic basis of two aspects of psychosis-proneness (specific schizotypy and general psychoticism. Thirty healthy participants (final N=26 underwent fMRI during a blocked, periodic sequence-learning task which, in previous studies, has been shown to reveal impaired performance in schizophrenia patients given drugs blocking the DA D2 receptor subtype (DRD2, and to correspond with manipulation of DA activity and elicit fronto-striatal-cerebellar activity in healthy people. Psychosis-proneness was indexed by the Psychoticism scale of the Eysenck Personality Questionnaire-Revised (EPQ-R; 1991 and the Schizotypal Personality Scale (STA; 1984. EPQ-R Extraversion and Neuroticism scores were also examined to establish discriminant validity. We found a positive correlation between the two psychosis-proneness measures (r=0.43, and a robust and unique positive association between EPQ-R Psychoticism and BOLD signal in the putamen, caudate, thalamus, insula and frontal regions. STA schizotypy score correlated positively with activity in the right middle temporal gyrus. As DA is a key transmitter in the basal ganglia, and the thalamus contains the highest levels of DRD2 receptors of all extrastriatal regions, our results support a dopaminergic basis of psychosis-proneness as measured by the EPQ-R Psychoticism.

  8. Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice

    Directory of Open Access Journals (Sweden)

    B.D. Palma

    2009-03-01

    Full Text Available Sleep disturbances have far-reaching effects on the neuroendocrine and immune systems and may be linked to disease manifestation. Sleep deprivation can accelerate the onset of lupus in NZB/NZWF1 mice, an animal model of severe systemic lupus erythematosus. High prolactin (PRL concentrations are involved in the pathogenesis of systemic lupus erythematosus in human beings, as well as in NZB/NZWF1 mice. We hypothesized that PRL could be involved in the earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. We also investigated its binding to dopaminergic receptors, since PRL secretion is mainly controlled by dopamine. Female NZB/NZWF1 mice aged 9 weeks were deprived of sleep using the multiple platform method. Blood samples were taken for the determination of PRL concentrations and quantitative receptor autoradiography was used to map binding of the tritiated dopaminergic receptor ligands [³H]-SCH23390, [³H]-raclopride and [³H]-WIN35,428 to D1 and D2 dopaminergic receptors and dopamine transporter sites throughout the brain, respectively. Sleep deprivation induced a significant decrease in plasma PRL secretion (2.58 ± 0.95 ng/mL compared with the control group (25.25 ± 9.18 ng/mL. The binding to D1 and D2 binding sites was not significantly affected by sleep deprivation; however, dopamine transporter binding was significantly increased in subdivisions of the caudate-putamen - posterior (16.52 ± 0.5 vs 14.44 ± 0.6, dorsolateral (18.84 ± 0.7 vs 15.97 ± 0.7 and ventrolateral (24.99 ± 0.5 vs 22.54 ± 0.7 µCi/g, in the sleep-deprived mice when compared to the control group. These results suggest that PRL is not the main mechanism involved in the earlier onset of the disease observed in sleep-deprived NZB/NZWF1 mice and the reduction of PRL concentrations after sleep deprivation may be mediated by modifications in the dopamine transporter sites of the caudate-putamen.

  9. Basic components of construction enterprises’ management marketing activities system

    OpenAIRE

    Seleznova Olha Olexandrivna

    2015-01-01

    This article investigated the basic components of construction enterprises’ management marketing activities system. It is developed the model of the construction enterprises’ management marketing activities system. The article explores the essence of the stages of forming the construction enterprises’ management marketing activities system. The article reveals the basic elements of marketing management – mission, goals, strategy. It describes the basic functions of marketing management system...

  10. Sex-dependent neurochemical effects of environmental enrichment in the visual system.

    Science.gov (United States)

    Bessinis, D P; Dalla, C; Kokras, N; Pitychoutis, P M; Papadopoulou-Daifoti, Z

    2013-12-19

    Sex differences in the visual system have been reported in aspects of human vision, such as color perception, peripheral vision and even in the activation of the primary visual cortex. Similarly sex differences have been identified in the visual system of laboratory animals such as monkeys and rats. On the other hand, environmental enrichment (EE) has long been known to affect visual tissues. Taking into consideration the variation in the experimental approaches concerning EE and the sex differences in the visual system, we investigated in male and female rats the serotonergic and dopaminergic effects of EE in the retina and the visual cortex at different time points (i.e. P0-25, P0-P90 and P90-P150). Early EE in adulthood increased the serotonergic activity of the male visual cortex and the female retina (P0-P90). In addition early enrichment (P0-P90) increased dopaminergic activity in the female retina and in the visual cortex of both sexes. Late enrichment increased the serotonergic activity in the retina and visual cortex of both sexes (P90-P150), but increased the dopaminergic activity in the visual cortex only in male animals. In the present study we expose marked sex differences in the neurochemistry of visual tissues and we demonstrate for the first time that EE can in fact modify the serotonergic and dopaminergic neurotransmission in the retina and visual cortex. Overall, the present study underpins the sex-dependent neurochemical status of the visual system and provides insights into the different mechanisms underlying visual processing in the two sexes.

  11. Activity theory as a challenge to systems design

    DEFF Research Database (Denmark)

    Bødker, Susanne

    1991-01-01

    This paper suggests an improvement of the theoretical foundation of information systems research of the 1990s. This foundation is found in human activity theory. The paper deals with how human activity theory can help systems design change, theoretically and practically. Applying activity theory...

  12. Robust Vehicle Suspension System by Converting Active & Passive Control of a Vehicle to Semi-Active Control System Analytically

    Directory of Open Access Journals (Sweden)

    Hassan Elahi

    2014-12-01

    Full Text Available In this research work a simplified translational model of an automotive suspension system is constructed by only considering the translation motion of one wheel of a car. Passive Vehicle Suspension System is converted into Semi Active Vehicle System. Major advantage achieved by this system is that it adjusts the damping of the suspension system without the application of any actuator by using MATLAB® simulations. The semi-active control is found to control the vibration of suspension system very well.

  13. Process of activation of a palladium catalyst system

    Science.gov (United States)

    Sobolevskiy, Anatoly; Rossin, Joseph A.; Knapke, Michael J.

    2011-08-02

    Improved processes for activating a catalyst system used for the reduction of nitrogen oxides are provided. In one embodiment, the catalyst system is activated by passing an activation gas stream having an amount of each of oxygen, water vapor, nitrogen oxides, and hydrogen over the catalyst system and increasing a temperature of the catalyst system to a temperature of at least 180.degree. C. at a heating rate of from 1-20.degree./min. Use of activation processes described herein leads to a catalyst system with superior NOx reduction capabilities.

  14. Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

    Science.gov (United States)

    Wang, Nan; Shen, Xiaofeng; Bao, Senzhu; Feng, Shan-Wu; Wang, Wei; Liu, Yusheng; Wang, Yiquan; Wang, Xian; Guo, Xirong; Shen, Rong; Wu, Haibo; Lei, Liming; Xu, Shiqin; Wang, Fuzhou

    2016-01-01

    The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine's role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated

  15. CALBINDIN CONTENT AND DIFFERENTIAL VULNERABILITY OF MIDBRAIN EFFERENT DOPAMINERGIC NEURONS IN MACAQUES

    Directory of Open Access Journals (Sweden)

    Iria G Dopeso-Reyes

    2014-12-01

    Full Text Available Calbindin (CB is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%, followed by neurons located in the SNcd (34.7%. As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%, whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%. Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus. As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTP-induced degeneration, our data clearly demonstrated that these neurons are not

  16. The melanin-concentrating hormone (MCH system modulates behaviors associated with psychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Shinjae Chung

    Full Text Available Deficits in sensorimotor gating measured by prepulse inhibition (PPI of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH system has been shown to modulate dopamine-related responses. Its receptor (MCH1R is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

  17. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Eric W Fish

    Full Text Available Fragile X syndrome (FXS is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y mice with intracranial self-stimulation (ICSS and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynylpyridine (MPEP, was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

  18. Amisulpride versus Bromocriptine in Infantile Autism: A Controlled Crossover Comparative Study of Two Drugs with Opposite Effects on Dopaminergic Function.

    Science.gov (United States)

    Dollfus, Sonia; And Others

    1992-01-01

    This study compared the clinical efficacy of a dopaminergic antagonist (amisulpride) and a dopaminergic agonist (bromocriptine) with 9 children (ages 4-13) with autism and probable severe mental retardation. The amisulpride acted preferentially on specific autism symptoms and the bromocriptine on motor hyperactivity and attention symptoms.…

  19. THE PARABRACHIAL NUCLEUS IS A CRITICAL LINK IN THE TRANSMISSION OF SHORT LATENCY NOCICEPTIVE INFORMATION TO MIDBRAIN DOPAMINERGIC NEURONS

    NARCIS (Netherlands)

    Coizet, V.; Dommett, E. J.; Klop, E. M.; Redgrave, P.; Overton, P. G.

    2010-01-01

    Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of retro

  20. Histopathological and electrophysiological indices of rotenone-evoked dopaminergic toxicity: Neuroprotective effects of acetyl-L-carnitine.

    Science.gov (United States)

    Sarkar, S; Gough, B; Raymick, J; Beaudoin, M A; Ali, S F; Virmani, A; Binienda, Z K

    2015-10-01

    the activation of both microglia and astroglia after rotenone treatment. Data indicate neuroprotective effects of ALC in rotenone-evoked dopaminergic neurotoxicity. PMID:26321151

  1. Active vibration control of lightweight floor systems

    Science.gov (United States)

    Baader, J.; Fontana, M.

    2016-04-01

    Wide-span and lightweight floors are often prone to structural vibrations due to their low resonance frequency and poor material damping. Their dynamic behaviour can be improved using passive, semi-active or active vibration control devices. The following article proposes a novel method for the controller synthesis for active vibration control. An existing passive TMD (tuned mass damper) is modelled and equipped with an actuator in order to provide more efficient damping. Using an iterative optimization approach under constraints, an optimal controller is found which minimizes a quadratic cost function in frequency domain. A simulation of an existing test bench shows that the active vibration control device is able to provide increased damping compared to the passive TMD.

  2. Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands.

    Science.gov (United States)

    Párraga, Javier; Andujar, Sebastián A; Rojas, Sebastián; Gutierrez, Lucas J; El Aouad, Noureddine; Sanz, M Jesús; Enriz, Ricardo D; Cabedo, Nuria; Cortes, Diego

    2016-10-21

    Dopamine receptors (DR) ligands are potential drug candidates for treating neurological disorders including schizophrenia or Parkinson's disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl-1,2,3,7,8,8a-hexahydrocyclopenta[ij]-IQs (HCPIQs) (series 2) and (E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3), were prepared to determine their affinity for both D1 and D2-like DR. The effect of different substituents on the nitrogen atom (methyl or allyl), the dioxygenated function (methoxyl or catechol), the substituent at the β-position of the THIQ skeleton, and the presence or absence of the cyclopentane motif, were studied. We observed that the most active compounds in the three series (2c, 2e, 3a, 3c, 3e, 5c and 5e) possessed a high affinity for D2-like DR and these remarkable features: a catechol group in the IQ-ring and the N-substitution (methyl or allyl). The series showed the following trend to D2-RD affinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, the substituent at the β-position of the THIQ and the cyclopentane ring also modulated this affinity. Among these dopaminergic isoquinolines, HCPIQs stood out for unexpected selectivity to D2-DR since the Ki D1/D2 ratio reached values of 2465, 1010 and 382 for compounds 3a, 3c and 3e, respectively. None of the most active THIQs in D2 DR displayed relevant cytotoxicity in human neutrophils and HUVEC. Finally, and in agreement with the experimental data, molecular modeling studies on DRs of the most characteristic ligands of the three series revealed stronger molecular interactions with D2 DR than with D1 DR, which further supports to the encountered enhanced selectivity to D2 DR. PMID:27343851

  3. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

    DEFF Research Database (Denmark)

    Christiansen, Mia Apuschkin; Stilling, Sara; Rahbek-Clemmensen, Troels;

    2015-01-01

    Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting...... of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co-localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co......-localization of the eGFP reporter signal with DAT and TH in the ventral midbrain showed that a vast majority of eGFP-expressing neurons are DAergic. Importantly, expression profiles also revealed DAergic heterogeneity when comparing substantia nigra and ventral tegmental area. Dat1-eGFP mice showed neither change...

  4. Activity-promoting gaming systems in exercise and rehabilitation

    OpenAIRE

    Matthew J. D. Taylor, PhD; Darren McCormick, BSc; Teshk Shawis, MBChB, FRCP; Rebecca Impson, MSc; Murray Griffin, PhD

    2011-01-01

    Commercial activity-promoting gaming systems provide a potentially attractive means to facilitate exercise and rehabilitation. The Nintendo Wii, Sony EyeToy, Dance Dance Revolution, and Xbox Kinect are examples of gaming systems that use the movement of the player to control gameplay. Activity-promoting gaming systems can be used as a tool to increase activity levels in otherwise sedentary gamers and also be an effective tool to aid rehabilitation in clinical settings. Therefore, the aim of t...

  5. Automotive active noise control (ANC) system. Jidoshayo active noise control (ANC) system

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, S. (Nissan Motor Co. Ltd., Tokyo (Japan))

    1992-11-25

    This paper introduces a successful development of an active noise control (ANC) system that selects and controls noise in an automobile compartment. This is a system that Nissan has developed for practical use for the first time in the world by using an adaptive control theory and a digital signal processor (DSP) that uses ultra-high speed operating elements. The principle for noise silencing in the ANC system utilizes interference of cyclic amplitude of sound with opposite phase. Sounds in an automobile include informative sounds, agreeable sounds, and noise, and combinations of these sounds work complexly on people in a car, of which extent varies depending on individuals. The adaptive control minimizes sounds picked up by a microphone into controlled speaker sound via an multiple error filtered algorithm (MEF-[sub X]LMS) and an adaptive digital filter. Major components of the system include a microphone, a speaker, and a control unit (comprising the adaptive algorithm and the adaptive filter), all having been developed newly. A DSP that operates on ultra-high speed operating elements was used for speedy compliance with complex algorithms, so that the controlled sound combined of engine noise with compartment sound field can be calculated. The noise was reduced by more than 10 dB at maximum. 7 figs.

  6. Robust Vehicle Suspension System by Converting Active & Passive Control of a Vehicle to Semi-Active Control System Analytically

    OpenAIRE

    Hassan Elahi; Dr. Riffat Asim Pasha; Dr. Asif Israr; Dr. M. Zubair Khan

    2014-01-01

    In this research work a simplified translational model of an automotive suspension system is constructed by only considering the translation motion of one wheel of a car. Passive Vehicle Suspension System is converted into Semi Active Vehicle System. Major advantage achieved by this system is that it adjusts the damping of the suspension system without the application of any actuator by using MATLAB® simulations. The semi-active control is found to control the vibration of suspens...

  7. Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist

    Energy Technology Data Exchange (ETDEWEB)

    Jaton, A.L.; Giger, R.K.A.; Vigouret, J.M.; Enz, A.; Frick, W.; Closse, A.; Markstein, R.

    1986-01-13

    The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by ..gamma..-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for /sup 3/H-dopamine and /sup 3/H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs. 29 references, 5 figures, 3 tables.

  8. Visible Light Activated Photocatalytic Water Polishing System Project

    Data.gov (United States)

    National Aeronautics and Space Administration — This proposal targets development of a LED light activated photocatalytic water polishing system that enables reduction of organic impurities (TOC and...

  9. Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons.

    Science.gov (United States)

    Majumdar, Debanjana; Kanafi, Mohammad; Bhonde, Ramesh; Gupta, Pawan; Datta, Indrani

    2016-09-01

    Based on early occurrence in chronological age, stem-cells from human exfoliated deciduous teeth (SHED) has been reported to possess better differentiation-potential toward certain cell-lineage in comparison to stem-cells from adult teeth (DPSCs). Whether this same property between them extends for the yield of functional central nervous system neurons is still not evaluated. Hence, we aim to assess the neuronal plasticity of SHED in comparison to DPSCs toward dopaminergic-neurons and further, if the difference is reflected in a differential expression of sonic-hedgehog (SHH)-receptors and basal-expressions of tyrosine-hydroxylase [TH; through cAMP levels]. Human SHED and DPSCs were exposed to midbrain-cues [SHH, fibroblast growth-factor8, and basic fibroblast growth-factor], and their molecular, immunophenotypical, and functional characterization was performed at different time-points of induction. Though SHED and DPSCs spontaneously expressed early-neuronal and neural-crest marker in their naïve state, only SHED expressed a high basal-expression of TH. The upregulation of dopaminergic transcription-factors Nurr1, Engrailed1, and Pitx3 was more pronounced in DPSCs. The yield of TH-expressing cells decreased from 49.8% to 32.16% in SHED while it increased from 8.09% to 77.47% in DPSCs. Dopamine release and intracellular-Ca(2+) influx upon stimulation (KCl and ATP) was higher in induced DPSCs. Significantly lower-expression of SHH-receptors was noted in naïve SHED than DPSCs, which may explain the differential neuronal plasticity. In addition, unlike DPSCs, SHED showed a down-regulation of cyclic adenosine-monophosphate (cAMP) upon exposure to SHH; possibly another contributor to the lesser differentiation-potential. Our data clearly demonstrates for the first time that DPSCs possess superior neuronal plasticity toward dopaminergic-neurons than SHED; influenced by higher SHH-receptor and lower basal TH expression. J. Cell. Physiol. 231: 2048-2063, 2016. © 2016

  10. Interactions of dopaminergic agonists and antagonists with dopaminergic D3 binding sites in rat striatum. Evidence that (/sup 3/H)dopamine can label a high affinity agonist-binding state of the D1 dopamine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.E.; Creese, I.

    1985-02-01

    The interactions of dopaminergic agonists and antagonists with /sup 3/H-agonist labeled D3 dopaminergic binding sites of rat striatum have been characterized by radioligand-binding techniques. When the binding of (/sup 3/H)dopamine and (/sup 3/H)apomorphine to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone, these ligands appear to label selectively the previously termed D3 binding site. Antagonist/(/sup 3/H)dopamine competition curves are of uniformly steep slope (nH . 1.0), suggesting the presence of a single D3 binding site. The relative potencies of antagonists to inhibit D3 specific (/sup 3/H)dopamine binding are significantly correlated with their potencies to block D1 dopamine receptors as measured by the inhibition of both dopamine-stimulated adenylate cyclase and (/sup 3/H)flupentixol-binding activities. The affinities of agonists to inhibit D3 specific (/sup 3/H)dopamine binding are also correlated with estimates of these agonists affinities for the high affinity binding component of agonist/(/sup 3/H)flupentixol competition curves. Both D3 specific (/sup 3/H) dopamine binding and the high affinity agonist-binding component of dopamine/(/sup 3/H)flupentixol competition curves show a similar sensitivity to guanine nucleotides. Taken together, these data strongly suggest that the D3 binding site is related to a high affinity agonist-binding state of the D1 dopamine receptor.

  11. Performance Assessment and Active System Monitoring for Refrigeration Systems

    DEFF Research Database (Denmark)

    Green, Torben

    The refrigeration system in a supermarket is an important part of the business for the supermarkets, both in terms of the possibility it provides and because of the associated cost of operating the system. It provides the possibility of selling chilled and frozen food but on the other hand...... the operation of the refrigeration system is associated with a signicant cost. Cost ecient operation of the refrigeration system is therefore very important for the supermarkets. To ensure that the systems are operated cost efficient a performance assessment scheme is required. In addition, there exists a need...... for algorithms that ensures or improves the performance of the system. A supermarket refrigeration system is usually a complex and distributed control system, and it can therefore be difficult to assess the performance without a formal method. The main interest for a supermarket, with respect...

  12. Cognitive Judgment Bias Interacts with Risk Based Decision Making and Sensitivity to Dopaminergic Challenge in Male Rats.

    Science.gov (United States)

    Drozd, Robert; Cieslak, Przemyslaw E; Rychlik, Michal; Rodriguez Parkitna, Jan; Rygula, Rafal

    2016-01-01

    Although the cognitive theory has implicated judgment bias in various psychopathologies, its role in decision making under risk remains relatively unexplored. In the present study, we assessed the effects of cognitive judgment bias on risky choices in rats. First, we trained and tested the animals on the rat version of the probability-discounting (PD) task. During discrete trials, the rats chose between two levers; a press on the "small/certain" lever always resulted in the delivery of one reward pellet, whereas a press on the "large/risky" lever resulted in the delivery of four pellets. However, the probability of receiving a reward from the "large/risky" lever gradually decreased over the four trial blocks. Subsequently, the rats were re-trained and evaluated on a series of ambiguous-cue interpretation (ACI) tests, which permitted their classification according to the display of "optimistic" or "pessimistic" traits. Because dopamine (DA) has been implicated in both: risky choices and optimism, in the last experiment, we compared the reactivity of the dopaminergic system in the "optimistic" and "pessimistic" animals using the apomorphine (APO; 2 mg/kg s.c.) sensitivity test. We demonstrated that as risk increased, the proportion of risky lever choices decreased significantly slower in "optimists" compared with "pessimists" and that these differences between the two groups of rats were associated with different levels of dopaminergic system reactivity. Our findings suggest that cognitive judgment bias, risky decision-making and DA are linked, and they provide a foundation for further investigation of the behavioral traits and cognitive processes that influence risky choices in animal models. PMID:27601984

  13. Water Districts - MO 2010 Active Public Drinking Water Systems (SHP)

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This point layer represents active public drinking water systems. Each public drinking water system's distribution or service area is represented by a single point.

  14. Acidosis activates complement system in vitro

    Directory of Open Access Journals (Sweden)

    Michael Emeis

    1998-01-01

    Full Text Available We investigated the in vitro effect of different form s of acidosis (pH 7.0 on the formation of anaphylatoxins C3a and C5a. Metabolic acidosis due to addition of hydrochloric acid (10 μ mol/ml blood or lactic acid (5.5 μ mol/ml to heparin blood (N=12 caused significant activation of C3a and C5a compared to control (both p=0.002. Respiratory acidosis activated C3a (p=0.007 and C5a (p=0.003 compared to normocapnic controls. Making blood samples with lactic acidosis hypocapnic resulted in a median pH of 7.37. In this respiratory compensated metabolic acidosis, C3a and C5a were not increased. These experiments show that acidosis itself and not lactate trigger for activation of complement components C3 and C5.

  15. Acidosis activates complement system in vitro.

    Science.gov (United States)

    Emeis, M; Sonntag, J; Willam, C; Strauss, E; Walka, M M; Obladen, M

    1998-01-01

    We investigated the in vitro effect of different forms of acidosis (pH 7.0) on the formation of anaphylatoxins C3a and C5a. Metabolic acidosis due to addition of hydrochloric acid (10 micromol/ml blood) or lactic acid (5.5 micromol/ml) to heparin blood (N=12) caused significant activation of C3a and C5a compared to control (both p=0.002). Respiratory acidosis activated C3a (p=0.007) and C5a (p=0.003) compared to normocapnic controls. Making blood samples with lactic acidosis hypocapnic resulted in a median pH of 7.37. In this respiratory compensated metabolic acidosis, C3a and C5a were not increased. These experiments show that acidosis itself and not lactate trigger for activation of complement components C3 and C5. PMID:9927235

  16. Hybrid energy storage systems utilizing redox active organic compounds

    Science.gov (United States)

    Wang, Wei; Xu, Wu; Li, Liyu; Yang, Zhenguo

    2015-09-08

    Redox flow batteries (RFB) have attracted considerable interest due to their ability to store large amounts of power and energy. Non-aqueous energy storage systems that utilize at least some aspects of RFB systems are attractive because they can offer an expansion of the operating potential window, which can improve on the system energy and power densities. One example of such systems has a separator separating first and second electrodes. The first electrode includes a first current collector and volume containing a first active material. The second electrode includes a second current collector and volume containing a second active material. During operation, the first source provides a flow of first active material to the first volume. The first active material includes a redox active organic compound dissolved in a non-aqueous, liquid electrolyte and the second active material includes a redox active metal.

  17. Evaluation of Active Cooling Systems for Non-Residential Buildings

    OpenAIRE

    M.A. Othuman Mydin

    2014-01-01

    Cooling systems are an essential element in many facets of modern society including cars, computers and buildings. Cooling systems are usually divided into two types: passive and active. Passive cooling transfers heat without using any additional energy while active cooling is a type of heat transfer that uses powered devices such as fans or pumps. This paper will focus on one particular type of passive cooling: air-conditioning systems. An air-conditioning system is defined as controlled air...

  18. Intrinsic innervation and dopaminergic markers after experimental denervation in rat thymus

    Directory of Open Access Journals (Sweden)

    F. Mignini

    2010-04-01

    Full Text Available The aim of this study was to examine rat thymus innervation using denervation techniques and to explore the related micro-anatomical localization of dopamine, D1, D2 receptors and dopamine membrane transporter (DAT. In the thymus subcapsular region, the parenchymal cholinergic fibers belong exclusively to phrenic nerve branching. No somatic phrenic nerve branching was detected in any other analysed thymus lobule regions. In rats subjected to sympathetic or parasympathetic ablation, it was observed that catecholaminergic and cholinergic nerve fibers respectively contributed to forming plexuses along vessel walls. In the subcapsular and septal region, no parenchymal nerve branching, belonging to sympathetic or parasympathetic nervous system was noted. Instead, in the deep cortical region, cortico-medullary junction (CM-j and medulla, catecholaminergic and cholinergic nerve fibers were detected along the vessels and parenchyma. Dopamine and dopamine receptors were widely diffused in the lobular cortico-medullary junction region and in the medulla, where the final steps of thymocyte maturation and their trafficking take place. No variation in dopamine and DAT immune reaction was observed following total or partial parasympathectomy or phrenic nerve cutting. After chemical or surgical sympathectomy however, neither dopamine nor DAT immune reaction was noted again. Instead, D1 and D2 dopamine receptor expression was not affected by thymus denervation. In rats subjected to specific denervation, it was observed the direct intraparenchymal branching of the phrenic nerve and sympathetic and parasympathetic fibers into thymus parenchyma along vessels. These findings on the dopaminergic system highlight the importance of neurotransmitter receptor expression in the homeostasis of neuroimmune modulation.

  19. Active filter solutions in energy systems

    OpenAIRE

    RÜSTEMLİ, SABİR; CENGİZ, MEHMET SAİT

    2015-01-01

    Recent developments in power electronics have increased the usage of nonlinear loads in energy systems. With increases in the usage of semiconductor-sourced nonlinear loads, the adverse effects of harmonics-sensitive loads (e.g., protection control circuits and circuit breakers) have also increased. Generally, the negative effects of harmonics in power systems include the following: increased power losses; motor, generator, and transformer overheating; faulty operation of measurement and prot...

  20. The stromal factors SDF1α, sFRP1 and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells

    OpenAIRE

    Catherine M Schwartz; Tavakoli, Tahereh; Jamias, Charmaine; Park, Sung-Soo; Maudsley, Stuart; Martin, Bronwen; Phillips, Terry M.; Pamela J. Yao; Itoh, Katsuhiko; Ma, Wu; Mahendra S Rao; Arenas, Ernest; Mattson, Mark P

    2012-01-01

    Human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons hold potential for treating Parkinson’s disease (PD) through cell replacement therapy. Generation of DA neurons from hESCs has been achieved by co-culture with the stromal cell line PA6, a source of stromal cell-derived inducing activity (SDIA). However, the factor(s) produced by stromal cells that constitute SDIA are largely undefined. We previously reported that medium conditioned by PA6 cells can generate functional DA neur...

  1. Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

    Science.gov (United States)

    Hayashi, Takuya; Wakao, Shohei; Kitada, Masaaki; Ose, Takayuki; Watabe, Hiroshi; Kuroda, Yasumasa; Mitsunaga, Kanae; Matsuse, Dai; Shigemoto, Taeko; Ito, Akihito; Ikeda, Hironobu; Fukuyama, Hidenao; Onoe, Hirotaka; Tabata, Yasuhiko; Dezawa, Mari

    2012-01-01

    A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease. PMID:23202734

  2. THE EFFECT OF 2 DOPAMINERGIC DRUGS ON MENSTRUAL FUNCTION AND PSYCHOLOGICAL STATE IN HYPERPROLACTINEMIA

    NARCIS (Netherlands)

    LAPPOHN, RE; VANDEWIEL, HBM; BROWNELL, J

    1992-01-01

    Objective: To investigate the effect of dopaminergic drugs on the well being in hyperprolactinemic patients. Design: A psychometric test for well being, the SCL-90, was applied at baseline and in the 24th week of a double-blind randomized prospective study comparing the effectiveness and safety of t

  3. Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons.

    Science.gov (United States)

    Neuhaus, Johannes F G; Baris, Olivier R; Hess, Simon; Moser, Natasha; Schröder, Hannsjörg; Chinta, Shankar J; Andersen, Julie K; Kloppenburg, Peter; Wiesner, Rudolf J

    2014-02-01

    Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that catecholamine metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify catecholamine metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons.

  4. Lmx1b controls peptide phenotypes in serotonergic and dopaminergic neurons

    Institute of Scientific and Technical Information of China (English)

    Rui Yan; Tianwen Huang; Zhiqin Xie; Guannan Xia; Hui Qian; Xiaolin Zhao; Leping Cheng

    2013-01-01

    Serotonin (5-HT) neurons synthesize a variety of peptides.How these peptides are controlled during development remains unclear.It has been reported that the co-localization of peptides and 5-HT varies by species.In contrast to the situations in the rostral 5-HT neurons of human and rat brains,several peptides do not coexist with 5-HT in the rostral 5-HT neurons of mouse brain.In this study,we found that the peptide substance P and peptide genes,including those encoding peptides thyrotropin-releasing hormone,enkephalin,and calcitonin gene-related peptide,were expressed in the caudal 5-HT neurons of mouse brain; these findings are in line with observations in rat and monkey 5-HT neurons.We also revealed that these peptides/peptide genes partially overlapped with the transcription factor Lmx1b that specifies the 5-HT cell fate.Furthermore,we found that the peptide cholecystokinin was expressed in developing dopaminergic neurons and greatly overlapped with Lmx1b that specifies the dopaminergic cell fate.By examining the phenotype of Lmx1b deletion mice,we found that Lmx1b was required for the expression of above peptides expressed in 5-HT or dopaminergic neurons.Together,our results indicate that Lmx1b,a key transcription factor for the specification of 5-HT and dopaminergic transmitter phenotypes during embryogenesis,determines some peptide phenotypes in these neurons as well.

  5. Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation.

    Science.gov (United States)

    Robison, Gregory; Sullivan, Brendan; Cannon, Jason R; Pushkar, Yulia

    2015-05-01

    Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson's disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40-200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism. PMID:25695229

  6. The cellular and Genomic response of rat dopaminergic neurons (N27) to coated nanosilver

    Science.gov (United States)

    This study examined if nanosilver (nanoAg) of different sizes and coatings were differentially toxic to oxidative stress-sensitive neurons. N27 rat dopaminergic neurons were exposed (0.5-5ppm) to a set of nanoAg of different sizes (10nm, 75nm) and coatings (PVP, citrate) and thei...

  7. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease: A case report

    Directory of Open Access Journals (Sweden)

    Mette Buhl Callesen

    2013-07-01

    Full Text Available Dopaminergic medication for motor symptoms in Parkinson’s disease recently has been linked with impulse control disorders, including pathological gambling, which affects up to 8% of patients. Pathological gambling often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with Parkinson’s disease and concomitant pathological gambling. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that pathological gambling in Parkinson’s disease is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related pathological gambling in Parkinson’s disease and underscore the importance of taking clinical variables, such as age and personality, into account when patients with Parkinson’s disease are medicated, to reduce the risk of pathological gambling.

  8. Stem cell-based generation of midbrain dopaminergic neurons : towards cellular tools to study Parkinson's disease

    NARCIS (Netherlands)

    Rössler, Reinhard Albrecht

    2012-01-01

    Het selectief afsterven van dopaminerge (DA) neuronen in de substantia nigra pars compacta (SNc) is het belangrijkste kenmerk van de ziekte van Parkinson. Het verlorcn gaan van deze groep neuronen en hun verbindingen naar het striatum en andere hersenregio's lddt tot veel van de karakteristieke symp

  9. Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation

    Science.gov (United States)

    Robison, Gregory; Sullivan, Brendan; Cannon, Jason R.; Pushkar, Yulia

    2015-01-01

    Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson’s disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40–200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism. PMID:25695229

  10. Generation of dopaminergic neurons directly from mouse fibroblasts and fibroblast-derived neural progenitors

    Institute of Scientific and Technical Information of China (English)

    Chao Sheng; Lei Liu; Wei Li; Zhong-Hua Liu; Xiao-Yang Zhao; Liu Wang; Zhiguo Chen; Qj Zhou; Qinyuan Zheng; Jianyu Wu; Zhen Xu; Lisi Sang; Libin Wang; Changlong Guo; Wanwan Zhu; Man Tong

    2012-01-01

    Dear Editor,Parkinson's disease (PD) is a neurodegenerative disease that afflicts around 1% of the population over age 65 [1].One of the pathological hallmarks of PD is the degeneration of dopaminergic (DA) neurons at midbrain and the relatively focal lesion feature of PD makes cell replacement a promising approach for treating the disease [2].

  11. Engrailed 1 shapes the dopaminergic and serotonergic landscape through proper isthmic organizer maintenance and function

    NARCIS (Netherlands)

    W.M. Kouwenhoven; J.V. Veenvliet; J.A. van Hooft; L.P. van der Heide; M.P. Smidt

    2016-01-01

    The isthmic organizer (IsO) is a signaling center that specifies the correct and distinct embryonic development of the dopaminergic midbrain and serotonergic hindbrain. The IsO is a linear boundary between the two brain regions, emerging at around embryonic day 7-8 of murine embryonic development, t

  12. Three Dopaminergic Polymorphisms Are Associated with Academic Achievement in Middle and High School

    Science.gov (United States)

    Beaver, Kevin M.; Vaughn, Michael G.; Wright, John Paul; DeLisi, Matt; Howard, Matthew O.

    2010-01-01

    Although academic achievement is a heritable construct, to date research has yet to explore its molecular genetic underpinnings. Drawing on data from the National Longitudinal Study of Adolescent Health, the current longitudinal study investigated the associations between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4) and…

  13. Dopaminergic Polymorphisms and Educational Achievement: Results from a Longitudinal Sample of Americans

    Science.gov (United States)

    Beaver, Kevin M.; Wright, John Paul; DeLisi, Matt; Vaughn, Michael G.

    2012-01-01

    Although educational attainment has been found to be moderately heritable, research has yet to explore candidate genes for it. Drawing on data from the National Longitudinal Study of Adolescent Health, in the current study, we examined the association between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4), a dopamine index, and…

  14. Reduced spontaneous eye blink rates in recreational cocaine users: Evidence for dopaminergic hypoactivity

    NARCIS (Netherlands)

    L.S. Colzato; W.P.M. van den Wildenberg; B. Hommel

    2008-01-01

    Chronic use of cocaine is associated with a reduced density of dopaminergic D2 receptors in the striatum, with negative consequences for cognitive control processes. Increasing evidence suggests that cognitive control is also affected in recreational cocaine consumers. This study aimed at linking th

  15. Study of apoptosis pattern of dopaminergic neurons and neuroprotective effect of nicotine in MPTP mouse model

    Institute of Scientific and Technical Information of China (English)

    Dan Hu; Wei Cao; Shenggang Sun

    2007-01-01

    Objective:To investigate the apoptosis of dopaminergic neurons and the protective effect of nicotine in 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. Methods :The mouse model of Parkinson's disease were formed by MPTP (30 mg/kg/d×7, i.p.); and the loss and apoptosis of dopaminergic neurons was observed by Tyrosine Hydroxylase (TH) and TUNEL stains. In "Nicotime plus MPTP" group, mice were pretreated with nicotine before MPTP injection. The putative protective effect of nicotine was analyzed. Results:The number of TH-positive cells decreased during MPTP treatment. Apoptotic neurons began to appear after three injections of MPTP and peaked on the 8th day.In the MPTP-intoxicated mice treated with nicotine, the loss of TH-positive cells was significantly less than that of MPTP-treated group (30 mg/kg/d×7)(P < 0.05). Conclusion:The chronic treatment of MPTP can induce the apoptosis of dopaminergic neurons in substantia nigra, and nicotine might have a neuroprotecitve effect on dopaminergic neurons against MPTP toxicity.

  16. Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Xuefeng Jing

    Full Text Available Cells of the neural stem cell lineage in the adult subventricular zone (SVZ respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA-mediated signal. We conclude that activation of EphA receptor-mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinson's disease.

  17. Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α-synuclein.

    Science.gov (United States)

    Schlachetzki, Johannes C M; Grimm, Thomas; Schlachetzki, Zinayida; Ben Abdallah, Nada M B; Ettle, Benjamin; Vöhringer, Patrizia; Ferger, Boris; Winner, Beate; Nuber, Silke; Winkler, Jürgen

    2016-01-01

    Nonmotor symptoms of cognitive and affective nature are present in premotor and motor stages of Parkinson's disease