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Sample records for activity dopaminergic systems

  1. Differential activation of dopaminergic systems in rat brain basal ganglia by morphine and methamphetamine.

    Mori, T; Iwase, Y; Saeki, T; Iwata, N; Murata, A; Masukawa, D; Suzuki, T

    2016-05-13

    Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system. PMID:26820597

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

    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...

  3. The dopaminergic system in the aging brain of Drosophila

    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

  4. INFLUENCE OF DOPAMINERGIC SYSTEM ON INTERNET ADDICTION

    Jelena Jović

    2011-03-01

    Full Text Available Internet addiction is a clinical anomaly with strong negative consequences on social, work-related, family, financial, and economic function of a person. It is regarded as a serious public health issue. The basic idea of this paper is to, based on the currently available body of research work on this topic, point out to neurobiological pathos of Internet addiction, and its connection to the dopaminergic system. Dopamine contains all physiological functions of neurotransmitters and it is a part of chatecholamine family. Five dopaminergic receptors (D1 - D5 belong to the super family of receptors related to G-protein. Through these receptors, dopamine achieves its roles: regulation of voluntary movement, regulation of center of pleasure, hormonal regulation, and regulation of hypertension. In order to recognize an Internet user as an addict, he or she needs to comply with the criteria suggested by the American Psychiatric Association (APA. Phenomenological, neurobiological, and pharmacological data indicates similarities in pathopsychology of substance addiction and pathological gambling, which are indirectly related to the similarity with the Internet addiction. Responding to stimuli from the game, addicts have shown more brain activity in the nape region, left dorsolateral, prefrontal cortex, and left parachipocampal gyrus than in the control group. After the six-week bupropion therapy, desire to play Internet and video games, the total duration of playing, and induced brain activity in dorsolateral prefrontal cortex are lowered with the addicts.

  5. Dopaminergic system abnormalities Etiopathogenesis of dystonia

    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

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

    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, ...

  7. Renin angiotensin system and gender differences in dopaminergic degeneration

    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.

  8. Decoding of dopaminergic mesolimbic activity and depressive behavior.

    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

  9. Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): a self-feeding approach.

    Leal, Esther; Fernández-Durán, Begoña; Agulleiro, Maria Josep; Conde-Siera, Marta; Míguez, Jesús Manuel; Cerdá-Reverter, José Miguel

    2013-06-01

    Dopamine is synthesized from l-dopa and subsequently processed into norepinephrine and epinephrine. Any excess neurotransmitter can be taken up again by the neurons to be broken down enzymatically into DOPAC. The effect of dopamine on mammalian food intake is controversial. Mice unable to synthesize central dopamine die of starvation. However, studies have also shown that central injection of dopamine inhibits food intake. The effect of dopaminergic system in the fish feeding behavior has been scarcely explored. We report that the inclusion of l-dopa in the diets results in the activation of sea bass central dopaminergic system but also in the significant increase of the hypothalamic serotonin levels. Dietary l-dopa induces a decrease of food intake and feed conversion efficiency that drives a decline of all growth parameters tested. No behavioral effects were observed after l-dopa treatment. l-dopa treatment stimulated central expression of NPY and CRF. It suggests that CRF might mediate l-dopa effects on food intake but also that CRF neurons lie downstream of NPY neurons in the hierarchical forebrain system, thus controlling energy balance. Unexpectedly, dietary administration of haloperidol, a D2-receptor antagonist, cannot block dopamine effects but also induces a decline of the food intake. This decrease seems to be a side effect of haloperidol treatment since fish exhibited a decreased locomotor activity. We conclude that oral l-dopa inhibits sea bass food intake and growth. Mechanism could also involve an increase of hypothalamic serotoninergic tone. PMID:23747830

  10. Brain dopaminergic systems : imaging with positron tomography

    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

  11. Modulation of the basal ganglia dopaminergic system in a transgenic mouse exhibiting dystonia-like features

    Giannakopoulou, D.; Armata, I.A.; Mitsacos, A.; Shashidharan, P.; Giompres, P.

    2010-01-01

    Dystonia is a movement disorder characterized by involuntary excessive muscle activity and abnormal postures. There are data supporting the hypothesis that basal ganglia dysfunction, and specifically dopaminergic system dysfunction, plays a role in dystonia. In the present study, we used hyperkinetic transgenic mice generated as a model of DYT1 dystonia and compared the basal ganglia dopaminergic system between transgenic mice exhibiting hyperkinesia (affected) transgenic mice not showing mov...

  12. PET tracers for imaging of the dopaminergic system

    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

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

    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...

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

    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

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

    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. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.

    Costall, B; Domeney, A M; Naylor, R J; Tyers, M. B.

    1987-01-01

    1 The ability of the selective 5-HT3 receptor antagonist GR38032F to reduce raised mesolimbic dopaminergic activity was studied in behavioural experiments in the rat and marmoset. 2 GR38032F injected into the nucleus accumbens (0.01-1 ng) or peripherally (0.01-1 mg kg-1 i.p.) inhibited the locomotor hyperactivity caused by the acute intra-accumbens injection of amphetamine (10 micrograms) in the rat. Similar treatments with sulpiride and fluphenazine also inhibited the amphetamine-induced hyp...

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

    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...

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

    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

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

    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

    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.

    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.

    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

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

    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.

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

    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...

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

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

  6. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

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

    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...

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

    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.

  9. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging. PMID:24345178

  10. Sulpiride and the role of dopaminergic receptor blockade in the antipsychotic activity of neuroleptics

    It is now generally recognized that dopamine receptors excist in the CNS as different subtypes: D1 receptors, associated with adenylyl cyclase activity, and D2 receptor, uncoupled to a cyclic APM generating system. In order to understand the role of D1 and D2 receptors in the antipsychotic action of neuroleptics, we have performed subchronic treatment with haloperidol, a drug which acts on D1 receptors, and sulpiride, a selective antagonist to D2 receptors. Long-term treatment with haloperidol does not induce significant supersensitivity of the D2 receptors. In fact under these conditions 3H-(-)-sulpiride binding, which is a marker of D2 receptor function, does not increase in rat striatum, while the long-term administration of sulpiride, itself produces supersensitivity of D2 receptors. Moreover, sulpiride does not induce supersensitivity of the D1 receptors, characterized by 3H-spiroperidol binding. These data suggest that both types of dopamine receptors may be involved in the clinical antipsychotic effects of neuroleptics. Unilateral leison of the nigrostriatal dopaminergic pathway produces an increase of striatal dopaminergic receptors, measured either by 3H-spiroperidol and 3H-(-)-sulpiride binding. These findings suggest that D1 and D2 receptors are present in postsynaptic membranes while it is still not known whether they exist in the same cellular elements. (author)

  11. Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

    Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

    2015-08-01

    Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

  12. Cocaine modulates the expression of transcription factors related to the dopaminergic system in zebrafish.

    Barreto-Valer, K; López-Bellido, R; Rodríguez, R E

    2013-02-12

    Nodal-related protein, Ndr2, and transcription factors such as Lmx1b, Otp, Nurr1 and Pitx3 are very important in the differentiation, function and maintenance of mesodiencephalic dopaminergic neurons, and are necessary for the activation of tyrosine hydroxylase (TH) and dopamine (DA) transporter expression. Hence, the aim of the present work was to evaluate the effects of cocaine on the expression of genes related to the embryogenesis development of the dopaminergic system. Zebrafish embryos were exposed to cocaine hydrochloride at 5h post-fertilization (hpf), and collected at two important stages - 24 and 48hpf - to study the effects of cocaine on the expression of ndr2, the lmx1b.1, lmx1b.2, otpa, otpb, nurr1 transcription factors, and their target genes: TH and DA transporter expression. Our results by qPCR showed that cocaine affects the expression of these genes in different ways, depending on the stage of development. Furthermore by in situ hybridization we observed a change in the spatial distribution of lmx1b.1 and lmx1b.2 at both stages (24 and 48hpf) due to exposure to cocaine. We also show the importance of Lmx1b and Otp in th expression through the knockdown of Lmx1b.1 and Lmx1b.2, and of Otpa and Otpb. Additionally, cocaine produced an increase and a decrease in TH levels at 24 and at 48hpf, respectively, possibly due to the change in the expression of the transcription factors and ndr2 expression. We conclude that cocaine alters the correct development of dopaminergic system affecting the expression of transcription factors, during the embryogenesis. PMID:23219907

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

    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.

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

    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.

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

    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.

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

    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.

  17. Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes.

    Nedic Erjavec, Gordana; Nenadic Sviglin, Korona; Nikolac Perkovic, Matea; Muck-Seler, Dorotea; Jovanovic, Tanja; Pivac, Nela

    2014-10-01

    The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO-B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, -1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogeneous unrelated Caucasian subjects for future meta-analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence. PMID:25035107

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

    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.

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

    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

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

    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...

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

    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...

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

    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

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

    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

  4. Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation.

    Chung, Young C; Bok, Eugene; Huh, Sue H; Park, Ju-Young; Yoon, Sung-Hwa; Kim, Sang R; Kim, Yoon-Seong; Maeng, Sungho; Park, Sung Hyun; Jin, Byung K

    2011-12-15

    This study examined whether the cannabinoid receptor type 1 (CB(1)) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB(1) receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB(1) receptor. The present in vivo and in vitro findings clearly indicate that the CB(1) receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson's disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage

  5. Activity enhances dopaminergic long-duration response in Parkinson disease

    Auinger, Peggy; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Mendis, Tilak

    2012-01-01

    Objective: We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined. Methods: We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks. Results: The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands. Conclusions: Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects. PMID:22459675

  6. Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H transduction of dopaminergic neurons in vivo.

    Kyoung Hoon Jeong

    Full Text Available Ciliary neurotrophic factor (CNTF is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα. It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson's disease (PD patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc, suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb, with an S16H mutation [hRheb(S16H], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H may have therapeutic potential in the treatment of PD.

  7. Comprehensive catecholaminergic projectome analysis reveals single-neuron integration of zebrafish ascending and descending dopaminergic systems

    Tay, Tuan Leng; Ronneberger, Olaf; Ryu, Soojin; Nitschke, Roland; Driever, Wolfgang

    2011-01-01

    Essential components of animal behaviour are modulated by dopaminergic (DA) and noradrenergic circuitry. In this study, we reveal at cellular resolution the complete set of projections ('projectome') of every single type of DA and noradrenergio neurons in the central nervous system of zebrafish larvae. The most extensive DA projections are established by posterior tubercular otp-dependent neurons, with individual somata integrating the ascending DA system, the descending diencephalospinal, as...

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

    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

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

    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.

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

    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...

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

    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.

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

    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.

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

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

    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.

  15. Suppressed tyrosine hydroxylase gene expression in the tuberoinfundibular dopaminergic system during lactation.

    Wang, H J; Hoffman, G E; Smith, M S

    1993-10-01

    Suckling-induced PRL secretion is regulated in part by a reduction in tuberoinfundibular dopamine (TIDA) neuronal activity. We have examined the effects of suckling on TIDA activity in the arcuate nucleus by measuring changes in gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. TH gene expression was assessed by performing in situ hybridization, using a 35S-labeled antisense riboprobe for quantitating TH mRNA and analyzing grain density with the aid of an Optimas Bioscan image analysis system. Lactating rats suckled by eight pups were studied on postpartum day 10, and diestrous day 1 rats were used as controls. The results showed that lactation suppressed TH mRNA content throughout the arcuate nucleus to about 10% of diestrous levels. The dramatic reduction in TH mRNA during lactation was specific to the arcuate nucleus, as TH mRNA levels in the zona incerta were similar during lactation and diestrus. The suckling stimulus was the primary signal responsible for the suppression of TH mRNA in the arcuate nucleus, as removal of the pups for 6 h restored TH mRNA content to diestrous levels. By 24 h after pup removal, TH mRNA had reached almost twice diestrous levels. In view of the dramatic reduction in TH mRNA levels during lactation, we examined whether TH protein in the arcuate nucleus was similarly diminished. TH protein was detected by immunocytochemistry using a monoclonal antibody to TH. Qualitatively, TH staining was heavier in cell bodies, nerve fibers, and median eminence during diestrus. There was a small, but significant, decrease in TH-positive cell numbers during lactation (14% reduction) compared to those on diestrus. These data provide clear evidence that TH expression is suppressed during lactation, as evidenced by the decrease in TH mRNA and TH protein. The reduction in TH expression most likely contributes to the decrease in dopaminergic tone during lactation. PMID:8104777

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

    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

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

    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

  18. Iron modulates neuroleptic-induced effects related to the dopaminergic system.

    Ben-Shachar, D; Livne, E; Spanier, I; Zuk, R; Youdim, M B

    1993-09-01

    Long-term neuroleptic medication to schizophrenic patients is often associated with extrapyramidal side effects, of which tardive dyskinesia is the most severe. The mechanism by which neuroleptics induce these side effects is unclear. The dopaminergic system is the main target with which the neuroleptics interact in the brain. Intact dopaminergic function is dependent on normal iron metabolism. Thus, the relationship between iron and the neuroleptics may elucidate some new aspects of their mechanism of action. Indeed, peripheral iron status plays a crucial role in neuroleptic-induced dopamine supersensitivity. Moreover, neuroleptics such as haloperidol and chlorpromazine, alter the blood brain barrier (BBB) of the rat and enhance the normally restricted iron transport into the brain. Increased brain iron levels may be related to the toxic effects of these drugs since clozapine, an atypical neuroleptic with a low incidence of extrapyramidal side effects, prohibits iron uptake into the brain but causes sedimentation of iron in brain blood vessels. The demonstration that peripheral iron concentrations affect neuroleptic-induced dopamine receptor supersensitivity as well as iron transport into the brain may have therapeutic significance. In addition, the different potentials of typical and atypical neuroleptics to increase iron transport into the brain may be related to the severity of the side effects they induce and to the pathophysiology of tardive dyskinesia. PMID:7901181

  19. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Schärer, Yan-Ping Zhang; Shum, Jennifer; Moressis, Anastasios; Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordin...

  20. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homologue of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell record...

  1. The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish.

    da Silva, Raquel Bohrer; Siebel, Anna Maria; Bonan, Carla Denise

    2015-12-01

    Depression is a serious disease characterized by low mood, anhedonia, loss of interest in daily activities, appetite and sleep disturbances, reduced concentration, and psychomotor agitation. There is a growing interest in NMDA antagonists as a promising target for the development of new antidepressants. Considering that purinergic and dopaminergic systems are involved in depression and anxiety states, we characterized the role of these signaling pathways on MK-801-induced antidepressant effects in zebrafish. Animals treated with MK-801 at the doses of 5, 10, 15, or 20μM during 15, 30, or 60min spent longer time in the top area of aquariums in comparison to control group, indicating an anxiolytic/antidepressant effect induced by this drug. Animals treated with MK-801 spent longer time period at top area until 2 (5μM MK-801) and 4 (20μM MK-801) hours after treatment, returning to basal levels from 24h to 7days after exposure. Repeated MK-801 treatment did not induce cumulative effects, since animals treated daily during 7days had the same behavioral response pattern observed since the first until the 7th day. In order to investigate the effects of adenosine A1 and A2A receptor antagonist and agonist and the influence of modulation of adenosine levels on MK-801 effects, we treated zebrafish with caffeine, DPCPX, CPA, ZM 241385, CGS 21680, AMPCP, EHNA, dipyridamole, and NBTI during 30min before MK-801 exposure. The non-specific adenosine receptor antagonist caffeine (50mg/kg) and the selective A1 receptor antagonist DPCPX (15mg/kg) prevented the behavioral changes induced by MK-801. The non-specific nucleoside transporter (NT) inhibitor dipyridamole (10mg/kg) exacerbated the behavioral changes induced by MK-801. Dopamine receptor antagonists (sulpiride and SCH 23390) did not change the behavioral alterations induced by MK-801. Our findings demonstrated that antidepressant-like effects of MK-801 in zebrafish are mediated through adenosine A1 receptor activation. PMID

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

    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. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.

    Pascual, Maria; Boix, Jordi; Felipo, Vicente; Guerri, Consuelo

    2009-02-01

    Adolescence is a developmental period which the risk of drug and alcohol abuse increases. Since mesolimbic dopaminergic system undergoes developmental changes during adolescence, and this system is involved in rewarding effects of drugs of abuse, we addressed the hypothesis that ethanol exposure during juvenile/adolescent period over-activates mesolimbic dopaminergic system inducing adaptations which can trigger long-term enduring behavioural effects of alcohol abuse. We treated juvenile/adolescent or adult rats with ethanol (3 g/kg) for two-consecutive days at 48-h intervals over 14-day period. Here we show that intermittent ethanol treatment during the juvenile/adolescence period alters subsequent ethanol intake. In vivo microdialysis demonstrates that ethanol elicits a similar prolonged dopamine response in the nucleus accumbens of both adolescent and adult animals pre-treated with multiple doses of ethanol, although the basal dopamine levels were higher in ethanol-treated adolescents than in adult-treated animals. Repeated ethanol administration also down-regulates the expression of DRD2 and NMDAR2B phosphorylation in prefrontal cortex of adolescent animals, but not of adult rats. Finally, ethanol treatment during adolescence changes the acetylation of histones H3 and H4 in frontal cortex, nucleus accumbens and striatum, suggesting chromatin remodelling changes. In summary, our findings demonstrate the sensitivity of adolescent brain to ethanol effects on dopaminergic and glutamatergic neurotransmission, and suggest that abnormal plasticity in reward-related processes and epigenetic mechanisms could contribute to the vulnerability of adolescents to alcohol addiction. PMID:19077056

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

    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. Formyl-methionyl-leucyl-phenylalanine–Induced Dopaminergic Neurotoxicity via Microglial Activation: A Mediator between Peripheral Infection and Neurodegeneration?

    Gao, Xi; Hu, Xiaoming; Qian, Li; Yang, Sufen; ZHANG Wei; Zhang, Dan; Wu, Xuefei; Fraser, Alison; Wilson, Belinda; Flood, Patrick M; Block, Michelle; Hong, Jau-Shyong

    2008-01-01

    Background Parkinson disease (PD), a chronic neurodegenerative disease, has been proposed to be a multifactorial disorder resulting from a combination of environmental mechanisms (chemical, infectious, and traumatic), aging, and genetic deficits. Microglial activation is important in the pathogenesis of PD. Objectives We investigated dopaminergic (DA) neurotoxicity and the underlying mechanisms of formyl-methionyl-leucyl-phenylalanine (fMLP), a bacteria-derived peptide, in relation to PD. MET...

  6. Effect of incubation temperature and androgens on dopaminergic activity in the leopard gecko, Eublepharis macularius.

    Dias, Brian George; Ataya, Ramona Sousan; Rushworth, David; Zhao, Jun; Crews, David

    2007-04-01

    Male leopard geckos that hatch from eggs incubated at a female-biased temperature (Tf) behave differently when compared with males hatching at a temperature which produces a male-biased sex ratio (Tm). We investigated the effect of incubation temperature and androgen implantation on aspects of the dopaminergic system of Tf and Tm males. Our data suggest that more dopamine (DA) is stored in the nucleus accumbens of naive Tf males compared with naïve Tm males when they encounter a receptive female conspecific across a barrier. No difference was measured in the preoptic area and the ventral tegmental area (VTA). This difference in intracellular DA levels in a motivation-related brain nucleus might be correlated with differences in sociosexual behavior observed between the two morphs. There were no differences in tyrosine hydroxylase (TH) expressing cell numbers in the VTA of cholesterol (CH)-implanted naive castrated Tf and Tm males. Only Tf males implanted with testosterone had significantly higher TH immunopositive cell numbers in the VTA compared with CH- and dihydrotestosterone-implanted Tf males. These data indicate that both the embryonic environment as well as the circulating hormonal milieu can modulate neurochemistry, which might in turn be a basis for individual variation in behavior. PMID:17443813

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

    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

  8. PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome.

    Turjanski, N; Sawle, G V; Playford, E D; Weeks, R; Lammerstma, A A; A. J. Lees; Brooks, D. J.

    1994-01-01

    Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-d...

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

    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 therapeutic agents for the treatments of Parkinson’s disease and schizophrenia. With these therapeutic uses in mind, the pharmacological profiles of the enantiomers of N-0437 were considered. The pathophys...

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

    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...

  11. 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

    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...

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

    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

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

    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 ...

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

    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...

  15. IBZM- and CIT-SPECT of the dopaminergic system in Parkinsonism

    Parkinsonism is most of the time caused by idiopathic Parkinson's disease (IPD). Considering the differences in therapeutic response and prognosis. in viva discrimination between IPD and 'Parkinsonism-plus' syndromes is important. Recently, ligands have become available for imaging the pre- and postsynaptic dopaminergic system by Single Photon Emission Computed Tomography (SPECT). Visualization of postsynaptic D2 dopamine receptors using 123I-iodobenzamide (123I-IBZM) may contribute to the differential diagnosis between IPD and 'Parkinsonism-plus' syndromes as IPD is a pure presynaptic disease. Imaging of the presynaptic dopamine transporters using [123I]β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) may be used as a diagnostic technique. Early disease detection in subjects suspected to be at risk for developing IPD has become possible using [123I]β-CIT or other ligands for the dopamine transporter. Furthermore, with SPECT one is probably able to monitor in an objective way the efficacy of new pharmacological therapies. (author)

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

    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.

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

    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

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

    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.

  19. Molecular Signatures of Natural Selection for Polymorphic Genes of the Human Dopaminergic and Serotonergic Systems: A Review

    Taub, Daniel R.; Page, Joshua

    2016-01-01

    A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular “footprints” in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20–25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4.

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

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

  1. Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson's disease

    Hunter Randy L

    2006-03-01

    Full Text Available Abstract Background Accumulating evidence suggests that inflammation plays an important role in the progression of Parkinson's disease (PD. Among many inflammatory factors found in the PD brain, cyclooxygenase (COX, specifically the inducible isoform, COX-2, is believed to be a critical enzyme in the inflammatory response. Induction of COX-2 is also found in an experimental model of PD produced by administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP. Method COX-2-deficient mice or C57BL/6 mice were treated with MPTP to investigate the effects of COX-2 deficiency or by using various doses of valdecoxib, a specific COX-2 inhibitor, which induces inhibition of COX-2 on dopaminergic neuronal toxicity and locomotor activity impairment. Immunohistochemistry, stereological cell counts, immunoblotting, an automated spontaneous locomotor activity recorder and rotarod behavioral testing apparatus were used to assess microglial activation, cell loss, and behavioral impariments. Results MPTP reduced tyrosine hydroxylase (TH-positive cell counts in the substantia nigra pars compacta (SNpc; total distance traveled, vertical activity, and coordination on a rotarod; and increased microglia activation. Valdecoxib alleviated the microglial activation, the loss of TH-positive cells and the decrease in open field and vertical activity. COX-2 deficiency attenuated MPTP-induced microglial activation, degeneration of TH-positive cells, and loss of coordination. Conclusion These results indicate that reducing COX-2 activity can mitigate the secondary and progressive loss of dopaminergic neurons as well as the motor deficits induced by MPTP, possibly by suppression of microglial activation in the SNpc.

  2. Age-related changes in the renal dopaminergic system and expression of renal amino acid transporters in WKY and SHR rats.

    Pinto, Vanda; Amaral, João; Silva, Elisabete; Simão, Sónia; Cabral, José Miguel; Afonso, Joana; Serrão, Maria Paula; Gomes, Pedro; Pinho, Maria João; Soares-da-Silva, Patrício

    2011-01-01

    This study examined age-related changes in renal dopaminergic activity and expression of amino acid transporters potentially involved in renal tubular uptake of l-DOPA in Wistar Kyoto (WKY) and spontaneously hypertensive rats. Aging (from 13 to 91 weeks) was accompanied by increases in systolic blood pressure (SBP) in both WKY and SHR. The sum of urinary dopamine and DOPAC and the urinary dopamine/l-DOPA ratio were increased in aged SHR but not in aged WKY. The urinary dopamine/renal delivery of l-DOPA ratio was increased in both rat strains with aging. LAT2 abundance was increased in aged WKY and SHR. The expression of 4F2hc was markedly elevated in aged SHR but not in aged WKY. ASCT2 was upregulated in both aged WKY and SHR. Plasma aldosterone levels and urinary noradrenaline levels were increased in aged WKY and SHR though levels of both entities were more elevated in aged SHR. Activation of the renal dopaminergic system is more pronounced in aged SHR than in aged WKY and is associated with an upregulation of renal cortical ASCT2 in WKY and of LAT2/4F2hc and ASCT2 in SHR. This activation may be the consequence of a counter-regulatory mechanism for stimuli leading to sodium reabsorption. PMID:21699911

  3. EFFECTS OF TRIMETHYLTIN ON DOPAMINERGIC AND SEROTONERGIC FUNCTION IN THE CENTRAL NERVOUS SYSTEM

    The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic ...

  4. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Rainer W. Friedrich

    2012-10-01

    Full Text Available Dopamine (DA is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homologue of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordings revealed no obvious effects of DA on membrane potential or input resistance in the majority of Dp neurons. Electrical stimulation of the olfactory tracts produced a complex sequence of synaptic currents in Dp neurons. DA selectively decreased inhibitory currents with little or no effect on excitatory components. Multiphoton calcium imaging showed that population responses of Dp neurons to olfactory tract stimulation or odor application were enhanced by DA, consistent with its effect on inhibitory synaptic transmission. These effects of DA were blocked by an antagonist of D2-like receptors. DA therefore disinhibits and reorganizes sensory responses in Dp. This modulation may affect sensory perception and could be involved in the experience-dependent modification of odor representations.

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

    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.

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

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

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

    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

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

    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...

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

    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.

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

    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.

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

    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

  12. The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development.

    Lange, M; Norton, W; Coolen, M; Chaminade, M; Merker, S; Proft, F; Schmitt, A; Vernier, P; Lesch, K-P; Bally-Cuif, L

    2012-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. PMID:22508465

  13. Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

    Conceição, E P S; Carvalho, J C; Manhães, A C; Guarda, D S; Figueiredo, M S; Quitete, F T; Oliveira, E; Moura, E G; Lisboa, P C

    2016-05-01

    Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins. PMID:26929129

  14. The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice.

    Farahmandfar, Maryam; Bakhtazad, Atefeh; Akbarabadi, Ardeshir; Zarrindast, Mohammad-Reza

    2016-06-15

    Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1μg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition. PMID:27041647

  15. 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.

    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

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

    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)

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

    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

  18. Activation of CNTF/CNTFRα Signaling Pathway by hRheb(S16H) Transduction of Dopaminergic Neurons In Vivo

    Jeong, Kyoung Hoon; Nam, Jin Han; Jin, Byung Kwan; Kim, Sang Ryong

    2015-01-01

    Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα). It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson’s disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRα signaling pathway may be a u...

  19. α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation

    Liu Yuan

    2012-05-01

    Full Text Available Abstract Background Although evidence suggests that the prevalence of Parkinson’s disease (PD is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the α7 nicotinic acetylcholine receptor (α7-nAChR seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model occurs via α7-nAChR-mediated inhibition of astrocytes. Methods Both in vivo (MPTP and in vitro (1-methyl-4-phenylpyridinium ion (MPP+ and lipopolysaccharide (LPS models of PD were used to investigate the role(s of and possible mechanism(s by which α7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF-α assays, and western blotting, were used to elucidate the mechanisms of the α7-nAChR-mediated neuroprotection. Results Systemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA. In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP+-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-α and inhibition of extracellular regulated kinase1/2 (Erk1/2 and p38 activation in

  20. Disinhibition Bursting of Dopaminergic Neurons

    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.

  1. The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder: A Meta-Analysis.

    Li, Lizhuo; Bao, Yijun; He, Songbai; Wang, Gang; Guan, Yanlei; Ma, Dexuan; Wang, Pengfei; Huang, Xiaolong; Tao, Shanwei; Zhang, Dewei; Liu, Qiwen; Wang, Yunjie; Yang, Jingyun

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a complex mental disorder and can severely interfere with the normal life of the affected people. Previous studies have examined the association of PTSD with genetic variants in multiple dopaminergic genes with inconsistent results.To perform a systematic literature search and conduct meta-analysis to examine whether genetic variants in the dopaminergic system is associated with PTSD.PubMed, Cochrane Library, Embase, Google Scholar, and HuGE.The studies included subjects who had been screened for the presence of PTSD; the studies provided data for genetic variants of genes involved in the dopaminergic system; the outcomes of interest included diagnosis status of PTSD; and the studies were case-control studies.Odds ratio was used as a measure of association. We used random-effects model in all the meta-analyses. Between-study heterogeneity was assessed using I, and publication bias was evaluated using Egger test. Findings from meta-analyses were confirmed using random-effects meta-analyses under the framework of generalized linear model (GLM).A total of 19 studies met the eligibility criteria and were included in our analyses. We found that rs1800497 in DRD2 was significantly associated with PTSD (OR = 1.96, 95% CI: 1.15-3.33; P = 0.014). The 3'-UTR variable number tandem repeat (VNTR) in SLC6A3 also showed significant association with PTSD (OR = 1.62, 95% CI: 1.12-2.35; P = 0.010), but there was no association of rs4680 in COMT with PTSD (P = 0.595).Sample size is limited for some studies; type and severity of traumatic events varied across studies; we could not control for potential confounding factors, such as age at traumatic events and gender; and we could not examine gene-environment interaction due to lack of data.We found that rs1800497 in DRD2 and the VNTR in SLC6A3 showed significant association with PTSD. Future studies controlling for confounding factors, with large sample sizes and more

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

    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.

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

    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

  4. Dopaminergic Circuitry Underlying Mating Drive.

    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

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

    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.

  6. 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

    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.)

  7. 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

    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 [123I]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 (BPNP) 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 BPNP 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.)

  8. Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.

    García-Pérez, Daniel; López-Bellido, Roger; Hidalgo, Juana M; Rodríguez, Raquel E; Laorden, Maria Luisa; Núñez, Cristina; Milanés, Maria Victoria

    2015-01-01

    Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. PMID:23927484

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

    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.

  10. Effects of Tityus serrulatus crude venom on the GABAergic and dopaminergic systems of the rat brain.

    Dorce, V A; Sandoval, M R

    1994-12-01

    This study was designed to investigate the effect of T. serrulatus scorpion venom on dopamine (DA) and gamma amino butyric acid (GABA) concentrations in different regions of the brain. The ratio of homovanillic acid (HVA) to DA, and the glutamic acid decarboxylase (GAD) activity were determined following intravenous or intracerebral venom injections. The increase in the HVA/DA ratio in the striatum after i.v. or intrastriatal injection could indicate an increase in DA turnover. One hour after i.v. injection of the venom GAD activity was shown to be decreased in the striatum and hypothalamus. After 24 hr GAD activity increased in the striatum and decreased in the hypothalamus and brain stem. These results could indicate different effects of the venom on the GABA system in different areas of the brain. After intrastriatal injection of the scorpion venom, the animals showed stereotyped behavior and rotation activity. Following intrahippocampal injection, myoclonus and orofacial automatisms, which constitute pro-convulsive signals, were observed. These behavioral alterations could be, at least in part, related to the GABA and dopamine alterations caused by the venom, since stereotypy, circling behavior and convulsions are dependent on dopamine and/or GABA. PMID:7725331

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

    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

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

    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

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

    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

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

    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

  15. Genetic analysis of dopaminergic neuron survival

    Aron, Liviu

    2010-01-01

    Pathological changes in the dopaminergic system account for a number of devastating illnesses including schizophrenia, psychosis, depression, addiction, obsessive compulsive disorder or the most well known Parkinson’s disease (PD). The nigrostriatal pathway is an important component of the dopaminergic (DA) system mediating voluntary movement and originates in the ventral midbrain from where substantia nigra pars compacta (SN) neurons send their axons to the dorsal striatum. Massive loss of S...

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

    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...

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

    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

  18. Dopaminergic agonists for hepatic encephalopathy

    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....

  19. Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia

    Calcagno, B; Eyles, D; Alphen, B. van; van Swinderen, B

    2013-01-01

    It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the “dopamine ontogeny hypothesis of schizophrenia”. To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain mo...

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

    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...

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

    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...

  2. Methylphenidate alters basal ganglia neurotensin systems through dopaminergic mechanisms: a comparison with cocaine treatment.

    Alburges, Mario E; Hoonakker, Amanda J; Horner, Kristen A; Fleckenstein, Annette E; Hanson, Glen R

    2011-05-01

    Methylphenidate (MPD) is a psychostimulant widely used to treat behavioral problems such as attention deficit hyperactivity disorder. MPD competitively inhibits the dopamine (DA) transporter. Previous studies demonstrated that stimulants of abuse, such as cocaine (COC) and methamphetamine differentially alter rat brain neurotensin (NT) systems through DA mechanisms. As NT is a neuropeptide primarily associated with the regulation of the nigrostriatal and mesolimbic DA systems, the effect of MPD on NT-like immunoreactivity (NTLI) content in several basal ganglia regions was assessed. MPD, at doses of 2.0 or 10.0 mg/kg, s.c., significantly increased the NTLI contents in dorsal striatum, substantia nigra and globus pallidus; similar increases in NTLI were observed in these areas after administration of COC (30.0 mg/kg, i.p.). No changes in NTLI occurred within the nucleus accumbens, frontal cortex and ventral tegmental area following MPD treatment. In addition, the NTLI changes in basal ganglia regions induced by MPD were prevented when D(1) (SCH 23390) or D(2) (eticlopride) receptor antagonists were coadministered with MPD. MPD treatment also increased dynorphin (DYN) levels in basal ganglia structures. These findings provide evidence that basal ganglia, but not limbic, NT systems are significantly affected by MPD through D(1) and D(2) receptor mechanisms, and these NTLI changes are similar, but not identical to those which occurred with COC administration. In addition, the MPD effects on NT systems are mechanistically distinct from the effects of methamphetamine. PMID:21323925

  3. Quality assurance methods for some agents used in PET studies of the dopaminergic system

    In the authors' laboratory, quality assurance rests on establishing good manufacturing practice supported by routine quality control. In establishing good manufacturing practice, indirect techniques (e.g. NMR spectroscopy) and direct techniques (e.g. radiochromatography) are extensively applied to characterize the product from a developing procedure, and to investigate any contamination. In order to establish radiochemical purity, chemical purity, and specific activity before radiopharmaceutical product administration, they have developed rapid routine quality control procedures based on analytical HPLC methods for L-6-[18F]fluoro-DOPA, S-[N-methyl-11C]nomifensine, and [O-methyl-11C]raclopride

  4. Neonatal chlorpyrifos exposure induces loss of dopaminergic neurons in young adult rats

    Increasing epidemiological and toxicological evidence suggests that pesticides and other environmental exposures may be associated with the development of Parkinson’s disease (PD). Chlorpyrifos (CPF) is a widely used organophosphorous pesticide with developmental neurotoxicity. Its neurotoxicity, notably on the monoamine system, suggests that exposure of CPF may induce dopaminergic neuronal injury. We investigated whether neonatal exposure to CPF contributes to initiation and progression of dopaminergic neurotoxicity and explored the possible underlying mechanisms. The newborn rats were administrated 5 mg/kg CPF subcutaneously from postnatal day (PND) 11 to PND 14 daily. The effect of CPF on dopaminergic neurons, microglia, astrocyte, nuclear factor-κB (NF-κB) p. 65 and p. 38 mitogen-activated protein kinase (MAPK) signaling pathways was analyzed in the substantia nigra of rats at 12 h, 24 h, 72 h, 16 d and 46 d after exposure. CPF-treated rats exhibited significant reduction of dopaminergic neurons at 16 d and 46 d after exposure, and a significant increase in the expression of microglia and astrocytes in the substantia nigra after CPF exposure. Intense activation of NF-κB p. 65 and p. 38 MAPK inflammatory signaling pathways was observed. Our findings indicate that neonatal exposure to CPF may induce long-term dopaminergic neuronal damage in the substantia nigra mediated by the activation of inflammatory response via NF-κB p. 65 and p. 38 MAPK pathways in the nigrostriatal system

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

    Planeta, C.S.; Lepsch, L.B.; Alves, R.; Scavone, C.

    2013-01-01

    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 ...

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

    Vindas, M.A.; Höglund, Erik; Folkedal, O.; Johansen, I.B.; Braastad, B.O.; Stien, L.H.; Kristiansen, T.S.; Overli, O.

    For several reasons, such as easy maintenance, rapid generation times, and increasingly mapped genomes, teleost fishes are emerging as an alternative to small mammals in biomedical, neural, and behavioral research. Behavioral, genetic, and physiological screening of high numbers of individuals...... signalling system, manifest as a potentiated response to novel, stressful stimuli. Similarities between fish and mammals in this response to unpredictability illustrates a role for teleost fish as models to understand the development of different types of DA dysfunction...

  7. A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning.

    Lee, In-Seon; Lee, Bombi; Park, Hi-Joon; Olausson, Håkan; Enck, Paul; Chae, Younbyoung

    2015-01-01

    We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems. PMID:26602173

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

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

    across treatments and generations is one particularly attractive feature of fish model systems. Both animal welfare considerations and fundamental scientific questions regarding the evolution of learning and memory have directed particular attention towards possible cognitive and emotional processes in....... 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...

  9. Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development

    Willaredt Marc

    2007-12-01

    Full Text Available Abstract Background: Dopaminergic neurons form in diverse areas of the vertebrate di- and mesencephalon to constitute several major neuromodulatory systems. While much is known about mammalian mesencephalic dopaminergic neuron development, little is known about the specification of the diencephalic dopaminergic groups. The transcription factors Pitx3 and Lmx1b play an important role in mammalian mesencephalic dopaminergic specification, and Nurr1/Nr4a2 has been shown to contribute to specification of the dopaminergic neurotransmitter phenotype. We use zebrafish to analyze potentially evolutionarily conserved roles of these transcription factors in a vertebrate brain that lacks a mesencephalic dopaminergic system, but has an ascending dopaminergic system in the ventral diencephalon. Results: We use a combination of fluorescent in situ hybridization and immunohistochemistry to determine whether nr4a2, lmx1b, and pitx3 genes are expressed in mature dopaminergic neurons or in potential precursor populations. We identify a second nr4a2 paralogue, nr4a2a, and find it co-expressed with Tyrosine hydroxylase in preoptic, pretectal and retinal amacrine dopaminergic neurons, while nr4a2b is only expressed in preoptic and retinal dopaminergic neurons. Both zebrafish nr4a2 paralogues are not expressed in ventral diencephalic dopaminergic neurons with ascending projections. Combined morpholino antisense oligo mediated knock-down of both nr4a2a and nr4a2b transcripts reveals that all zebrafish dopaminergic neurons expressing nr4a2a depend on Nr4a2 activity for tyrosine hydroxylase and dopamine transporter expression. Zebrafish lmx1b.1 is expressed in noradrenergic neurons of the locus coeruleus and medulla oblongata, but knock-down reveals that it is specifically required for tyrosine hydroxylase expression only in the medulla oblongata area postrema noradrenergic neurons. Both lmx1b genes and pitx3 are not expressed in dopaminergic neurons, but in a

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

    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.

  11. Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression.

    Pérez-Fernández, Juan; Stephenson-Jones, Marcus; Suryanarayana, Shreyas M; Robertson, Brita; Grillner, Sten

    2014-12-01

    The dopaminergic system influences motor behavior, signals reward and novelty, and is an essential component of the basal ganglia in all vertebrates including the lamprey, one of the phylogenetically oldest vertebrates. The intrinsic organization and function of the lamprey basal ganglia is highly conserved. For instance, the direct and indirect pathways are modulated through dopamine D1 and D2 receptors in lamprey and in mammals. The nucleus of the tuberculum posterior, a homologue of the substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) is present in lamprey, but only scarce data exist about its connectivity. Likewise, the D2 receptor is expressed in the striatum, but little is known about its localization in other brain areas. We used in situ hybridization and tracer injections, both in combination with tyrosine hydroxylase immunohistochemistry, to characterize the SNc/VTA efferent and afferent connectivity, and to relate its projection pattern with D2 receptor expression in particular. We show that most features of the dopaminergic system are highly conserved. As in mammals, the direct pallial (cortex in mammals) input and the basal ganglia connectivity with the SNc/VTA are present as part of the evaluation system, as well as input from the tectum as the evolutionary basis for salience/novelty detection. Moreover, the SNc/VTA receives sensory information from the olfactory bulbs, optic tectum, octavolateral area, and dorsal column nucleus, and it innervates, apart from the nigrostriatal pathway, several motor-related areas. This suggests that the dopaminergic system also contributes to the control of different motor centers at the brainstem level. PMID:24942187

  12. Disruption in dopaminergic innervation during photoreceptor degeneration.

    Ivanova, Elena; Yee, Christopher W; Sagdullaev, Botir T

    2016-04-15

    Dopaminergic amacrine cells (DACs) release dopamine in response to light-driven synaptic inputs, and are critical to retinal light adaptation. Retinal degeneration (RD) compromises the light responsiveness of the retina and, subsequently, dopamine metabolism is impaired. As RD progresses, retinal neurons exhibit aberrant activity, driven by AII amacrine cells, a primary target of the retinal dopaminergic network. Surprisingly, DACs are an exception to this physiological change; DACs exhibit rhythmic activity in healthy retina, but do not burst in RD. The underlying mechanism of this divergent behavior is not known. It is also unclear whether RD leads to structural changes in DACs, impairing functional regulation of AII amacrine cells. Here we examine the anatomical details of DACs in three mouse models of human RD to determine how changes to the dopaminergic network may underlie physiological changes in RD. By using rd10, rd1, and rd1/C57 mice we were able to dissect the impacts of genetic background and the degenerative process on DAC structure in RD retina. We found that DACs density, soma size, and primary dendrite length are all significantly reduced. Using a novel adeno-associated virus-mediated technique to label AII amacrine cells in mouse retina, we observed diminished dopaminergic contacts to AII amacrine cells in RD mice. This was accompanied by changes to the components responsible for dopamine synthesis and release. Together, these data suggest that structural alterations of the retinal dopaminergic network underlie physiological changes during RD. PMID:26356010

  13. The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate.

    Drijgers, Rosa L; Verhey, Frans R J; Tissingh, Gerrit; van Domburg, Peter H M F; Aalten, Pauline; Leentjens, Albert F G

    2012-09-15

    In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. PMID:22824349

  14. 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

    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.

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

    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

  16. Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.

    Guo, Chuang; Hao, Li-Juan; Yang, Zhao-Hui; Chai, Rui; Zhang, Shuai; Gu, Yu; Gao, Hui-Ling; Zhong, Man-Li; Wang, Tao; Li, Jia-Yi; Wang, Zhan-You

    2016-06-01

    Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator widely used in clinical settings, has been reported to improve motor deficits and dopaminergic neuronal survival in animal models of PD, DFO has poor penetration to cross the blood-brain barrier and elicits side effects. We evaluated whether an intranasal administration of DFO improves the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic neurons in the nigrostriatal axis and investigated the molecular mechanisms of intranasal DFO treatment in preventing MPTP-induced neurodegeneration. Treatment with DFO efficiently alleviated behavioral deficits, increased the survival of tyrosine hydroxylase (TH)-positive neurons, and decreased the action of astrocytes in the SN and striatum in an MPTP-induced PD mouse model. Interestingly, we found that DFO up-regulated the expression of HIF-1α protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of α-synuclein, divalent metal transporter with iron-responsive element (DMT1+IRE), and transferrin receptor (TFR). This was accompanied by a decrease in iron-positive cells in the SN and striatum of the DFO-treated group. We further revealed that DFO treatment significantly inhibited the MPTP-induced phosphorylation of the c-Jun N-terminal kinase (JNK) and differentially enhanced the phosphorylation of extracellular regulated protein kinases (ERK) and mitogen-activated protein kinase (MAPK)/P38 kinase. Additionally, the effects of DFO on increasing the Bcl-2/Bax ratio were further validated in vitro and in vivo. In SH-SY5Y cells, the DFO-mediated up-regulation of HIF-1α occurred via the activation of

  17. Early specification of dopaminergic phenotype during ES cell differentiation

    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.

  18. Systemic administration of valproic acid and zonisamide promotes the survival and differentiation of induced pluripotent stem cell–derived dopaminergic neurons

    Tatsuya Yoshikawa

    2013-02-01

    Full Text Available Cell replacement therapy using embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs is a promising strategy for the treatment of neurologic diseases such as Parkinson’s disease (PD. However, a limiting factor for effective cell transplantation is the low survival rate of grafted cells, especially neurons. In this study, we modified the host environment and investigated whether the simultaneous administration of soluble factors can improve the survival and differentiation of murine iPSC-derived dopaminergic (DA neurons in host brains. With the goal of applying this technology in clinical settings in the near future, we selected drugs that were already approved for clinical use. The drugs included two commonly used anticonvulsants, valproic acid (VPA and zonisamide (ZNS, and estradiol (E2, also known as biologically active estrogen. Following neural induction of murine iPSCs, we collected neural progenitor cells by sorting PSA-NCAM+ cells, then treated the PSA-NCAM+ cells with drugs for four days. An immunofluorescence study revealed that 0.01 mM and 0.1 mM of VPA and 10 nM of E2 increased the percentage of tyrosine hydroxylase+ (TH: a DA neuron marker cells in vitro. Furthermore, 0.1 mM of VPA increased the percentage of TH+ cells that simultaneously express the midbrain markers FOXA2 and NURR1. Next, in order to determine the effects of the drugs in vivo, the iPSC-derived NPCs were transplanted into the striata of intact SD rats. The animals received intraperitoneal injections of one of the drugs for four weeks, then were subjected to an immunofluorescence study. VPA administration (150 mg/kg/daily increased the number of NeuN+ postmitotic neurons and TH+ DA neurons in the grafts. Furthermore, VPA (150 mg/kg/daily and ZNS (30 mg/kg/daily increased the number of TH+FOXA2+ midbrain DA neurons. These results suggest that the systemic administration of VPA and ZNS may improve the efficiency of cell replacement therapy using i

  19. Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

    Areal, Lorena B; Rodrigues, Livia C M; Andrich, Filipe; Moraes, Livia S; Cicilini, Maria A; Mendonça, Josideia B; Pelição, Fabricio S; Nakamura-Palacios, Ester M; Martins-Silva, Cristina; Pires, Rita G W

    2015-09-01

    Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("escape jumping"). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine. PMID:25940765

  20. 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.

    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

  1. 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.

    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

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

    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.)

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

    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

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

    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.

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

    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...

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

    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.

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

    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.

  8. 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.

    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

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

    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...

  10. Acute Administration of Dopaminergic Drugs has Differential Effects on Locomotion in Larval Zebrafish

    Irons, T.D.; Kelly, P; Hunter, D.L.; MacPhail, R.C; Padilla, S.

    2012-01-01

    Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-leth...

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

    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...

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

    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

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

    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.

  14. 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

    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.)

  15. Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: A molecular, cellular and behavioral analysis.

    Gillies, G E; Virdee, K; McArthur, S; Dalley, J W

    2014-06-01

    The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. This may be driven by sex differences in the hormonal environment during adulthood ('activational' effects) and development (perinatal and/or pubertal 'organizational' effects), as well as genetic factors, especially the SRY gene on the Y chromosome in males, which is expressed in a sub-population of adult midbrain dopaminergic neurons. Stress and stress hormones, especially glucocorticoids, are important factors which interact with the VTA dopaminergic systems in order to achieve behavioral adaptation and enable the individual to cope with environmental change. Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and treatment of

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

    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. ...

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

    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

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

    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...

  19. Dopaminergic function and intertemporal choice.

    Joutsa, J; Voon, V; Johansson, J; Niemelä, S; Bergman, J; Kaasinen, V

    2015-01-01

    The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson's disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson's disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions. PMID:25562841

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

    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...

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

    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

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

    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

  3. Regulation of a sapogenin from Rhizoma Anemarrhenae, ZMR on dopaminergic system in a chronic model of Parkinson's disease

    Objective: The significant neuropathological features of Parkinson's disease include sharp decrease of striatal dopamine (DA) and downregulation of striatal dopamine transporter (DAT) density in nigrostriatal pathway. The purpose of this research was to investigate the effects of ZMR on the DAT and DA metabolism in the brain of a chronic 1 -methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Methods: C57BL/6 mice were divided into four groups: control mice, model mice, model mice treated with 10 mg/kg of ZMR (ZMR-10) and model mice treated with 26 mg/kg of ZMR (ZMR-26). All mice except control received ten doses of MPTP (15 mg/kg, subcutaneous injection) plus probenecid (250 mg/kg, intraperitoneal injection) twice a week in five weeks. Mice in groups of ZMR- 10 and ZMR-26 were administrated 10 mg/kg and 26 mg/kg of ZMR by oral garage once daily for 60 d respectively. Striatal DAT was detected by autoradiography using 125I-2β-carbomethoxy-3 [3-(4-iodophenyl)-N-(3- fluoropropropyl) nortropane (FP-CIT), Uonoamine oxidase B (MAO-B) activity was determined with a commercial kit. DA and its metabolites were determined by high performance liquid chromatography-electro-chemical detection (HPLC-ECD). Statistical analysis was performed With SAS 6.12 software, and the one- way ANOVA, grouped t-test were used to analyze the data. Results: Compared with vehicle treated model mice, ZMR-10 and ZMR-26 increased striatal DAT density from 0.212 ± 0.012 to 0.268 ± 0.019 and 0.281 ± 0.018 respectively (t=2.5314, 3.1124, P<0.05 and <0.01 respectively), raised striatal DA levels from (3.00 ± 0.25) μg/g to (4.21 ± 0.32) μg/g and (4.58 ± 0.39) μg/g respectively (t= 2.9879, 3.4163, P<0.05 and <0.01 respectively). However, ZMR-10 and ZMR-26 did not affect the MAO-B activity. Conclusion: ZMR raises striatal DA levels in chronic MPTP-model mice, which is closely related to the elevation of striatal DAT density but not related to catabolism of DA

  4. 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)

    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.)

  5. Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice.

    Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K

    2015-07-23

    , when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively. PMID:25943484

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

    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...

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

    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.

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

    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

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

    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

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

    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

  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)

    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

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

    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

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

    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.

  14. Addictive drugs and plasticity of glutamatergic synapses on dopaminergic neurons: what have we learned from genetic mouse models?

    Jan Rodriguez Parkitna; David Engblom

    2012-01-01

    Drug-induced changes in the functional properties of neurons in the mesolimbic dopaminergic system are attractive candidates for the molecular underpinnings of addiction. A central question in this context has been how drugs of abuse affect synaptic plasticity on dopaminergic cells in the ventral tegmental area. We now know that the intake of addictive drugs is accompanied by a complex sequence of alterations in the properties of excitatory synapses on dopaminergic neurons, mainly driven by s...

  15. Striatal vessels receive phosphorylated tyrosine hydroxylase-rich innervation from midbrain dopaminergic neurons

    Sonia Garcia-Hernandez

    2014-08-01

    Full Text Available Nowadays it is assumed that besides its roles in neuronal processing, dopamine (DA is also involved in the regulation of cerebral blood flow. However, studies on the hemodynamic actions of DA have been mainly focused on the cerebral cortex, but the possibility that vessels in deeper brain structures receive dopaminergic axons and the origin of these axons have not been investigated. Bearing in mind the evidence of changes in the blood flow of basal ganglia in Parkinson’s disease, and the pivotal role of the dopaminergic mesostriatal pathway in the pathophysiology of this disease, here we studied whether striatal vessels receive inputs from midbrain dopaminergic neurons. The injection of an anterograde neuronal tracer in combination with immunohistochemistry for dopaminergic, vascular and astroglial markers, and dopaminergic lesions, revealed that midbrain dopaminergic axons are in close apposition to striatal vessels and perivascular astrocytes. These axons form dense perivascular plexuses restricted to striatal regions in rats and monkeys. Interestingly, they are intensely immunoreactive for tyrosine hydroxylase (TH phosphorylated at Ser19 and Ser40 residues. The presence of phosphorylated TH in vessel terminals indicates they are probably the main source of basal TH activity in the striatum, and that after activation of midbrain dopaminergic neurons, DA release onto vessels precedes that onto neurons. Furthermore, the relative weight of this “vascular component” within the mesostriatal pathway suggests that it plays a relevant role in the pathophysiology of Parkinson’s disease.

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

    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.

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

    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

  18. Pharmacological imaging as a tool to visualise dopaminergic neurotoxicity.

    Schrantee, A; Reneman, L

    2014-09-01

    Dopamine abnormalities underlie a wide variety of psychopathologies, including ADHD and schizophrenia. A new imaging technique, pharmacological magnetic resonance imaging (phMRI), is a promising non-invasive technique to visualize the dopaminergic system in the brain. In this review we explore the clinical potential of phMRI in detecting dopamine dysfunction or neurotoxicity, assess its strengths and weaknesses and identify directions for future research. Preclinically, phMRI is able to detect severe dopaminergic abnormalities quite similar to conventional techniques such as PET and SPECT. phMRI benefits from its high spatial resolution and the possibility to visualize both local and downstream effects of dopaminergic neurotransmission. In addition, it allows for repeated measurements and assessments in vulnerable populations. The major challenge is the complex interpretation of phMRI results. Future studies in patients with dopaminergic abnormalities need to confirm the currently reviewed preclinical findings to validate the technique in a clinical setting. Eventually, based on the current review we expect that phMRI can be of use in a clinical setting involving vulnerable populations (such as children and adolescents) for diagnosis and monitoring treatment efficacy. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. PMID:23851258

  19. 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

    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.

  20. alpha4beta2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief

    McGranahan, Tresa M.; Patzlaff, Natalie E.; Grady, Sharon R.; Heinemann, Stephen F.; Booker, T.K.

    2012-01-01

    Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addition, mental illness and movement control in humans. We developed a unique model system to examine the role of alpha4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the alpha4 subunit from dopaminergic neurons in mice. The loss alpha4 mRNA and alpha4beta2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of alpha4beta2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. Alpha4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. Alpha4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze and elimination of alpha4-beta2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of alpha4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression, however nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine behaviors. PMID:21795541

  1. α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.

    McGranahan, Tresa M; Patzlaff, Natalie E; Grady, Sharon R; Heinemann, Stephen F; Booker, T K

    2011-07-27

    Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors. PMID:21795541

  2. Dopaminergic response to drug words in cocaine addiction

    Goldstein, Rita Z.; Tomasi, Dardo; Alia-Klein, Nelly; Carrillo, Jean Honorio; Maloney, Thomas; Woicik, Patricia A.; Wang, Ruiliang; Telang, Frank; Volkow, Nora D.

    2009-01-01

    When exposed to drug conditioned cues (stimuli associated with the drug) addicted individuals experience an intense desire for the drug, which is associated with increased dopamine cell firing. We hypothesized that drug related words can trigger activation in the mesencephalon where dopaminergic cells are located. During functional magnetic resonance imaging (fMRI) 15 individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed for color of drug-relat...

  3. Naringin: A Protector of the Nigrostriatal Dopaminergic Projection

    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 ...

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

    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

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

    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.

  6. The Conserved Dopaminergic Diencephalospinal Tract Mediates Vertebrate Locomotor Development In Zebrafish Larvae

    Lambert, Aaron M.; Bonkowsky, Joshua L.; Mark A Masino

    2012-01-01

    The most conserved part of the vertebrate dopaminergic system is the orthopedia (otp)-expressing diencephalic neuronal population that constitutes the dopaminergic diencephalospinal tract (DDT). While studies in the neonatal murine spinal cord in vitro suggest an early locomotor role of the DDT, the function of the DDT in developing vertebrates in vivo remains unknown. Here, we investigated the role of the DDT in the locomotor development of zebrafish larvae. To assess the development of the ...

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

    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...

  8. Dopaminergic neurotransmission triggers ischemia-induced hyperactivity in Mongolian gerbils.

    Yamamoto T

    2001-10-01

    Full Text Available It is recognized that sustained ischemia-induced hyperactivity is related to abnormalities in dopamine function. However, it is unclear that dopaminergic neurotransmission triggers such ischemia-induced hyperactivity. Therefore, the relationship between dopaminergic neurotransmission and ischemia-induced hyperactivity was investigated in an animal model using Mongolian gerbils. When haloperidol 2 mg/kg was administered i.p. 30 min after ischemia, the ischemia-induced hyperactivity at 24 h after ischemia was blocked. General behavior was similar to that of sham-operated animals. Haloperidol at doses of 0.1 and 0.2 mg/kg had no effect on locomotor activity in sham-operated animals and decreased ischemia-induced hyperactivity when the drug was administered 24 h after ischemia; these doses did not have any effect on ischemia-induced hyperactivity when the drug was administered 30 min after ischemia. On the other hand, when the animal was confined to a small, restrictive cage for the 24 h period immediately following ischemic injury, locomotor activity at 24 h after ischemia increased. Such behavior also increased in animals when they were returned to their original more permissive cages immediately after ischemia. It is conceivable that the decrease in the level of activity was not related to ischemia-induced hyperactivity. These data suggested that the inhibition of ischemia-induced hyperactivity can be induced by complete blockage of dopaminergic receptors immediately after ischemia.

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

    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.

  10. Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development

    Willaredt Marc; Ryu Soojin; Dürr Katrin; Filippi Alida; Holzschuh Jochen; Driever Wolfgang

    2007-01-01

    Abstract Background: Dopaminergic neurons form in diverse areas of the vertebrate di- and mesencephalon to constitute several major neuromodulatory systems. While much is known about mammalian mesencephalic dopaminergic neuron development, little is known about the specification of the diencephalic dopaminergic groups. The transcription factors Pitx3 and Lmx1b play an important role in mammalian mesencephalic dopaminergic specification, and Nurr1/Nr4a2 has been shown to contribute to specific...

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

    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 ...

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

    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...

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

    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

  14. Counteraction by nitric oxide synthase inhibitor of neurochemical alterations of dopaminergic system in 6-OHDA-lesioned rats under L-DOPA treatment.

    Del-Bel, Elaine; Padovan-Neto, Fernando Eduardo; Szawka, Raphael Escorsim; da-Silva, Célia Aparecida; Raisman-Vozari, Rita; Anselmo-Franci, Janete; Romano-Dutra, Angélica Caroline; Guimaraes, Francisco Silveira

    2014-01-01

    Nitric oxide synthase inhibitors reduce L-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, 2005) 4-dihydroxyphenylalanine (L-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with L-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before L-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. L-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. L-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of L-DOPA-induced dyskinesia with potential

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

    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.

  16. System of Volcanic activity

    P. HÉDERVARI

    1972-06-01

    Full Text Available A comparison is made among the systems of B. G.
    Escher (3, of R. W. van Bemmelen (1 and that of the author (4. In this
    connection, on the basis of Esclier's classification, the terms of "constructiv
    e " and "destructive" eruptions are introduced into the author's system and
    at the same time Escher's concept on the possible relation between the depth
    of magma-chamber and the measure of the gas-pressure is discussed briefly.
    Three complementary remarks to the first paper (4 011 the subject of system
    of volcanic activity are added.

  17. Measurement of the dopaminergic degeneration in Parkinson's disease with [123I]β-CIT and SPECT

    The cocaine derivative [123I]β-CIT binds with high affinity to dopamine uptake sites in the striatum and can be used to visualize dopaminergic nerve terminals in vivo in the human brain with SPECT. It has been validated that the calculation of a simple ratio of specific/non-displaceable binding during a period of binding-equilibrium in the striatum about 20 hrs after bolus injection of the tracer gives a strong and reliable index of the binding potential of dopamine uptake sites. Our own results in a group of 113 patients with PD demonstrate a 45 % loss of striatal [123I]β-CIT binding in comparison to age corrected control values. Highly significant correlations of SPECT findings with clinical data obtained from the UPDRS rating scale such as akinesia, rigidity, axial symptoms and activities of daily living are demonstrated, while no correlation is found with tremor. The signal loss in a region comprising the whole striatum ranges from 35 % in Hoehn/Yahr stage I to over 72 % in stage V and is highly significantly correlated to the different stages of disease severity. Data in 9 patients with multiple system atrophy (MSA) and 4 patients with progressive supranuclear palsy (PSP) are similar to the findings in PD although the differences between caudate and putamen are somewhat less marked. These data demonstrate that the dopaminergic nerve cell loss in PD and other disorders with a dopaminergic lesion can be quantified with [123I]β-CIT and SPECT and that hopefully a preclinical or very early diagnosis is made possible. Such studies might also open the way for a better evaluation of neuroprotective strategies in PD. It does not seem to be possible however to differentiate PD and MSA or PSP with this method in individual cases. (author)

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

    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...

  19. Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

    Machado, A.; A. J. Herrera; J. L. Venero; Santiago, M; De Pablos, R. M.; R. F. Villarán; Espinosa-Oliva, A. M.; S. Argüelles; Sarmiento, M.; M. J. Delgado-Cortés; R. Mauriño; Cano, J.

    2011-01-01

    We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2 μg of the potent p...

  20. PET measurements od dopaminergic pathways in the brain

    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.

  1. PET measurements od dopaminergic pathways in the brain

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

    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.

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

    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

  4. ADASY (Active Daylighting System)

    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

  5. Cooperatively active sensing system

    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.)

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

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

    2002-01-01

    the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription. We conclude that GDNF, in addition to its action in structural differentiation, also promotes differentiation regarding expression and enzymatic activity of a crucial component in the...

  7. 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

    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

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

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

    2012-01-01

    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...

  9. Histamine in the central nervous system: characterization of release and effects of other neurotransmitters on the activity of histaminergic neurons

    The release of endogenous histamine and the involvement of adrenergic, dopaminergic and glutamatergic neurons in the modulation of histamine release was investigated by the push-pull technique. The posterior hypothalamus of conscious rats was superfused through a push-pull cannula with artificial cerebrospinal fluid containing neuroactive compounds. Histamine was determined radioenzymatically or by HPLC with fluorimetric detection. Experiments with depolarizing, channel-blocking and enzyme-inhibiting agents proved the neuronal origin of the histamine analysed. Superfusion with agonists and antagonists of α-adrenoceptors led to the conclusion that under in vivo conditions the neuronal histamine released is modulated by noradrenergic α2-adrenoceptors in a negative way, but not by β-adrenoceptors. Findings with dopaminergic agents suggested that dopaminergic neurons of the hypothalamus influence the release of histamine in a dual way: D2-heteroreceptors stimulate, D3-heteroreceptors inhibit the release. The anterior and medial hypothalamus possess glutamate-heteroreceptors, which modulate the histamine release in a positive way. We further studied the influence of the GABA- and NO-system on the manifestation of genetic hypertension and connections to the histaminergic system. The chronical activation of both systems led to distinct effects on blood pressure and histamine contents of main brain areas of normo- and hypertensive rats (WKY, SHR). However, a primary contribution of both systems to the manifestation of hypertension must be excluded. (author)

  10. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans.

    Levran, Orna; Randesi, Matthew; da Rosa, Joel Correa; Ott, Jurg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

    2015-05-01

    Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent. PMID:25875614

  11. Tracers tor the investigation of cerebral presynaptic dopaminergic function with positron emission tomography

    Two pharmacologic concepts, open-quotes metabolic precursorsclose quotes and open-quotes enzyme inhibitorsclose quotes have been applied to the design of PET tracers for the metabolic aspects of the neurotransmitter dopamine. As the result, highly useful, positron-emitting radiotracers have been developed with which to visualize and measure the cerebral distribution and metabolism of dopaminergic neurons. Positron emitter-labeled DOPA, particularly 6-[18F]fluoro-L-DOPA, is being used to obtain information about the neurochemical anatomy of the dopamine system, and potentially, the rate constant of dopamine biosynthesis. 6-[18F]Fluoro-L- meta-tyrosine delineates the dopaminergic structures even better than 6-[18F]fluoro-L-DOPA but cannot provide kinetic information about dopamine biosynthesis. The in vivo activity of the enzyme aromatic L-aminoacid decarboxylase and that of monoamine oxidase types A and B can be measured with a-fluoro-methyl-6-[18F]fluoro-L-DOPA, [11C]clorgyline and L-[11C]deprenyl, respectively. Thus, neuropharmacologic investigations of human presynaptic dopamine pharmacology are now possible in vivo

  12. Evidence of dopaminergic processing of executive inhibition.

    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.

  13. Role of Slit and Robo proteins in the development of dopaminergic neurons.

    Cornide-Petronio, María Eugenia; Barreiro-Iglesias, Antón

    2013-01-01

    Dopamine plays a number of important roles in the nervous system and the dopaminergic system is affected in several brain disorders. It is therefore of great interest to study the axonal guidance systems that specifically participate in the correct establishment of dopaminergic projections during development and possibly during regenerative processes. In recent years, several reports have shown that Slits and their Robo receptors control the growth of longitudinal (both ascending and descending) mesodiencephalic dopaminergic axons to their appropriate target areas. In vitro studies have shown that Slit1, 2 and 3 are potent repellents of dopamine neurite extension. In vivo studies using both mice and zebrafish mutants for Slits and Robos have shown that Slits and Robos control the lateral and dorsoventral positioning of dopaminergic longitudinal projections during early development. In the present review, we aimed to compile the existing knowledge from both in vitro and in vivo studies on the role of Slit and Robo proteins in the development of dopaminergic neurons as a basis for future studies. PMID:23796505

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

    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...... gambling, SCR differed in PG and HC subjects (Pb0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (Pb0.0001) in the baseline, compared to normal sensation-seeking (NS) PG...

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

    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...

  16. Addictive drugs and plasticity of glutamatergic synapses on dopaminergic neurons: what have we learned from genetic mouse models?

    Jan Rodriguez Parkitna

    2012-08-01

    Full Text Available Drug-induced changes in the functional properties of neurons in the mesolimbic dopaminergic system are attractive candidates for the molecular underpinnings of addiction. A central question in this context has been how drugs of abuse affect synaptic plasticity on dopaminergic cells in the ventral tegmental area. We now know that the intake of addictive drugs is accompanied by a complex sequence of alterations in the properties of excitatory synapses on dopaminergic neurons, mainly driven by signaling and redistribution of NMDA- and AMPA-receptors. It has, however, been unclear how these molecular changes are related to the behavioral effects of addictive drugs. Recently, new genetic tools have permitted researchers to perform genetic intervention with plasticity-related molecules selectively in dopaminergic cells and to subsequently study the behaviors of genetically modified mice. These studies have started to reveal how plasticity and drug-induced behavior are connected as well as what role plasticity in dopaminergic cells may have in general reward learning. The findings thus far show that there is not a one-to-one relation between plastic events and specific behaviors and that the early responses to drugs of abuse are to a large extent independent of the types of synaptic plasticity so far targeted. In contrast, plasticity in dopaminergic cells indeed is an important regulator of the persistence of behaviors driven by drug associations, making synaptic plasticity in dopaminergic cells an important field of study for understanding the mechanisms behind relapse.

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

    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

  18. Dopaminergic Polymorphisms, Academic Achievement, and Violent Delinquency.

    Yun, Ilhong; Lee, Julak; Kim, Seung-Gon

    2015-12-01

    Recent research in the field of educational psychology points to the salience of self-control in accounting for the variance in students' report card grades. At the same time, a novel empirical study from molecular genetics drawing on the National Longitudinal Study of Adolescent Health (Add Health) data has revealed that polymorphisms in three dopaminergic genes (dopamine transporter [DAT1], dopamine D2 receptor [DRD2], and dopamine D4 receptor [DRD4]) are also linked to adolescents' grade point averages (GPAs). Juxtaposing these two lines of research, the current study reanalyzed the Add Health genetic subsample to assess the relative effects of these dopaminergic genes and self-control on GPAs. The results showed that the effects of the latter were far stronger than those of the former. The interaction effects between the dopaminergic genes and a set of environmental factors on academic performance were also examined, producing findings that are aligned with the "social push hypothesis" in behavioral genetics. Finally, based on the criminological literature on the link between academic performance and delinquency, we tested whether dopaminergic effects on violent delinquency were mediated by GPAs. The results demonstrated that academic performance fully mediated the linkage between these genes and violent delinquency. PMID:25326467

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

    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...

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

    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.

  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

    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. Increased Spreading Activation in Depression

    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…

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

    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.

  4. Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish.

    Irons, T D; Kelly, P E; Hunter, D L; Macphail, R C; Padilla, S

    2013-02-01

    Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-lethal concentrations (0.2-50 μM) of dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (butaclamol, SCH-23390, and haloperidol) were administered at 6 days post-fertilization (dpf). An initial experiment identified the time of peak effect of each drug (20-260 min post-dosing, depending on the drug). Locomotor activity was then assessed for 70 min in alternating light and dark at the time of peak effect for each drug to delineate dose-dependent effects. All drugs altered larval locomotion in a dose-dependent manner. Both the D1- and D2-like selective agonists (SKF-38393 and quinpirole, respectively) increased activity, while the selective antagonists (SCH-23390 and haloperidol, respectively) decreased activity. Both selective antagonists also blunted the response of the larvae to changes in lighting conditions at higher doses. The nonselective drugs had biphasic effects on locomotor activity: apomorphine increased activity at the low dose and at high doses, while butaclamol increased activity at low to intermediate doses, and decreased activity at high doses. This study demonstrates that (1) larval zebrafish locomotion can be altered by dopamine receptor agonists and antagonists, (2) receptor agonists and antagonists generally have opposite effects, and (3) drugs that target dopaminergic receptors in mammals appear, in general, to elicit similar locomotor responses in zebrafish larvae. PMID:23274813

  5. Dopaminergic modulation of emotional conflict in Parkinson’s disease

    Vanessa Fleury

    2014-07-01

    Full Text Available Neuropsychiatric fluctuations in Parkinson’s disease (PD are frequent and disabling. One way to investigate them is to assess the ability to inhibit distractive emotional information by a modified emotional Stroop (ES task. We compared non-depressed, non-demented PD patients with healthy controls. During an acute levodopa challenge, patients performed a modified ES task during functional MRI and a neuropsychological assessment including Visual Analog Mood (VAMS and Apathy scales. Ten patients and 12 controls completed the study. The VAMS scores were significantly improved by the acute intake of levodopa (p = 0.02, as was the apathy score (p = 0.03. Negative ES task (i.e. fearful facial expressions with the words “happy” or “fear” written across them, induced a lengthening of the mean reaction time during the incongruent trials compared with the congruent trials in controls (relative difference = 2.7%, p5 uncorrected. No difference in the activation of the pACC was found between controls and ON patients, suggesting a normalization of the activation following levodopa administration. These results suggest that emotional conflict processes could be dopamine-dependent. Pregenual ACC hypoactivation could be directly due to the degeneration of dopaminergic mesocorticolimbic pathway. Our results propose that neuropsychiatric fluctuations in PD patients could be partially explained by pACC hypoactivation and that adjustments of dopaminergic medication might be helpful for their treatment.

  6. Dopaminergic involvement during mental fatigue in health and cocaine addiction

    Moeller, S J; Tomasi, D; Honorio, J; Volkow, N D; Goldstein, R Z

    2012-01-01

    Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction. PMID:23092980

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

    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

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

    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

  9. Dopaminergic neuron destruction reduces hippocampal serotonin 1A receptor uptake of trans-[18F]Mefway

    The purpose of the present study is to investigate the relationship between dopaminergic neuron destruction and 5-HT system changes in a hemiparkinsonian rat model. We performed PET imaging studies with trans-[18F]Mefway in a hemiparkinsonian model of unilateral 6-hydroxydopamine (6-OHDA) rats. Region-of-interests (ROIs) were drawn in the hippocampus (HP) and cerebellum (CB). HP uptake, the ratios of specific binding to non-specific binding in the HP, and non-displaceable binding potential (BPND) in the HP were compared between 6-OHDA and control rats. As a result, unilateral 6-OHDA-lesioned rats exhibited significant bilateral reduction of HP uptake and trans-[18F]Mefway BPND compared to the intact control group. Therefore, the results demonstrate that destruction of the dopaminergic system causes the reduction of the serotonergic system. - Graphical abstract: Serotonin PET after destruction of dopaminergic system. - Highlights: • The 5-HT system is implicated in mood related-non-motor symptoms of parkinson's disease. • We examine changes of 5-HT1A receptor in a hemiparkinsonian rat model. • The non-displaceable binding potential of HP and were calculated. • The destruction of dopaminergic system causes the reduction of the serotonergic system

  10. Meta-type analysis of dopaminergic effects on gene expression in the neuroendocrine brain of female goldfish

    JasonTPopesku

    2012-11-01

    Full Text Available Dopamine (DA is a major neurotransmitter important for neuroendocrine control and recent studies have described genomic signalling pathways activated and inhibited by DA agonists and antagonists in the goldfish brain. Here we perform a meta-type analysis using microarray datasets from experiments conducted with female goldfish to characterize the gene expression responses that underlie dopaminergic signalling. Sexually mature, pre-spawning (GSI 4.5 ± 1.3% or sexually regressing ( GSI 3 ± 0.4% female goldfish (15-40 g injected intraperitoneally with either SKF 38393, LY 171555, SCH 23390, sulpiride, or a combination of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and α-methyl-p-tyrosine. Microarray meta-type analysis identified 268 genes in the telencephalon and hypothalamus as having reciprocal (i.e. opposite between agonism and antagonism/depletion fold change responses, suggesting that these transcripts are likely targets for DA-mediated regulation. Noteworthy genes included ependymin, vimentin, and aromatase, genes that support the significance of DA in neuronal plasticity and tissue remodelling. Sub-network enrichment analysis (SNEA was used to identify common gene regulators and binding proteins associated with the differentially expressed genes mediated by DA. SNEA analysis identified gene expression targets that were related to three major categories that included cell signalling (STAT3, SP1, SMAD, Jun/Fos, immune response (IL6, IL1β, TNFs, cytokine, NF-κB, and cell proliferation and growth (IGF1, TGFβ1. These gene networks are also known to be associated with neurodegenerative disorders such as Parkinsons’ disease, well-known to be associated with loss of dopaminergic neurons. This study identifies genes and networks that underlie DA signalling in the vertebrate CNS and provides targets that may be key neuroendocrine regulators. The results provide a foundation for future work on dopaminergic regulation of gene expression in fish

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

    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

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

    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.

  13. Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

    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.

  14. The effects of opioid drugs on dopamine mediated locomotor activity in rats

    Opioid drugs influence various behavioural parameters including locomotor activity in experimental animals. The interaction between the opioid and dopaminergic systems is one possible explanation for the effect of opioid drugs on locomotor activity. In this study behavioural and biochemical assays were done to investigate the interaction between the opioid and dopaminergic systems. Behavioural studies were done by measurement of locomotor activity (LA) of rats after acute or chronic pretreatment with opioid and/or dopaminergic drugs. Biochemical studies were in the form of radioligand binding assays, the effect on the number (Bmax) and affinity (KD) of receptors was measured after chronic pretreatment with opioid and/or dopaminergic drugs. The opioid drugs used are morphine, nalbuphine and naloxone. Dopaminergic drugs used included: agonists-apomorphine and piribedil; antagonists-pimozide, haloperidol, chlorpromazine. In the acute situation increased LA was obtained with morphine and the DA agonists. A correlation between the behavioural and biochemical assays was found. Chronic pretreatment with morphine enhanced apomorphine induced LA, this supersensitivity was also measured as an increased receptor density (Bmax) of D2 receptors in the striatum. Chronic morphine pretreatment caused a decrease in morphine induced LA, while this subsensitivity was not apparent in the ligand binding assays - where no change in receptor number was observed. Chronic naloxone pretreatment enhanced morphine induced LA, as well as increased the Bmax of opioid receptors in the whole brain. It is concluded that an interaction between the opioid and dopaminergic systems does exist, and may account for the mechanism of action of the opioids

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

    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.

  16. Improved Active Vibration Isolation Systems

    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.

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

    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

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

    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

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

    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. Information system development activities and inquiring systems

    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...... provides a new way to see the development of a system in terms of the knowledge created in the process. The main practical implication of the framework is that it improves the managers' ability to guide ISD activities as knowledge activities embedded in a knowledge process, a crucial element in development...... 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...

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

    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

  2. Chemogenetic ablation of dopaminergic neurons leads to transient locomotor impairments in zebrafish larvae.

    Godoy, Rafael; Noble, Sandra; Yoon, Kevin; Anisman, Hymie; Ekker, Marc

    2015-10-01

    To determine the impact of a controlled loss of dopaminergic neurons on locomotor function, we generated transgenic zebrafish, Tg(dat:CFP-NTR), expressing a cyan fluorescent protein-nitroreductase fusion protein (CFP-NTR) under the control of dopamine transporter (dat) cis-regulatory elements. Embryonic and larval zebrafish express the transgene in several groups of dopaminergic neurons, notably in the olfactory bulb, telencephalon, diencephalon and caudal hypothalamus. Administration of the pro-drug metronidazole (Mtz) resulted in activation of caspase 3 in CFP-positive neurons and in a reduction in dat-positive cells by 5 days post-fertilization (dpf). Loss of neurons coincided with impairments in global locomotor parameters such as swimming distance, percentage of time spent moving, as well as changes in tail bend parameters such as time to maximal bend and angular velocity. Dopamine levels were transiently decreased following Mtz administration. Recovery of some of the locomotor parameters was observed by 7 dpf. However, the total numbers of dat-expressing neurons were still decreased at 7, 12, or 14 dpf, even though there was evidence for production of new dat-expressing cells. Tg(dat:CFP-NTR) zebrafish provide a model to correlate altered dopaminergic neuron numbers with locomotor function and to investigate factors influencing regeneration of dopaminergic neurons. PMID:26118896

  3. The ascidian prophenoloxidase activating system

    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.

  4. The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration

    Calon Frédéric

    2011-10-01

    Full Text Available Abstract Background Mounting evidence supports a significant role of inflammation in Parkinson's disease (PD pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD. Methods Based on the fact that the myeloid differentiation primary response gene (88 (MyD88 is the most common adaptor protein implicated in toll-like receptor (TLR signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-, following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence. Results Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice. Conclusions Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in

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

    Stankowska, Arwen Urrsula Malgorzata; Gjedde, Albert

    2013-01-01

    People attempt to change their lifestyle when obesity impairs their quality of life. The attempts often fail when multiple habits must be changed in unison. Here we explore relations among food addiction, the neurobiology of habits, and caloric restriction, when people seek to return to normal...... 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 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...

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

    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...

  7. Automated activation-analysis system

    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. High precision liquid chromatography analysis of dopaminergic and serotoninergic responses to acute alcohol exposure in zebrafish

    Chatterjee, Diptendu; Gerlai, Robert

    2009-01-01

    Zebrafish is gaining popularity in behavioral neuroscience in general and in alcohol research in particular. Alcohol is known to affect numerous molecular mechanisms depending on dose and administration regimen. Prominent among these mechanisms are several neurotransmitter systems. Here we analyze the responses of the dopaminergic and serotoninergic neurotransmitter systems of zebrafish to acute alcohol treatment (1 h long exposure of adult fish to 0.00%, 0.25%, 0.50%, or 1.00% ethyl alcohol)...

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

    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

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

    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

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

    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

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

    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...

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

    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.

  14. Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson’s disease

    Muellner, Julia; Gharrad, Iman; Habert, Marie-Odile; Kas, Aurélie; Martini, Jean-Baptiste; Cormier-Dequaire, Florence; Tahiri, Khadija; Vidailhet, Marie; Meier, Niklaus; Brice, Alexis; Schuepbach, Michael; Mallet, Alain; Hartmann, Andreas; Corvol, Jean-Christophe

    2015-01-01

    Background : Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL) and low metabolizers (Met/Met, COMTLL). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype.Methods : Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating sca...

  15. vglut2 and gad Expression Reveal Distinct Patterns of Dual GABAergic Versus Glutamatergic Cotransmitter Phenotypes of Dopaminergic and Noradrenergic Neurons in the Zebrafish Brain

    Filippi, Alida; Mueller, Thomas; Driever, Wolfgang

    2014-01-01

    Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafi...

  16. Midbrain dopaminergic neurons generate calcium and sodium currents and release dopamine in the striatum of pups

    Constance Hammond

    2012-03-01

    Full Text Available Midbrain dopaminergic neurons (mDA neurons are essential for the control of diverse motor and cognitive behaviors. However, our understanding of the activity of immature mDA neurons is rudimentary. Rodent mDA neurons migrate and differentiate early in embryonic life and dopaminergic axons enter the striatum and contact striatal neurons a few days before birth, but when these are functional is not known. Here, we recorded Ca2+ transients and Na+ spikes from embryonic (E16-E18 and early postnatal (P0-P7 mDA neurons with dynamic two photon imaging and patch clamp techniques in slices from tyrosine hydroxylase-GFP mice, and measured evoked dopamine release in the striatum with amperometry. We show that half of identified E16-P0 mDA neurons spontaneously generate non-synaptic, intrinsically-driven Ca2+ spikes and Ca2+ plateaus mediated by N- and L-type voltage-gated Ca2+ channels. Starting from E18-P0, half of the mDA neurons also reliably generate overshooting Na+ spikes with an abrupt maturation at birth (P0 = E19. At that stage (E18-P0, dopaminergic terminals release dopamine in a calcium-dependent manner in the striatum in response to local stimulation. We propose that the intrinsic spontaneous activity of mouse mDA neurons may impact the development/activity of the striatal network from birth.

  17. Active Image Authentication System (AIAS

    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

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

    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

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

    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.

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

    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

  1. Apex, actively positioned exploration system.

    Greger, B

    1990-01-01

    A conceptually new, modularly designed exploration system for the deep sea (600 m) has been constructed and tested. In its base unit, different soil sampling tools can be integrated. These are, for the time being, a drill core barrel with 0 48 mm iD and a length of 500 mm for rocky basements as a box corer for softer soils as well as an orange peel grab. Towed along via a coaxial cable from a research vessel, the system is TV-guided and can be actively positioned by means of 2 thrusters in or...

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

    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...

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

    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. Targeting retinal dopaminergic neurons in tyrosine hydroxylase-driven green fluorescent protein transgenic zebrafish

    Meng, Shi; Ryu, Soojin; Zhao, Bin; Zhang, Dao-Qi; Driever, Wolfgang; McMahon, Douglas G.

    2008-01-01

    Purpose Dopamine plays key roles in a variety of basic functions in the central nervous system. To study developmental and functional roles of dopaminergic cells in zebrafish, we have generated a transgenic line of zebrafish expressing green fluorescent protein (GFP) under the control of the tyrosine hydroxylase (th1) promoter. Methods A 12 kb gene fragment that contains the th1 promoter was isolated and ligated to the MmGFP coding sequence, linearized, microinjected into 1–2 cell stage embry...

  5. Cocaine induces striatal c-fos-immunoreactive proteins via dopaminergic D1 receptors.

    Young, S T; Porrino, L J; Iadarola, M. J.

    1991-01-01

    The protooncogene c-fos produces a phosphoprotein, Fos, which regulates gene transcription processes. In neuronal systems, Fos has been proposed to couple synaptic transmission to changes in gene expression by acting in the cell nucleus in concert with other proteins to form complexes in the promoter regions of target genes. We report here that the acute administration of a single dose of the indirect-acting dopaminergic agonist cocaine increases multiple Fos proteins in rat caudate nucleus. ...

  6. Dopaminergic Meso-Cortical Projections to M1: Role in Motor Learning and Motor Cortex Plasticity

    JonasAurelHosp

    2013-01-01

    Although the architecture of a dopaminergic (DA) system within the primary motor cortex (M1) was well characterized anatomically, its functional significance remained obscure for a long time. Recent studies in rats revealed that the integrity of DA 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 M1 circuitry at multiple levels thereby promoting plastic changes that are required for inf...

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

    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

  8. ELECTROPHYSIOLOGICAL CHARACTERIZATION OF DOPAMINERGIC AND NONDOPAMINERGIC NEURONS IN ORGANOTYPIC SLICE CULTURES OF THE RAT VENTRAL MESENCEPHALON

    STEENSEN, BH; NEDERGAARD, S; OSTERGAARD, K;

    1995-01-01

    The aim of the present study was to characterize electrophysiologically neurones in organotypic cultures of the rat ventral mesencephalon and to compare these results with results published for the same neurones in other types of preparation. Intracellular recordings were obtained in 3- to 8-week...... (UV) light (365 nm). Short exposures to UV light did not affect the electrophysiological properties. There were no significant differences between dopaminergic and non-dopaminergic neurones with regard to resting membrane potential or action potential threshold and amplitude, and in both types of...... neurone spontaneous burst activity and glutamatergic excitatory postsynaptic potentials were seen. There were differences in the following parameters, which can be used to distinguish between the two types of neurone. Dopa minergic neurones had broad action potentials (2-9 ms), high input resistance (mean...

  9. Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease

    Callesen, Mette Buhl; Hansen, Kim Vang; Gjedde, Albert;

    2013-01-01

    -making, and altered striatal dopaminergic neurotransmission. Using [(11)C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [(11)C......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......]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky...

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

    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

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

    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…

  12. In vitro study of dopaminergic central neurons radiosensitivity

    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

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

    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 ...

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

    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

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

    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

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

    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.

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

    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

  18. [Dopaminergic effect of anisodamine on the microcirculation of the hydronephrotic kidney of rats].

    Zou, A P; Parekh, N; Steinhausen, M

    1991-01-01

    Anisodamine is an alkaloid extracted from the Tibetan plant "Anisodus tanguticus". Since 1965 it has been used in China for the treatment of shock but the mechanisms of its action are not fully known. The present study was performed to determine the effect of anisodamine on the renal microcirculation and to examine the underlying mechanism of its actions. The addition of anisodamine (10(-8) M to 10(-3) M) to the kidney bath resulted in a significant and dose dependent dilation of all preglomerular vessels. The maximal dilation (about 30% dilation) was found in the proximal interlobular artery. In contrast to preglomerular vessels anisodamine caused constriction of postglomerular vessels. The glomerular blood flow increased by about 50% at anisodamine concentration of 10(-3) M. Haloperidol, a dopamine receptor antagonist could abolish the renal vascular effect of anisodamine. It is suggested that anisodamine could improve renal function by the dilation of preglomerular vessels in combination with the constriction of postglomerular vessels, and the effect of anisodamine may be mediated by activation of the dopaminergic system. PMID:1687750

  19. Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons

    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

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

    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.

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

    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

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

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

    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.

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

    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

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

    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

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

    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

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

    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

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

    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

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

    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.

  10. Activity System Theory Approach to Healthcare Information System

    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...

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

    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...

  12. vglut2 and gad expression reveal distinct patterns of dual GABAergic versus glutamatergic cotransmitter phenotypes of dopaminergic and noradrenergic neurons in the zebrafish brain.

    Filippi, Alida; Mueller, Thomas; Driever, Wolfgang

    2014-06-15

    Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafish brains to determine which dopaminergic and noradrenergic groups may use GABA or glutamate as a second transmitter. Our results show that most dopaminergic neurons also express GABAergic markers, including the dopaminergic groups of the olfactory bulb (homologous to mammalian A16) and the subpallium, the hypothalamic groups (A12, A14), the prethalamic zona incerta group (A13), the preoptic groups (A15), and the pretectal group. Thus, the majority of catecholaminergic neurons are gad1b/2-positive and coexpress GABA. A very few gad1/2-negative dopaminergic groups, however, express vglut2 instead and use glutamate as a second transmitter. These glutamatergic dual transmitter phenotypes are the Orthopedia transcription factor-dependent, A11-type dopaminergic neurons of the posterior tuberculum. All together, our results demonstrate that all catecholaminergic groups in zebrafish are either GABAergic or glutamatergic. Thus, cotransmission of dopamine and noradrenaline with either GABA or glutamate appears to be a regular feature of zebrafish catecholaminergic systems. We compare our results with those that have been described for mammalian systems, discuss the phenomenon of transmitter dualism in the context of developmental specification of GABAergic and glutamatergic regions in the brain, and put this phenomenon in an evolutionary perspective. PMID:24374659

  13. Capturing dopaminergic modulation and bimodal membrane behaviour of striatal medium spiny neurons in accurate, reduced models

    Mark D Humphries

    2009-11-01

    Full Text Available Loss of dopamine from the striatum can cause both profound motor deficits, as in Parkinsons's disease, and disrupt learning. Yet the effect of dopamine on striatal neurons remains a complex and controversial topic, and is in need of a comprehensive framework. We extend a reduced model of the striatal medium spiny neuron (MSN to account for dopaminergic modulation of its intrinsic ion channels and synaptic inputs. We tune our D1 and D2 receptor MSN models using data from a recent large-scale compartmental model. The new models capture the input-output relationships for both current injection and spiking input with remarkable accuracy, despite the order of magnitude decrease in system size. They also capture the paired pulse facilitation shown by MSNs. Our dopamine models predict that synaptic effects dominate intrinsic effects for all levels of D1 and D2 receptor activation. We analytically derive a full set of equilibrium points and their stability for the original and dopamine modulated forms of the MSN model. We find that the stability types are not changed by dopamine activation, and our models predict that the MSN is never bistable. Nonetheless, the MSN models can produce a spontaneously bimodal membrane potential similar to that recently observed in vitro following application of NMDA agonists. We demonstrate that this bimodality is created by modelling the agonist effects as slow, irregular and massive jumps in NMDA conductance and, rather than a form of bistability, is due to the voltage-dependent blockade of NMDA receptors. Our models also predict a more pronounced membrane potential bimodality following D1 receptor activation. This work thus establishes reduced yet accurate dopamine-modulated models of MSNs, suitable for use in large-scale models of the striatum. More importantly, these provide a tractable framework for further study of dopamine's effects on computation by individual neurons.

  14. Dopaminergic modulation of the caudal photoreceptor in crayfish.

    Rodríguez-Sosa, Leonardo; Calderón-Rosete, Gabina; Calvillo, Minerva E; Guevara, Jorge; Flores, Gonzalo

    2011-06-01

    In our study we investigated the influence of dopamine (DA) on the caudal photoreceptor (CPR) in crayfish. Here we report the following: (a) the chromatographic determination of DA in the sixth abdominal ganglion (6th AG) shows a variation in the content during a 24-h cycle with the maximum value at dawn. (b) There are possibly dopaminergic neurons in the 6th AG with antityrosine hydroxylase antibodies. Immunopositive neurons (164) were located in the anterior and posterior regions of the 6th AG with the mean (± SE) diameter of their somata 23 ± 1 μm. In addition, there is immunopositive staining in axons, neuropilar fibers, and varicosities. (c) We also identified, using immunohistochemistry, 108 neurons in the sixth AG that contain dopamine D1-like receptors, with the mean (±SE) diameter of their somata 18 ± 1 μm. (d) We examined the exogenous action of DA on the electrical activity of the CPR in the isolated sixth AG by conventional extracellular-recording methods. This CPR displays spontaneous activity and phasic-tonic responses to light pulses. Topical application of dopamine to ganglia kept in the dark increased the spontaneous firing rate of the CPR, whereas the photoresponse of the CPR remained unchanged. The effect on the spontaneous activity is dose-dependent with an ED₅₀ of 33 μM, and is blocked by the dopamine D1-like antagonist SCH23390. These observations suggested that the DA is playing the role of a neurotransmitter or a neuromodulator of the CPR in the 6th AG in both species of crayfish, Procambarus clarkii and Cherax quadricarinatus. PMID:20936686

  15. Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

    Herz, Damian M.; Haagensen, Brian N.; Christensen, Mark S.; Madsen, Kristoffer Hougaard; Rowe, James B.; Løkkegaard, Annemette; Siebner, Hartwig R.

    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 allevia...

  16. Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

    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.

  17. Manually controlled neutron-activation system

    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.

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

    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...

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

    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...

  20. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-01-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos.

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

    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...

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

    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...

  3. Future testing of active safety systems

    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

  4. What Is an Activity? Appropriating an Activity-Centric System

    Yarosh, Svetlana; Matthews, Tara; Moran, Thomas P.; Smith, Barton

    Activity-Centric Computing (ACC) systems seek to address the fragmentation of office work across tools and documents by allowing users to organize work around the computational construct of an Activity. Defining and structuring appropriate Activities within a system poses a challenge for users that must be overcome in order to benefit from ACC support. We know little about how knowledge workers appropriate the Activity construct. To address this, we studied users’ appropriation of a production-quality ACC system, Lotus Activities, for everyday work by employees in a large corporation. We contribute to a better understanding of how users articulate their individual and collaborative work in the system by providing empirical evidence of their patterns of appropriation. We conclude by discussing how our findings can inform the design of other ACC systems for the workplace.

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

    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

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

    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...

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

    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

  8. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan S; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G

    2016-06-01

    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

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

    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.

  10. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    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...

  11. Roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in an insect

    Hatano Ai

    2009-08-01

    Full Text Available Abstract Background In insect classical conditioning, octopamine (the invertebrate counterpart of noradrenaline or dopamine has been suggested to mediate reinforcing properties of appetitive or aversive unconditioned stimulus, respectively. However, the roles of octopaminergic and dopaminergic neurons in memory recall have remained unclear. Results We studied the roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in olfactory and visual conditioning in crickets. We found that pharmacological blockade of octopamine and dopamine receptors impaired aversive memory recall and appetitive memory recall, respectively, thereby suggesting that activation of octopaminergic and dopaminergic neurons and the resulting release of octopamine and dopamine are needed for appetitive and aversive memory recall, respectively. On the basis of this finding, we propose a new model in which it is assumed that two types of synaptic connections are formed by conditioning and are activated during memory recall, one type being connections from neurons representing conditioned stimulus to neurons inducing conditioned response and the other being connections from neurons representing conditioned stimulus to octopaminergic or dopaminergic neurons representing appetitive or aversive unconditioned stimulus, respectively. The former is called 'stimulus-response connection' and the latter is called 'stimulus-stimulus connection' by theorists studying classical conditioning in higher vertebrates. Our model predicts that pharmacological blockade of octopamine or dopamine receptors during the first stage of second-order conditioning does not impair second-order conditioning, because it impairs the formation of the stimulus-response connection but not the stimulus-stimulus connection. The results of our study with a cross-modal second-order conditioning were in full accordance with this prediction. Conclusion We suggest that insect classical

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

    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.

  13. REM sleep deprivation promotes a dopaminergic influence in the striatal MT2 anxiolytic-like effects.

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

    2016-01-01

    The aim of this study was to investigate the possible anxiolytic-like effects of striatal MT2 activation, and its counteraction induced by the selective blockade of this receptor. Furthermore, we analyzed this condition under the paradigm of rapid eye movement (REM) sleep deprivation (REMSD) and the animal model of Parkinson's disease (PD) induced by rotenone. Male Wistar rats were infused with intranigral rotenone (12 μg/μL), and 7 days later were subjected to 24 h of REMSD. Afterwards the rats underwent striatal micro-infusions of selective melatonin MT2 receptor agonist, 8-M-PDOT (10 μg/μL) or selective melatonin MT2 receptor antagonist, 4-P-PDOT (5 μg/μL) or vehicle. Subsequently, the animals were tested in the open-field (OP) and elevated plus maze (EPM) tests. Results indicated that the activation of MT2 receptors produced anxiolytic-like effects. In opposite, the MT2 blockade did not show an anxiogenic-like effect. Besides, REMSD induced anxiolytic-like effects similar to 8-M-PDOT. MT2 activation generated a prevalent locomotor increase compared to MT2 blockade in the context of REMSD. Together, these results suggest a striatal MT2 modulation associated to the REMSD-induced dopaminergic supersensitivity causing a possible dopaminergic influence in the MT2 anxiolytic-like effects in the intranigral rotenone model of PD. PMID:27226821

  14. Age-associated striatal dopaminergic denervation and falls in community-dwelling subjects

    Bohnen, Nicolaas I.; Muller, Martijn L. T. M.; Kuwabara, Hiroto; Cham, Rakié; Constantine, Gregory M.; Studenski, Stephanie A.

    2016-01-01

    Older adults have a high prevalence of gait and balance disturbances and falls. Normal aging is associated with significant striatal dopaminergic denervation, which might be a previously unrecognized additional contributor to geriatric falls. This study investigated the relationship between the severity of age-associated striatal dopaminergic denervation (AASDD) and falls in community-dwelling subjects. Community-dwelling subjects who did not have a clinical diagnosis to explain falls (n = 77: 43 female, 34 male; mean age 61.4 +/− 16.4; range 20–85) completed clinical assessment and brain dopamine transporter (DAT) [11C]beta-CFT (2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) positron emission tomography imaging followed by 6 months of prospective fall monitoring using diaries. Results showed a significant inverse relationship between striatal DAT activity and age (r = −0.82, p < 0.001). A total of 26 subjects (33.8%) reported at least one fall, with 5 subjects (6.5%) reporting two or more falls. While no significant difference was noted in striatal DAT activity between nonfallers (n = 51) and fallers (n = 26; f = 0.02, not significant), striatal DAT activity was modestly reduced in the small subgroup of recurrent fallers compared with the other subjects (f = 5.07, p < 0.05). Findings indicate that AASDD does not explain isolated self-reported falls in community-dwelling subjects. However, it may be a contributing factor in the small subgroup of subjects with recurrent falls. PMID:20157861

  15. Do CSF levels of t-Tau, p-Tau and β1-42 amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A 123I-FP-CIT study in the early stages of the disease

    To investigate the relationships among cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and Aβ1-42 amyloid peptide and 123I-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 123I-FP-CIT SPECT scanning. The relationships were evaluated by means of linear regression analysis and Pearson correlation. Striatal 123I-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 123I-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 1-42 amyloid peptide and 123I-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 Aβ1-42 amyloid peptide seems not to be related to nigrostriatal degeneration in our series. (orig.)

  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

    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. Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment.

    McArthur, Simon; Pienaar, Ilse S; Siddiqi, Sindhu M; Gillies, Glenda E

    2016-06-01

    The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bias. PMID:25944572

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

    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

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

    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

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

    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

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

    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

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

    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

  3. Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain

    Dewey, S.L.; Brodie, J.D.; Fowler, J.S.; MacGregor, R.R.; Schlyer, D.J.; King, P.T.; Alexoff, D.L.; Volkow, N.D.; Shiue, C.Y.; Wolf, A.P. (Brookhaven National Lab., Upton, NY (USA))

    1990-01-01

    Interactions between the dopaminergic D2 receptor system and the muscarinic cholinergic system in the corpus striatum of adult female baboons (Papio anubis) were examined using positron emission tomography (PET) combined with (18F)N-methylspiroperidol (( 18F)NMSP) (to probe D2 receptor availability) and (N-11C-methyl)benztropine (to probe muscarinic cholinergic receptor availability). Pretreatment with benztropine, a long-lasting anticholinergic drug, bilaterally reduced the incorporation of radioactivity in the corpus striatum but did not alter that observed in the cerebellum or the rate of metabolism of (18F)NMSP in plasma. Pretreatment with unlabelled NMSP, a potent dopaminergic antagonist, reduced the incorporation of (N-11C-methyl)benztropine in all brain regions, with the greatest effect being in the corpus striatum greater than cortex greater than thalamus greater than cerebellum, but did not alter the rate of metabolism of the labelled benztropine in the plasma. These reductions in the incorporation of either (18F)NMSP or (N-11C-methyl)benztropine exceeded the normal variation in tracer incorporation in repeated studies in the same animal. This study demonstrates that PET can be used as a tool for investigating interactions between neurochemically different yet functionally linked neurotransmitters systems in vivo and provides insight into the consequences of multiple pharmacologic administration.

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

    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

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

    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.

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

    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...

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

    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 (...

  8. Active clusters in disordered systems

    We introduce an exact algorithm to calculate the distribution of large low energy clusters (droplets) in disordered manifolds and disordered magnets, and we analyze the extent to which these clusters can be treated as independent two-level systems. We show that interfaces in randomly diluted networks always have broad droplet distributions, while diluted antiferromagnets in a field can have either power law or exponential droplet distributions. copyright 1999 The American Physical Society

  9. Computer based integral gamma activity measurement system

    PC based Integral Gamma Activity measurement system has been developed for measuring the gross gamma activity. The Integral system comprises of the Ion chamber, electrometer amplifier and data acquisition system. This system is used for measuring the activity and also for recording of the decay characteristics. A windows based computer program has been developed for data acquisition and storage during the experiment. The system records the detector current output in the range of 10 pA to 10 nA. The measured current was converted into pre-calibrated gross gamma activity which was used for estimating the power distribution within the reactor core. The paper describes development of the system including the experiment results. (author)

  10. Implementation of Business Game Activity Support System

    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.

  11. System Specification for Immobilized Low Activity Waste (ILAW) Disposal System

    This specification provides the system level requirements for receiving, transporting, and disposing of the Immobilized Low-Activity Waste (ILAW) canisters generated by the RPP-Waste Treatment Plant. It also identified the requirements for the disposition of failed melters, both High Level and Low-Activity, and Low-Activity samples

  12. Compulsive use of dopaminergic drugs in Parkinson's disease.

    Evans, A H

    2008-01-01

    A small group of patients with Parkinson's disease (PD) compulsively use dopaminergic medications despite the frequent emergence of harmful physical, psychiatric and social effects. This behavioural syndrome has been termed the dopamine dysregulation syndrome (DDS) and although closely related, should be distinguished from impulse control disorders. The phenomenology, risk factors and neurobiology of DDS have been explored in a series of observational, neuropsychological and pharmacological c...

  13. Sensation-seeking: Dopaminergic modulation and risk for psychopathology

    Norbury, A. E.; M. Husain

    2015-01-01

    Sensation-seeking (SS) is a personality trait that refers to individual differences in motivation for intense and unusual sensory experiences. It describes a facet of human behaviour that has direct relevance for several psychopathologies associated with high social cost. Here, we first review ways of measuring SS behaviour in both humans and animals. We then present convergent evidence that implicates dopaminergic neurotransmission (particularly via D2-type receptors) in individual differenc...

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

    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

  15. Sensation-seeking: Dopaminergic modulation and risk for psychopathology.

    Norbury, Agnes; Husain, Masud

    2015-07-15

    Sensation-seeking (SS) is a personality trait that refers to individual differences in motivation for intense and unusual sensory experiences. It describes a facet of human behaviour that has direct relevance for several psychopathologies associated with high social cost. Here, we first review ways of measuring SS behaviour in both humans and animals. We then present convergent evidence that implicates dopaminergic neurotransmission (particularly via D2-type receptors) in individual differences in SS trait. Both high tonic dopamine levels and hyper-reactive midbrain dopaminergic responses to signals of forthcoming reward are evident in higher sensations-seekers. We propose that differences in the efficacy of striatal dopaminergic transmission may result in differential expression of approach-avoidance reactions to same intensity stimuli. This constitutes a quantitative trait of intensity preference for sensory stimulation that may underlie core features of the SS personality. We review the evidence that high trait SS is a vulnerability factor for psychopathologies related to changes in brain dopamine function, in particular substance and gambling addictions. Conversely, we consider the possibility that increased tolerance of high intensity stimulation may represent a protective mechanism against the development of trauma-related psychopathologies (e.g. post-traumatic stress disorder) in high sensation-seeking individuals. Further understanding of the brain mechanisms underlying SS trait might not only to shed light on the aetiology of these disorders, but also aid in developing individualised therapies and prevention strategies for psychopathologies. PMID:25907745

  16. Dopaminergic receptors in rat dura mater: pharmacological characteristics.

    Cavallotti, C; Frati, A; Cavallotti, D; Tranquilli Leali, F M

    2004-03-01

    1. The location and distribution of dopaminergic receptors in rat dura mater was studied by examining several dural zones (vascular, perivascular, intervascular) in different cranial and spinal regions. 2. The pharmacological characteristics and anatomical distribution of dopamine D1- and D2-like receptors sites were investigated using combined pharmacological techniques and immunofluorescent microscopy. 3. Samples of rat dura mater were obtained from 10 adult Wistar rats. On frozen slices, dopaminergic D1 and D2 receptors were stained immunohistochemically using monoclonal antibodies. 4. Inhibition studies were performed using fluorescent and non-fluorescent agonists or antagonists to define the pharmacological specificity of the immunostaining. 5. The greater sensitivity to displacement by amisulpride, bromocryptine, domperidone, haloperidol, raclopride and l-sulpiride than to displacement by N-propyl-nor-apomorphine, quinpirole and clozapine suggests that the immunofluorescent sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype. 6. Our observations provide evidence of the presence of D1 and D2 receptors in the wall of meningeal vessels. The dopaminergic receptors are located in the adventitia, media and intima of dural arteries. Furthermore, the density of receptors is higher in close proximity to arteries and decreases passing from the vascular to the perivascular and intervascular zones. 7. In the rat dura mater, dopamine regulates the meningeal blood vessels and, through this action, dopamine and its receptors can play an important role in the pathogenesis of cephalalgia. PMID:15008964

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

    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

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

    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

  19. 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

    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。

  20. Circumpolar Active-Layer Permafrost System (CAPS)

    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...

  1. Illumination controls dopaminergic differentiation regulating behavior

    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...

  2. On the physiology of jouissance: interpreting the mesolimbic dopaminergic reward functions from a psychoanalytic perspective

    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.

  3. Dopaminergic mesocortical projections to M1: role in motor learning and motor cortex plasticity

    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

  4. Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

    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.

  5. Severe dopaminergic neuron loss in rhesus monkey brain impairs morphine-induced conditioned place preference

    Ting Yan

    2015-10-01

    Full Text Available It is well known that dopamine is critical for reward, but the precise role of dopamine in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of dopamine-deficient rhesus monkeys in a morphine-induced conditioned place preference paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired dopamine system alters rewarding-seeking behavior in non-human primates.

  6. Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons.

    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

  7. SYSTEMIC BLOOD ACTIVATION DURING AND AFTER AUTOTRANSFUSION

    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

  8. Gamma band activity in the reticular activating system (RAS

    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

  9. Dopaminergic therapy affects learning and impulsivity in Parkinson’s disease

    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...

  10. Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease.

    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

  11. Phase Transitions in Model Active Systems

    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

  12. Active system monitoring applied on wind turbines

    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...

  13. Modeling dopamine system dysfunction in experimental animals

    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

  14. Financial Activities Taxes and Banks' Systemic Risk

    CANNAS GIUSEPPINA; Cariboni, Jessica; Marchesi, Massimo; Nicodème, Gaëtan; PETRACCO GIUDICI Marco; ZEDDA STEFANO

    2013-01-01

    The recent financial crisis has highlighted the risks posed by individual banks to the entire banking system. Next to the issue of determining individual contributions to systemic risk, the question of additional taxes on the financial sector has been debated. This paper uses SYMBOL, a micro-simulation model of the banking system, to estimate these individual contributions and compares them to the potential individual tax liabilities of banks under the assumption of a Financial Activity Tax.

  15. Active containment systems incorporating modified pillared clays

    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.

  16. A neural population model incorporating dopaminergic neurotransmission during complex voluntary behaviors.

    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

  17. Brain areas activated by uncertain reward-based decision-making in healthy volunteers

    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...

  18. The problem of activity in systemic scleroderma

    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.

  19. Aging assessment for active fire protection systems

    This study assessed the impact of aging on the performance and reliability of active fire protection systems including both fixed fire suppression and fixed fire detection systems. The experience base shows that most nuclear power plants have an aggressive maintenance and testing program and are finding degraded fire protection system components before a failure occurs. Also, from the data reviewed it is clear that the risk impact of fire protection system aging is low. However, it is assumed that a more aggressive maintenance and testing program involving preventive diagnostics may reduce the risk impact even further

  20. Study on cooperative active sensing system

    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.)

  1. ECOLOGICAL ACTIVITY IN THE ACCOUNTING SYSTEM

    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...

  2. A low cost active personal dosimetry system

    A reliable, low cost and compact active personal dosimeter with an on-line alarm facility has been a long-felt need of the nuclear industry. A low cost active personal dosimetry system based on a commercially available p-n junction Si diode detector with a preset dose alarm feature is proposed. A prototype of the compact badge with the alarm facility has been developed and the design features are presented. (author)

  3. Dopaminergic and brain-derived neurotrophic factor signalling in inbred mice exposed to a restricted feeding schedule.

    Gelegen, C; van den Heuvel, J; Collier, D A; Campbell, I C; Oppelaar, H; Hessel, E; Kas, M J H

    2008-07-01

    Increased physical activity and decreased motivation to eat are common features in anorexia nervosa. We investigated the development of these features and the potential implication of brain-derived neurotrophic factor (BDNF) and dopaminergic signalling in their development in C57BL/6J and A/J inbred mice, using the 'activity-based anorexia' model. In this model, mice on a restricted-feeding schedule are given unlimited access to running wheels. We measured dopamine receptor D2 and BDNF expression levels in the caudate putamen and the hippocampus, respectively, using in situ hybridization. We found that in response to scheduled feeding, C57BL/6J mice reduced their running wheel activity and displayed food anticipatory activity prior to food intake from day 2 of scheduled feeding as an indication of motivation to eat. In contrast, A/J mice increased running wheel activity during scheduled feeding and lacked food anticipatory activity. These were accompanied by increased dopamine receptor D2 expression in the caudate putamen and reduced BDNF expression in the hippocampus. Consistent with human linkage and association studies on BDNF and dopamine receptor D2 in anorexia nervosa, our study shows that dopaminergic and BDNF signalling are altered as a function of susceptibility to activity-based anorexia. Differences in gene expression and behaviour between A/J and C57BL/6J mice indicate that mouse genetic mapping populations based on these progenitor lines are valuable for identifying molecular determinants of anorexia-related traits. PMID:18363853

  4. Study on cooperative active sensing system

    In order to realize autonomous type nuclear plant, three-dimensional geometrical modelling method, and a basic technology on information collection and processing system preparation in some nuclear basic technology developments such as 'study on system evaluation of nuclear facility furnished with artificial intelligence for nuclear power' and 'study on adaptability evaluation of information collection and processing system into autonomous type plant' had already been developed. In this study, a study on sensing system required for constructing robot groups capable of conducting autonomously traveling inspection and maintenance in large scale, complicated and diverse plant has been processed by aiming at establishment of dispersed cooperative intelligent system technology. In 1997 fiscal year, integration of cooperative visual sensing technique was attempted. And, at the same time, upgrading of individual element technology and transportation method essential to the integrated system were investigated. As a result, an operative active sensing prototype system due to transportation robot groups furnished with real time processing capacity on diverse informations by integration of cooperative active sensing technique and real time active sensing technique developed independently plural transportation robot. (G.K.)

  5. Modulation of post-coital dopaminergic tone by prior parity

    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...

  6. Transcriptional comparison of human induced and primary midbrain dopaminergic neurons

    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...

  7. Pseudo energy wells in active systems

    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.

  8. CX3CR1 Disruption Differentially Influences Dopaminergic Neuron Degeneration in Parkinsonian Mice Depending on the Neurotoxin and Route of Administration.

    Tristão, Fabrine Sales Massafera; Lazzarini, Márcio; Martin, Sabine; Amar, Majid; Stühmer, Walter; Kirchhoff, Frank; Gomes, Lucas Araújo Caldi; Lanfumey, Laurance; Prediger, Rui D; Sepulveda, Julia E; Del-Bel, Elaine A; Raisman-Vozari, Rita

    2016-04-01

    Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine fractalkine (CX3CL1) is an exclusive ligand for the receptor CX3CR1 expressed on microglia. The CX3CL1/CX3CR1 signaling is important for sustaining microglial activity. Using a recently developed PD model, in which the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin is delivered intranasally, we hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results with those obtained using the classical PD models through intraperitonal MPTP or intrastriatal 6-hydroxydopamine (6-OHDA). The striatum from all genotypes (CX3CR1(+/+), CX3CR1(+/GFP) and CX3CR1-deficient mice) showed a significant dopaminergic depletion after intranasal MPTP inoculation. In contrast to that, we could not see differences in the number of dopaminergic neurons in the substantia nigra of CX3CR1-deficient animals. Similarly, after 6-OHDA infusion, the CX3CR1 deletion decreased the amphetamine-induced turning behavior observed in CX3CR1(+/GFP) mice. After the 6-OHDA inoculation, a minor dopaminergic neuronal loss was observed in the substantia nigra from CX3CR1-deficient mice. Distinctly, a more extensive neuronal cell loss was observed in the substantia nigra after the intraperitoneal MPTP injection in CX3CR1 disrupted animals, corroborating previous results. Intranasal and intraperitoneal MPTP inoculation induced a similar microgliosis in CX3CR1-deficient mice but a dissimilar change in the astrocyte proliferation in the substantia nigra. Nigral astrocyte proliferation was observed only after intraperitoneal MPTP inoculation. In conclusion, intranasal MPTP and 6-OHDA lesion in CX3CR1-deficient mice yield no nigral dopaminergic neuron loss, linked to the absence of astroglial proliferation. PMID:26403659

  9. Harmonic Reduction System Using Active Filter

    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.

  10. Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions

    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)

  11. Adaptive intelligent power systems: Active distribution networks

    Electricity networks are extensive and well established. They form a key part of the infrastructure that supports industrialised society. These networks are moving from a period of stability to a time of potentially major transition, driven by a need for old equipment to be replaced, by government policy commitments to cleaner and renewable sources of electricity generation, and by change in the power industry. This paper looks at moves towards active distribution networks. The novel transmission and distribution systems of the future will challenge today's system designs. They will cope with variable voltages and frequencies, and will offer more flexible, sustainable options. Intelligent power networks will need innovation in several key areas of information technology. Active control of flexible, large-scale electrical power systems is required. Protection and control systems will have to react to faults and unusual transient behaviour and ensure recovery after such events. Real-time network simulation and performance analysis will be needed to provide decision support for system operators, and the inputs to energy and distribution management systems. Advanced sensors and measurement will be used to achieve higher degrees of network automation and better system control, while pervasive communications will allow networks to be reconfigured by intelligent systems

  12. Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism

    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.

  13. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.

    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

  14. Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats.

    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

  15. The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons

    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.…

  16. System of strategic planning of enterprises activity

    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.

  17. Support system for Neutron Activation Analysis

    In the research reactor of JAERI, the Neutron Activation Analysis (NAA) has been utilized as a major part of an irradiation usage. To utilize NAA, research participants are always required to learn necessary technique. Therefore, we started to examine a support system that will enable to carry out INAA easily even by beginners. The system is composed of irradiation device, gamma-ray spectrometer and data analyzing instruments. The element concentration is calculated by using KAYZERO/SOLCOI software with the K0 standardization method. In this paper, we review on a construction of this INAA support system in JRR-3M of JAERI. (author)

  18. Active Fault Isolation in MIMO Systems

    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...

  19. Targeted activation in deterministic and stochastic systems

    Eisenhower, Bryan; Mezić, Igor

    2010-02-01

    Metastable escape is ubiquitous in many physical systems and is becoming a concern in engineering design as these designs (e.g., swarms of vehicles, coupled building energetics, nanoengineering, etc.) become more inspired by dynamics of biological, molecular and other natural systems. In light of this, we study a chain of coupled bistable oscillators which has two global conformations and we investigate how specialized or targeted disturbance is funneled in an inverse energy cascade and ultimately influences the transition process between the conformations. We derive a multiphase averaged approximation to these dynamics which illustrates the influence of actions in modal coordinates on the coarse behavior of this process. An activation condition that predicts how the disturbance influences the rate of transition is then derived. The prediction tools are derived for deterministic dynamics and we also present analogous behavior in the stochastic setting and show a divergence from Kramers activation behavior under targeted activation conditions.

  20. Communication Systems and Study Method for Active Distribution Power systems

    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...

  1. Orosensory self-stimulation by sucrose involves brain dopaminergic mechanisms.

    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

  2. Dopaminergic Genetic Polymorphisms Predict Rule-based Category Learning.

    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

  3. Green Bank Telescope active surface system

    Lacasse, Richard J.

    1998-05-01

    During the design phase of the Green Bank Telescope (GBT), various means of providing an accurate surface on a large aperture paraboloid, were considered. Automated jacks supporting the primary reflector were selected as the appropriate technology since they promised greater performance and potentially lower costs than a homologous or carbon fiber design, and had certain advantages over an active secondary. The design of the active surface has presented many challenges. Since the actuators are mounted on a tipping structure, it was required that they support a significant side-load. Such devices were not readily available commercially so they had to be developed. Additional actuator requirements include low backlash, repeatable positioning, and an operational life of at least 230 years. Similarly, no control system capable of controlling the 2209 actuators was commercially available. Again a prime requirement was reliability. Maintaining was also a very important consideration. The system architecture is tree-like. An active surface 'master-computer' controls interaction with the telescope control system, and controls ancillary equipment such as power supplies and temperature monitors. Two slave computers interface with the master- computer, and each closes approximately 1100 position loops. For simplicity, the servo is an 'on/off' type, yet achieves a positioning resolution of 25 microns. Each slave computer interfaces with 4 VME I/O cards, which in turn communicate with 140 control modules. The control modules read out the positions of the actuators every 0.1 sec and control the actuators' DC motors. Initial control of the active surface will be based on an elevation dependant structural model. Later, the model will be improved by holographic observations.Surface accuracy will be improved further by using laser ranging system which will actively measure the surface figure. Several tests have been conducted to assure that the system will perform as desired when

  4. Expert system aided operator's mental activities training

    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

  5. Active gated imaging in driver assistance system

    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.

  6. Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo.

    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

  7. A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

    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

  8. Study on cooperative active sensing system

    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.)

  9. Positron emission tomography in degenerative disorders of the dopaminergic system

    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 matebolic pattern was similar to that typically found in patients with Alzheimer's disease (AD). In the patients 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

  10. Positron emission tomography in degenerative disorders of the dopaminergic system

    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)

  11. Modular System to Enable Extravehicular Activity

    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

  12. Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice

    6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 μg) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [125I]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection.These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  13. Control Systems Cyber Security Standards Support Activities

    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.

  14. Active State Model for Autonomous Systems

    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.

  15. PCM Passive Cooling System Containing Active Subsystems

    Blanding, David E.; Bass, David I.

    2005-01-01

    A multistage system has been proposed for cooling a circulating fluid that is subject to intermittent intense heating. The system would be both flexible and redundant in that it could operate in a basic passive mode, either sequentially or simultaneously with operation of a first, active cooling subsystem, and either sequentially or simultaneously with a second cooling subsystem that could be active, passive, or a combination of both. This flexibility and redundancy, in combination with the passive nature of at least one of the modes of operation, would make the system more reliable, relative to a conventional cooling system. The system would include a tube-in-shell heat exchanger, within which the space between the tubes would be filled with a phase-change material (PCM). The circulating hot fluid would flow along the tubes in the heat exchanger. In the basic passive mode of operation, heat would be conducted from the hot fluid into the PCM, wherein the heat would be stored temporarily by virtue of the phase change.

  16. Active fault detection in MIMO systems

    Niemann, Hans Henrik; Poulsen, Niels Kjølstad

    2014-01-01

    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......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...

  17. Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study.

    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

  18. Spontaneous activity in the developing auditory system.

    Wang, Han Chin; Bergles, Dwight E

    2015-07-01

    Spontaneous electrical activity is a common feature of sensory systems during early development. This sensory-independent neuronal activity has been implicated in promoting their survival and maturation, as well as growth and refinement of their projections to yield circuits that can rapidly extract information about the external world. Periodic bursts of action potentials occur in auditory neurons of mammals before hearing onset. This activity is induced by inner hair cells (IHCs) within the developing cochlea, which establish functional connections with spiral ganglion neurons (SGNs) several weeks before they are capable of detecting external sounds. During this pre-hearing period, IHCs fire periodic bursts of Ca(2+) action potentials that excite SGNs, triggering brief but intense periods of activity that pass through auditory centers of the brain. Although spontaneous activity requires input from IHCs, there is ongoing debate about whether IHCs are intrinsically active and their firing periodically interrupted by external inhibitory input (IHC-inhibition model), or are intrinsically silent and their firing periodically promoted by an external excitatory stimulus (IHC-excitation model). There is accumulating evidence that inner supporting cells in Kölliker's organ spontaneously release ATP during this time, which can induce bursts of Ca(2+) spikes in IHCs that recapitulate many features of auditory neuron activity observed in vivo. Nevertheless, the role of supporting cells in this process remains to be established in vivo. A greater understanding of the molecular mechanisms responsible for generating IHC activity in the developing cochlea will help reveal how these events contribute to the maturation of nascent auditory circuits. PMID:25296716

  19. Preparation of 99Tcm-Annexin V and in vitro study of its binding characteristics in dopaminergic apoptotic neurons

    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)

  20. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    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

  1. Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model.

    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

  2. Global Positioning System Synchronized Active Light Autonomous Docking System

    Howard, Richard T. (Inventor); Book, Michael L. (Inventor); Bryan, Thomas C. (Inventor); Bell, Joseph L. (Inventor)

    1996-01-01

    A Global Positioning System Synchronized Active Light Autonomous Docking System (GPSSALADS) for automatically docking a chase vehicle with a target vehicle comprising at least one active light emitting target which is operatively attached to the target vehicle. The target includes a three-dimensional array of concomitantly flashing lights which flash at a controlled common frequency. The GPSSALADS further comprises a visual tracking sensor operatively attached to the chase vehicle for detecting and tracking the target vehicle. Its performance is synchronized with the flash frequency of the lights by a synchronization means which is comprised of first and second internal clocks operatively connected to the active light target and visual tracking sensor, respectively, for providing timing control signals thereto, respectively. The synchronization means further includes first and second Global Positioning System receivers operatively connected to the first and second internal clocks, respectively, for repeatedly providing simultaneous synchronization pulses to the internal clocks, respectively. In addition, the GPSSALADS includes a docking process controller means which is operatively attached to the chase vehicle and is responsive to the visual tracking sensor for producing commands for the guidance and propulsion system of the chase vehicle.

  3. The safeguards active response inventory system (SARIS)

    The Safeguards Active Response Inventory System (SARIS) is a computerized accountability system developed for nuclear materials control that incorporates elements of process monitoring, criticality safety, physical inventory and safeguards. It takes data from the process operations, stores it in an on-line database and translates the information into the formats needed by the various users. It traces the material through the process from feed to product; including recycle, waste and scraps streams. It models the process as the material changes form to ensure that artificial losses are not created. It automatically generates input to Nuclear Materials Management and Safeguards System (NMMSS), performs checks to prevent the possibility of a criticality accident, prepares an audit trail for Safeguards, prints labels for nuclear material containers, and produces DOE/NRC 741 forms. SARIS has been installed at three laboratories across the country

  4. Dopaminergic control of cognitive flexibility in humans and animals

    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.

  5. The Effects of The COMT val108/158met Polymorphism on BOLD Activation During Working Memory, Planning, and Response Inhibition: A Role for The Posterior Cingulate Cortex?

    Stokes, Paul Robert Alexander; Rhodes, Rebecca Anne; Grasby, Paul M.; Mehta, Mitul A

    2010-01-01

    Abstract Catechol-O-methyl transferase (COMT) val108/158met polymorphism impacts upon cortical dopamine levels and may influence functional magnetic resonance (fMRI) measures of task-related neuronal activity. Here, we investigate whether COMT genotype influences cortical activations, particularly prefrontal activations, by interrogating its effect across three tasks that have been associated with the dopaminergic system in a large cohort of healthy volunteers. 58 participants (13 ...

  6. Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

    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...

  7. The synchronous active neutron detection assay system

    We have begun to develop a novel technique for active neutron assay of fissile material in spent nuclear fuel. This approach will exploit a 14-MeV neutron generator developed by Schlumberger. The technique, termed synchronous active neutron detection (SAND), follows a method used routinely in other branches of physics to detect very small signals in presence of large backgrounds. Synchronous detection instruments are widely available commercially and are termed ''lock-in'' amplifiers. We have implemented a digital lock-in amplifier in conjunction with the Schlumberger neutron generator to explore the possibility of synchronous detection with active neutrons. The Schlumberger system can operate at up to a 50% duty factor, in effect, a square wave of neutron yield. Results are preliminary but promising. The system is capable of resolving the fissile material contained in a small fraction of the fuel rods in a cold fuel assembly; it also appears resilient to background neutron interference. The interrogating neutrons appear to be non-thermal and penetrating. Work remains to fully explore relevant physics and optimize instrument design

  8. Active Thermal Control System Development for Exploration

    Westheimer, David

    2007-01-01

    All space vehicles or habitats require thermal management to maintain a safe and operational environment for both crew and hardware. Active Thermal Control Systems (ATCS) perform the functions of acquiring heat from both crew and hardware within a vehicle, transporting that heat throughout the vehicle, and finally rejecting that energy into space. Almost all of the energy used in a space vehicle eventually turns into heat, which must be rejected in order to maintain an energy balance and temperature control of the vehicle. For crewed vehicles, Active Thermal Control Systems are pumped fluid loops that are made up of components designed to perform these functions. NASA has been actively developing technologies that will enable future missions or will provide significant improvements over the state of the art technologies. These technologies have are targeted for application on the Crew Exploration Vehicle (CEV), or Orion, and a Lunar Surface Access Module (LSAM). The technologies that have been selected and are currently under development include: fluids that enable single loop ATCS architectures, a gravity insensitive vapor compression cycle heat pump, a sublimator with reduced sensitivity to feedwater contamination, an evaporative heat sink that can operate in multiple ambient pressure environments, a compact spray evaporator, and lightweight radiators that take advantage of carbon composites and advanced optical coatings.

  9. Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study

    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)

  10. Active or passive systems? The EPR approach

    In attempting to review how EPR is contemplated to meet requirements applicable to future nuclear power plants, the authors indicate where they see the markets and the corresponding unit sizes for the EPR which is a generic key factor for competitiveness. There are no reason in industrialized countries, other than USA (where the investment and amortizing practices under control by Public Utility Commission are quite particular), not to build future plants in the 1000 to 1500 MWe range. Standardization, which has been actively applied all along the French program and for the Konvoi plants, does not prevent evolution and allows to concentrate large engineering effort in smooth realization of plants and achieve actual construction and commissioning without significant delays. In order to contribute to public trust renewal, a next generation of power reactors should be fundamentally less likely to incur serious accidents. To reach this goal the best of passive and active systems must be considered without forgetting that the most important source of knowledge is construction and operating experience. Criteria to assess passive systems investigated for possible implementation in the EPR, such as simplicity of design, impact on plant operation, safety and cost, are discussed. Examples of the principal passive systems investigated are described and reasons why they have been dropped after screening through the criteria are given. (author). 11 figs

  11. Noninvasive ambulatory measurement system of cardiac activity.

    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

  12. An active cooling system for photovoltaic modules

    The electrical efficiency of photovoltaic (PV) cell is adversely affected by the significant increase of cell operating temperature during absorption of solar radiation. A hybrid photovoltaic/thermal (PV/T) solar system was designed, fabricated and experimentally investigated in this work. To actively cool the PV cells, a parallel array of ducts with inlet/outlet manifold designed for uniform airflow distribution was attached to the back of the PV panel. Experiments were performed with and without active cooling. A linear trend between the efficiency and temperature was found. Without active cooling, the temperature of the module was high and solar cells can only achieve an efficiency of 8–9%. However, when the module was operated under active cooling condition, the temperature dropped significantly leading to an increase in efficiency of solar cells to between 12% and 14%. A heat transfer simulation model was developed to compare to the actual temperature profile of PV module and good agreement between the simulation and experimental results is obtained.

  13. Velocity distribution in active particles systems

    Marconi, Umberto Marini Bettolo; Gnan, Nicoletta; Paoluzzi, Matteo; Maggi, Claudio; di Leonardo, Roberto

    2016-03-01

    We derive an analytic expression for the distribution of velocities of multiple interacting active particles which we test by numerical simulations. In clear contrast with equilibrium we find that the velocities are coupled to positions. Our model shows that, even for two particles only, the individual velocities display a variance depending on the interparticle separation and the emergence of correlations between the velocities of the particles. When considering systems composed of many particles we find an analytic expression connecting the overall velocity variance to density, at the mean-field level, and to the pair distribution function valid in the limit of small noise correlation times. Finally we discuss the intriguing analogies and main differences between our effective free energy functional and the theoretical scenario proposed so far for phase-separating active particles.

  14. Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy.

    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

  15. Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.

    Tonouchi, Aine; Nagai, Jun; Togashi, Kentaro; Goshima, Yoshio; Ohshima, Toshio

    2016-06-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several lines of evidence suggest that neurodegeneration in PD is accelerated by a vicious cycle in which apoptosis in dopaminergic neurons triggers the activation of microglia and harmful inflammatory processes that further amplify neuronal death. Recently, we demonstrated that the deletion of collapsin response mediator protein 4 (CRMP4) suppresses inflammatory responses and cell death in a mouse model of spinal cord injury, leading to improved functional recovery. We thus hypothesized that Crmp4-/- mice may have limited inflammatory responses and a decrease in the loss of SNc dopaminergic neurons in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We observed CRMP4 expression in neurons, astrocytes, and microglia/macrophages following the injection of 25 mg/kg MPTP. We compared the number of dopaminergic neurons and the inflammatory response in SNc between Crmp4+/+ and Crmp4-/- mice after MPTP injection. Limited loss of SNc dopaminergic neurons and decreased activations of microglia and astrocytes were observed in Crmp4-/- mice. These results suggest that CRMP4 is a novel therapeutic target in the treatment of PD patients. We demonstrated that genetic CRMP4 deletion delays a vicious cycle of inflammation and neurodegeneration in a Parkinson's disease mouse model. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection to wild-type mice induces collapsin response mediator protein 4 (CRMP4) up-regulation in neurons, astrocytes, and microglia. CRMP4-deficient mice show reduced inflammation and suppressed dopaminergic neuronal death after MPTP injection. These findings suggest that CRMP4 deletion may be a new therapeutic strategy against Parkinson's diseases. PMID:26991935

  16. Actively controlled vibration welding system and method

    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

    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. The Safeguards Active Response Inventory System (SARIS)

    The Safeguards Active Response Inventory System (SARIS) was developed by Westinghouse Hanford Company (WHC) to perform material control and accountability on all the nuclear material under WHC's jurisdiction. SARIS has been in operation for four and one-half years. It has reduced physical inventory plant shutdown time from several days to a few hours. The user-friendly interface has proven successful, as the training time for a new operator is only two to three hours; also errors have been dramatically reduced. The modeling features of SARIS have reduced the reported inventory difference and provide better information for measurement of scrap and waste. The audit files have been usefull in resolving data entry errors and the backup features have averted several potential problems. SARIS as a computerized accountability system has replaced manual record keeping with a consequent increase in productivity. 4 refs

  19. Active balance system and vibration balanced machine

    Qiu, Songgang (Inventor); Augenblick, John E. (Inventor); Peterson, Allen A. (Inventor); White, Maurice A. (Inventor)

    2005-01-01

    An active balance system is provided for counterbalancing vibrations of an axially reciprocating machine. The balance system includes a support member, a flexure assembly, a counterbalance mass, and a linear motor or an actuator. The support member is configured for attachment to the machine. The flexure assembly includes at least one flat spring having connections along a central portion and an outer peripheral portion. One of the central portion and the outer peripheral portion is fixedly mounted to the support member. The counterbalance mass is fixedly carried by the flexure assembly along another of the central portion and the outer peripheral portion. The linear motor has one of a stator and a mover fixedly mounted to the support member and another of the stator and the mover fixedly mounted to the counterbalance mass. The linear motor is operative to axially reciprocate the counterbalance mass.

  20. Dopamine binds calmodulin during autoregulation of dopaminergic D2 receptor signaling through CaMKIIα-calmodulin complex.

    Laoye, B J; Okurumeh, O A; Obagaye, O V; Olagunju, M O; Bankole, O O; Olubiyi, O O; Ogundele, O M

    2016-06-01

    The role of dopaminergic D2 receptor (D2R) autoregulation in dopamine (DA) neurotransmission cannot be overemphasized in cause and progression of disorders associated with complex behaviors. Although previous studies have shown that D2R is structurally and physiologically linked with calcium/calmodulin-dependent kinase II (CaMKIIα), however, the role of calmodulin in the CaMKIIα complex in D2R regulation remains elusive. In this study, using structural biology modeling softwares (iGEMDOCK and CueMol), we have shown the interaction between D2R, CaMKIIα, calmodulin, and DA under varying conditions. The outcomes of this study suggest that CaMKIIα causes a change in DA binding affinity to the D2R receptive site while the detached DA binds to calmodulin to stop the activity of D2R in the D2R-dopaminergic D1 receptor (D1R) heteromer. Ultimately, we concluded that D2R autoregulates to stop its heteromeric combination with D1R. D2R interacts with D1R to facilitate calcium movement that activates calmodulin, then CaMKIIα. The CaMKIIα-calmodulin complex changes the affinity of DA-D2R causing DA to break free and bind with calmodulin. PMID:26446938

  1. Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of MPTP-induced Parkinson’s disease-like mice

    Shan, Xiaoyang; Chi, Liying; Bishop, Michael; Luo, Chun; Lien, Lindsey; Zhang, Zheng; Liu, Rugao

    2006-01-01

    Research reports on de novo neurogenesis, particularly dopaminergic (DA) neurogenesis in the adult mammalian substantia nigra (SN) remain very controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ reporter (pNes-LacZ) transgenic mouse model coupled with MPTP lesion system to investigate whether there are neurogenesis and DA neurogenesis in the SN of the adult normal and Parkinson’s disease (PD)–like mice. First, we demonstrated the presence of neural pr...

  2. Expression of the paralogous tyrosine hydroxylase encoding genes th1 and th2 reveals the full complement of dopaminergic and noradrenergic neurons in zebrafish larval and juvenile brain

    Filippi, Alida; Mahler, Julia; Schweitzer, Jörn; Driever, Wolfgang

    2009-01-01

    The development of dopaminergic and noradrenergic neurons has received much attention based on their modulatory effect on many behavioral circuits and their involvement in neurodegenerative diseases. The zebrafish (Danio rerio) has emerged as a new model organism with which to study development and function of catecholaminergic systems. Tyrosine hydroxylase is the entry enzyme into catecholamine biosynthesis and is frequently used as a marker for catecholaminergic neurons. A genome duplicatio...

  3. Coupling Neurogenetics (GARS™ and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS: Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

    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

  4. Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

    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

  5. Effects of Forskolin on Trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons

    Jensen, Pia; Ducray, A D; Widmer, H R;

    2015-01-01

    , suggesting that Forskolin induced TFF1 expression through diverse signaling pathways. In conclusion, distinct populations of cultured dopaminergic neurons express TFF1, and their numbers can be increased by factors known to influence survival and differentiation of dopaminergic cells....... shown that TFF1 is expressed in developing and adult rat ventral mesencephalic tyrosine hydroxylase-immunoreactive (TH-ir) dopaminergic neurons. Here, we investigated the expression of TFF1 in rat ventral mesencephalic dopaminergic neurons (embryonic day 14) grown in culture for 5, 7 or 10days in the...... numbers were significantly increased after the addition of GDNF (2.2-fold) or Forskolin (4.1-fold) compared to controls. Furthermore, the combination of GDNF and Forskolin had an additive effect and increased the number of TFF1-ir cells by 5.6-fold compared to controls. TFF1 expression was restricted to...

  6. Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.

    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.

  7. Identification of a Dopaminergic Enhancer Indicates Complexity in Vertebrate Dopamine Neuron Phenotype Specification

    Fujimoto, Esther; Stevenson, Tamara J.; Chien, Chi-Bin; Bonkowsky, Joshua L.

    2011-01-01

    The dopaminergic neurons of the basal ganglia play critical roles in CNS function and human disease, but specification of dopamine neuron phenotype is poorly understood in vertebrates. We performed an in vivo screen in zebrafish to identify dopaminergic neuron enhancers, in order to facilitate studies on the specification of neuronal identity, connectivity, and function in the basal ganglia. Based primarily on identification of conserved non-coding elements, we tested 54 DNA elements from fou...

  8. Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function

    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. ...

  9. Radioautographic visualization of dopaminergic fibers in the CNS of the rat

    A new radioautographic technique for the visualization of central dopaminergic fibers is described. This technique is based upon in vitro uptake of tritiated norepinephrine or tritiated dopamine in the presence of monoamine oxidase inhibitor and specific uptake inhibitor in noradrenergic fibers. After a short step in glutaraldehyde, the use of osmium vapours as a fixative, instead of osmic acid immersion, allows a satisfactory retention of tritiated amines within dopaminergic fibers

  10. Lack of sensorial innervation in the newborn female rats affects the activity of hypothalamic monoaminergic system and steroid hormone secretion during puberty.

    Quiróz, Ubaldo; Morales-Ledesma, Leticia; Morán, Carolina; Trujillo, Angélica; Domínguez, Roberto

    2014-06-01

    There is evidence that sensory innervation plays a role regulating ovarian functions, including fertility.Since sensory denervation by means of capsaicin in newborn female rats results in a lower response togonadotropins, the present study analyzed the effects that sensory denervation by means of capsaicin in neonatal rats has on the concentration of monoamines in the anterior(AH) and medium (MH) hypothalamus, and on steroid hormone levels in serum. Groups of newborn female rats were injected subcutaneously with capsaicin and killed at 10, 20, and 30 days of age and on the first vaginal estrous.The concentrations of noradrenaline, dopamine, serotonin(5-HT), and their metabolites in the AH and MH were measured using HPLC, and the levels of estradiol (E),progesterone (P), testosterone (T), FSH, and luteinizing hormone using radioimmunoanalysis. The results show thatat 20 days of age, capsaicin-treated rats have lowernoradrenergic and serotonergic activities in the AH, and that the dopaminergic activity was lower in the MH. These results suggest that the sensorial system connections within the monoaminergic systems of the AH and MH are different.Capsaicin-treated animals had lower T, E, and P levels than in the control group, suggesting that the lower activity in the AH monoaminergic system and lower hormonesecretion could be explained by the blockade of information mediated by the sensory innervation (probably substance P), mainly between the ovary and the AH. PMID:24122121

  11. Choice of dopaminergic therapy among early, mild Parkinson disease subjects in North America.

    Goudreau, John L; Pérez, Adriana; Aminoff, Michael J; Boyd, James T; Burau, Keith D; Christine, Chadwick W; Leehey, Maureen; Morgan, John C

    2016-07-15

    The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy. Baseline data from 1616 out of the 1741 participants were evaluated using univariable and multivariable logistic or generalized logit regression analyses for available factors associated with the choice of dopaminergic therapy. The dopaminergic therapy choice was determined as: (i) therapy that subjects recalled taking 180days before the study; (ii) therapy at baseline; and (iii) the longest duration of therapy reported by participants. Younger age, higher education level, longer length of time since PD diagnosis and use of an adjunctive, non-dopaminergic or monoamine oxidase inhibitor medication were associated with more frequent use of dopamine agonist compared to levodopa or combination therapy. PMID:27288780

  12. Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

    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

  13. The detection of novelty relies on dopaminergic signaling: evidence from apomorphine's impact on the novelty N2.

    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.

  14. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.

    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

  15. Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson's disease

    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.

  16. Effects of Nano-MnO2 on Dopaminergic Neurons and the Spatial Learning Capability of Rats

    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.

  17. Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

    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...

  18. 1-Methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neurons

    Decreased glutathione levels associated with increased oxidative stress are a hallmark of numerous neurodegenerative diseases, including Parkinson's disease. GSH is an important molecule that serves as an anti-oxidant and is also a major determinant of cellular redox environment. Previous studies have demonstrated that neurotoxins can cause changes in reduced and oxidized GSH levels; however, information regarding steady state levels remains unexplored. The goal of this study was to characterize changes in cellular GSH levels and its regulatory enzymes in a dopaminergic cell line (N27) following treatment with the Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP+). Cellular GSH levels were initially significantly decreased 12 h after treatment, but subsequently recovered to values greater than controls by 24 h. However, oxidized glutathione (GSSG) levels were increased 24 h following treatment, concomitant with a decrease in GSH/GSSG ratio prior to cell death. In accordance with these changes, ROS levels were also increased, confirming the presence of oxidative stress. Decreased enzymatic activities of glutathione reductase and glutamate-cysteine ligase by 20-25% were observed at early time points and partly account for changes in GSH levels after MPP+ exposure. Additionally, glutathione peroxidase activity was increased 24 h following treatment. MPP+ treatment was not associated with increased efflux of glutathione to the medium. These data further elucidate the mechanisms underlying GSH depletion in response to the Parkinsonian toxin, MPP+

  19. Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice

    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.

  20. Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date.

    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

  1. Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+ treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade

    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

  2. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

    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)

  3. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

    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)

  4. Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders.

    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

  5. A microfluidic method for dopamine uptake measurements in dopaminergic neurons.

    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

  6. Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPET study using {sup 123}I-{beta}-CIT and {sup 123}I-IBZM

    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.)

  7. Curcumin modulates dopaminergic receptor, CREB and phospholipase c gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats

    George Naijil

    2010-05-01

    Full Text Available Abstract Curcumin, an active principle component in rhizome of Curcuma longa, has proved its merit for diabetes through its anti-oxidative and anti-inflammatory properties. This study aims at evaluating the effect of curcumin in modulating the altered dopaminergic receptors, CREB and phospholipase C in the cerebral cortex and cerebellum of STZ induced diabetic rats. Radioreceptor binding assays and gene expression was done in the cerebral cortex and cerebellum of male Wistar rats using specific ligands and probes. Total dopaminergic receptor binding parameter, Bmax showed an increase in cerebral cortex and decrease in the cerebellum of diabetic rats. Gene expression studies using real time PCR showed an increased expression of dopamine D1 and D2 receptor in the cerebral cortex of diabetic rats. In cerebellum dopamine D1 receptor was down regulated and D2 receptor showed an up regulation. Transcription factor CREB and phospholipase C showed a significant down regulation in cerebral cortex and cerebellum of diabetic rats. We report that curcumin supplementation reduces diabetes induced alteration of dopamine D1, D2 receptors, transcription factor CREB and phospholipase C to near control. Our results indicate that curcumin has a potential to regulate diabetes induced malfunctions of dopaminergic signalling, CREB and Phospholipase C expression in cerebral cortex and cerebellum and thereby improving the cognitive and emotional functions associated with these regions. Furthermore, in line with these studies an interaction between curcumin and dopaminergic receptors, CREB and phospholipase C is suggested, which attenuates the cortical and cerebellar dysfunction in diabetes. These results suggest that curcumin holds promise as an agent to prevent or treat CNS complications in diabetes.

  8. Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPET study using 123I-β-CIT and 123I-IBZM

    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 [123I]2-β-carbomethoxy-3-β-(4-iodophenyl)tropane (β-CIT) and [123I]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 β-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.)

  9. Dopaminergic modulation of bulbofugal projections in the rat olfactory tubercle.

    Inokuchi, A; Mooney, K E; Snow, J B

    1987-01-01

    Neuronal activities following olfactory bulb electrical stimulation were examined before and after administration of dopamine and dopamine antagonist in the rat olfactory tubercle. The inhibitory response to olfactory bulb stimulation was attenuated by systemic haloperidol administration, but the excitatory response to olfactory bulb stimulation rarely was modulated. Topical application of dopamine by iontophoresis extended the duration of inhibition in 56% of the neurons sampled and diminished it in 25%; the excitatory response was modulated in 42% of neurons, most of which were attenuated. These findings suggest that dopamine in the olfactory tubercle could be involved in modulations of neuronal activities related to olfactory transduction. PMID:2820257

  10. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

    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

  11. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

    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

  12. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice.

    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

  13. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

    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.

  14. Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence

    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.

  15. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence.

    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.

  16. Alcohol consumption induces global gene expression changes in VTA dopaminergic neurons.

    Marballi, K; Genabai, N K; Blednov, Y A; Harris, R A; Ponomarev, I

    2016-03-01

    Alcoholism is associated with dysregulation in the neural circuitry that mediates motivated and goal-directed behaviors. The dopaminergic (DA) connection between the ventral tegmental area (VTA) and the nucleus accumbens is viewed as a critical component of the neurocircuitry mediating alcohol's rewarding and behavioral effects. We sought to determine the effects of binge alcohol drinking on global gene expression in VTA DA neurons. Alcohol-preferring C57BL/6J × FVB/NJ F1 hybrid female mice were exposed to a modified drinking in the dark (DID) procedure for 3 weeks, while control animals had access to water only. Global gene expression of laser-captured tyrosine hydroxylase (TH)-positive VTA DA neurons was measured using microarrays. A total of 644 transcripts were differentially expressed between the drinking and nondrinking mice, and 930 transcripts correlated with alcohol intake during the last 2 days of drinking in the alcohol group. Bioinformatics analysis of alcohol-responsive genes identified molecular pathways and networks perturbed in DA neurons by alcohol consumption, which included neuroimmune and epigenetic functions, alcohol metabolism and brain disorders. The majority of genes with high and specific expression in DA neurons were downregulated by or negatively correlated with alcohol consumption, suggesting a decreased activity of DA neurons in high drinking animals. These changes in the DA transcriptome provide a foundation for alcohol-induced neuroadaptations that may play a crucial role in the transition to addiction. PMID:26482798

  17. Screening for dopa-responsive dystonia in patients with Scans Without Evidence of Dopaminergic Deficiency (SWEDD).

    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

  18. Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

    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.

  19. The neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells.

    Kabiraj, Parijat; Valenzuela, Carlos A; Marin, Jose E; Ramirez, David A; Mendez, Lois; Hwang, Michael S; Varela-Ramirez, Armando; Fenelon, Karine; Narayan, Mahesh; Skouta, Rachid

    2015-10-01

    Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis. Ferroptosis cell death involved the generation of oxidative stress particularly lipid peroxide. In this work, we reported the neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells (SH-SY5Y). We first synthesized the Fer-1 and confirmed that it is not toxic toward the SH-SY5Y cells at concentrations up to 12.5 μM. Second, we showed that Fer-1 compound quenched the commercially available stable radical, the 2,2-diphenyl-1-picrylhydrazyl (DPPH), in non-cellular assay at 82 %. Third, Fer-1 inhibited the ROS/RNS generated under rotenone insult in SH-SY5Y cells. Fourth, we revealed the effective role of Fer-1 in ER stress mediated activation of apoptotic pathway. Finally, we reported that Fer-1 mitigated rotenone-induced α-syn aggregation. PMID:26385697

  20. Preliminary design activities for solar heating and cooling systems

    1978-01-01

    Information on the development of solar heating and cooling systems is presented. The major emphasis is placed on program organization, system size definition, site identification, system approaches, heat pump and equipment design, collector procurement, and other preliminary design activities.

  1. Extravehicular Activity Suit/Portable Life Support System Project

    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...

  2. Dopaminergic Modulation of Phase Reversal in Desert Locusts

    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.

  3. Alterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders.

    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.

  4. Conceptualization and Integration of Information Systems in Educational Business Activities

    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...

  5. Activity theory as a challenge to systems design

    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 to...... systems design, certain cornerstones become apparent, on which future systems design practice and research need to build. The paper will discuss these cornerstones, and the implications of the new understanding for design practice and research....

  6. Basic components of construction enterprises’ management marketing activities system

    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...

  7. Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons

    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.

  8. Kinematic analysis of dopaminergic effects on skilled handwriting movements in Parkinson's disease.

    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

  9. Music improves dopaminergic neurotransmission: demonstration based on the effect of music on blood pressure regulation.

    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

  10. Evidence for a non-GABAergic action of quaternary salts of bicuculline on dopaminergic neurones.

    Seutin, V; Scuvée-Moreau, J; Dresse, A

    1997-01-01

    Intracellular recordings were made from neurones, presumed to be dopaminergic, in the rat midbrain slice preparation. Bicuculline methiodide (BMI) and methochloride (BMC) reversibly blocked the slow, apamin-sensitive component of the afterhyperpolarization in these cells. The IC50 for this effect was about 26 microM. In comparison, BMC antagonized the input resistance decrease evoked by muscimol (3 microM) with an IC50 of 7 microM. The base of bicuculline was less potent in blocking the slow afterhyperpolarization. SR95531 (2-[carboxy-3'-propyl]-3-amino-6-paramethoxy-phenyl-pyridaziniu m bromide), another competitive GABA(A) antagonist, and picrotoxin, a non-competitive GABA(A) antagonist, also blocked the action of muscimol (IC50s: 2 and 12 microM respectively), but had no effect on the afterhyperpolarization at a concentration of up to 100 microM. Moreover, 100 microM SR95531 did not affect the blockade of the afterhyperpolarization by BMC. This blockade persisted in the presence of tetrodotoxin and was apparently not due to a reduction of calcium entry, suggesting that it involved a direct action on the channels which mediate this afterhyperpolarization. These results strongly suggest that quaternary salts of bicuculline act on more than one target in the central nervous system. Thus, the involvement of GABA(A) receptors in a given effect cannot be proven solely on the basis of its blockade by these agents. PMID:9517436

  11. Dopaminergic basis of the psychosis-prone personality investigated with functional magnetic resonance imaging of procedural learning

    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.

  12. Influence of temporal relationships between serotonergic and dopaminergic precursors on the regulation of gonadal development in birds.

    Chaturvedi, Chandra Mohini; Yadav, Suneeta

    2013-09-01

    This article is focused on the effect of specific phase relation of serotonergic and dopaminergic oscillations on the gonadal responses of different avian species. These species include (i) summer breeding birds - Red headed bunting (exhibiting post-reproductive absolute photorefractoriness) and Indian Weaver bird (which lacks absolute photorefractoriness), (ii) autumn breeding - Spotted munia and Lal munia (photoperiodic responses of which are distinctly different from that of any long day birds described thus far) and (iii) domesticated Japanese quail (which under natural day length breeds in summer, exhibits relative photorefractoriness, but breeds continuously if maintained in long photoperiod). Previous experiments have shown that daily administration of serotonin precursor 5-hydroxytryptophan and dopamine precursor L-dihydroxyphenylalanine given 8h apart during progressive phase of gonadal cycle can lead to a significant decrease in gonadal activity. However, if given at an interval of 12h it leads to an increase in gonadal activity and the effect of other intervals (0-, 4-, 16- and 20-h) were not different from control. Similar effects were observed during regressive phase of the gonadal cycle of above species except in those which display absolute photorefractory phase in their breeding cycle. This shows that, gonad of such species not only develop post-reproductive photorefractoriness but also becomes insensitive to the stimulatory effects of 5-HTP and L-DOPA when given at the interval of 12h. It is suggested that, temporal phase relation of circadian serotonergic and dopaminergic oscillations is the basis of seasonality in birds and may alter the activity of neuroendocrine-gonadal axis not only under natural day length but also under experimental/different photoperiodic conditions. These results are in agreement with the internal coincidence model of photoperiodic time measurement and indicate that birds can detect specific phase relationship between the

  13. Terpenóides com atividade sobre o Sistema Nervoso Central (SNC Terpenoids with activity in the Central Nervous System (CNS

    Carolina S. Passos

    2009-03-01

    Full Text Available Os terpenóides constituem um vasto grupo de metabólitos secundários com ações sobre o SNC, destacando-se suas atividades sedativa, ansiolítica, antinociceptiva, anticonvulsivante, pró-convulsivante e alucinógena. Neste trabalho foi realizada uma revisão bibliográfica sobre terpenóides com ações descritas no SNC, enfocando moléculas e sistemas neurotransmissores relacionados com sua atividade. As substâncias abordadas encontram-se divididas em mono, sesqui, di, tri e meroterpenóides e incluem compostos isolados e plantas que apresentam ação principalmente sobre os sistemas neurotransmissores GABAérgico, glutamatérgico, dopaminérgico e opióide.The terpenoids are a large group of secondary metabolites which display many activities in the CNS, such as sedative, ansiolytic, antinociceptive, anticonvulsant, pro-convulsant and hallucinogenic. In this work we performed a research on terpenoids that exert effects on the CNS, focusing molecules and neurotransmitter systems related to their actions. The substances approached were classified as mono, sesqui, di, tri and meroterpenoids and include isolated compounds and plants which exert activities mainly on GABAergic, glutamatergic, dopaminergic and opioid neurotransmitter systems.

  14. Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice

    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.

  15. Process of activation of a palladium catalyst system

    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.

  16. The melanin-concentrating hormone (MCH system modulates behaviors associated with psychiatric disorders.

    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. [Effect of beclin1 on vincristine-induced dopaminergic neurons injury in zebrafish].

    Hu, Zhan-Ying; Zhang, Jing-Pu

    2014-06-01

    To investigate vincristine-induced dopaminergic neurons toxicity and mechanism, and explore the molecular target to reduce the toxicity, zebrafish was chosen as a model animal, based on RT-PCR, Western blotting, whole mount in situ immunofluorescence and other technical means. The results showed that the transcription levels of tyrosine hydroxylase gene and dopamine transporter protein gene were inhibited. Furthermore, the number of dopaminergic neurons was decreased by vincristine. Autophagy was suppressed and beclin1 gene expression was inhibited in a dose-dependent manner by vincristine in larval zebrafish. Up-regulated beclin1 partly reduced vincristine-induced neurotoxicity, and down-regulated beclin1 increased toxicity. Beclin1 plays an important role in vincristine-induced dopaminergic neurons toxicity. PMID:25212030

  18. Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

    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

  19. CALBINDIN CONTENT AND DIFFERENTIAL VULNERABILITY OF MIDBRAIN EFFERENT DOPAMINERGIC NEURONS IN MACAQUES

    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

  20. Active vibration control of lightweight floor systems

    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.

  1. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

    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.

  2. Enhanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension

    Krabbe, Christina; Courtois, Elise; Jensen, Pia;

    2009-01-01

    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. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic different...

  3. THE PARABRACHIAL NUCLEUS IS A CRITICAL LINK IN THE TRANSMISSION OF SHORT LATENCY NOCICEPTIVE INFORMATION TO MIDBRAIN DOPAMINERGIC NEURONS

    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

  4. Retinal waves coordinate patterned activity throughout the developing visual system

    Ackman, James B.; Burbridge, Timothy J.; Crair, Michael C.

    2012-01-01

    The morphologic and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to demonstrate in...

  5. Activity-promoting gaming systems in exercise and rehabilitation

    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...

  6. Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist

    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.

  7. Effects of dopaminergic treatment on functional cortico-cortical connectivity in Parkinson's disease

    Zittel, S; Heinbokel, C; van der Vegt, J P M; Niessen, E; Buhmann, C; Gerloff, C; Siebner, H R; Münchau, A; Bäumer, T

    2015-01-01

    Interactions between dorsal premotor cortex (PMd) and primary motor cortex (M1) and interhemispheric inhibition (IHI) between M1 are impaired in Parkinson's disease (PD). We used dual-site transcranial magnetic stimulation to compare effects of first-time levodopa application with chronic dopamin...... cortico-cortical circuits during the course of PD....... patients under chronic dopaminergic stimulation, but not in de novo PD patients at low stimulus intensities at an ISI of 4 ms. First-time exposure to levodopa exerts different effects on cortico-cortical pathways than chronic dopaminergic stimulation in PD, suggesting a change in the responsiveness of...

  8. Histopathological and electrophysiological indices of rotenone-evoked dopaminergic toxicity: Neuroprotective effects of acetyl-L-carnitine.

    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

  9. Visible Light Activated Photocatalytic Water Polishing System Project

    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...

  10. Robust Vehicle Suspension System by Converting Active & Passive Control of a Vehicle to Semi-Active Control System Analytically

    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...

  11. Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands.

    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

  12. Noggin Over-Expressing Mouse Embryonic Fibroblasts and MS5 Stromal Cells Enhance Directed Differentiation of Dopaminergic Neurons from Human Embryonic Stem Cells

    Lim, Mi-sun; Shin, Min-Seop; Lee, Soo Young; Minn, Yang-Ki; Hoh, Jeong-Kyu; Cho, Youl-Hee; Kim, Dong-Wook; Lee, Sang-Hun; Kim, Chun-Hyung; Park, Chang-Hwan

    2015-01-01

    Directed methods for differentiating human embryonic stem cells (hESCs) into dopaminergic (DA) precursor cells using stromal cells co-culture systems are already well established. However, not all of the hESCs differentiate into DA precursors using these methods. HSF6, H1, H7, and H9 cells differentiate well into DA precursors, but CHA13 and CHA15 cells hardly differentiate. To overcome this problem, we modified the differentiation system to include a co-culturing step that exposes the cells ...

  13. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

    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...... 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...... synaptosomal DA uptake nor altered levels of DAT and TH in both striatum and midbrain. No behavioural difference between Dat1-eGFP and wild-type was found, suggesting that the strain is not aberrant. Finally, cell populations highly enriched in DAergic neurons can be obtained from postnatal mice by...

  14. Communication Systems and Study Method for Active Distribution Power systems

    Wei, Mu; Chen, Zhe

    2010-01-01

    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 Et...

  15. Hybrid energy storage systems utilizing redox active organic compounds

    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.

  16. 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

    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.

  17. Evaluation of Active Cooling Systems for Non-Residential Buildings

    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. Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons.

    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

  19. Active filter solutions in energy systems

    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. Active Sensor Configuration Validation for Refrigeration Systems

    Hovgaard, Tobias Gybel; Blanke, Mogens; Niemann, Hans Henrik; Izadi-Zamanabadi, Roozbeh

    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...... identify the sensor configuration. The method as such is generic and is shown in the paper to work convincingly on refrigeration systems with significant nonlinear behaviors...