Sample records for dopamine depletion induces

  1. DOPAMINE DEPLETION SLOWS RETINAL TRANSMISSION

    EPA Science Inventory

    In male hooded rats, depletion of norepinephrine and dopamine by a-methyl-paratyrosine (AMT) significantly increased the latencies of early peaks in flash-evoked potentials recorded from the visual cortex, lateral geniculate nucleus, and optic tract. These effects were not produc...

  2. Bromocriptine induces marked locomotor stimulation in dopamine-depleted mice when D-1 dopamine receptors are stimulated with SKF38393

    Microsoft Academic Search

    David M. Jackson; Mayko Hashizume

    1986-01-01

    In mice pretreated with reserpine plus alphamethyl-p-tyrosine, neither the D-2 selective agonist bromocriptine, nor the D-1 selective agonist SKF38393, produced any measurable increase in locomotion in mice. However, the combination of the two agonists produced a marked and dose-dependent increase in co-ordinated locomotor activity. In mice with their dopamine stores and dopamine synthesis intact, SKF38393 was inactive by itself, but

  3. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

    PubMed

    Ma, Delin; Shuler, Jeffrey M; Raider, Kayla D; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Stanford, John A

    2015-07-10

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1?), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist. PMID:25862572

  4. Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletion

    Microsoft Academic Search

    Taizo Kita; George C. Wagner; Martin A. Philbert; Linda A. King; Herbert E. Lowndes

    1995-01-01

    The formation of 6-hydroxydopamine (6-OHDA) from dopamine (DA) was investigated in the striatum of male Sprague-Dawley rats\\u000a following a single administration of methamphetamine hydrochloride (100 mg\\/kg, sc). Rats were sacrificed 30, 60, and 90 min,\\u000a and 1 wk after injection, and striatal 6-OHDA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by HPLC with electrochemical\\u000a detection. Methamphetamine decreased striatal DA and

  5. Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex

    Microsoft Academic Search

    Irina N. Krasnova; Elizabeth S. Betts; Abiola Dada; Akilah Jefferson; Bruce Ladenheim; Kevin G. Becker; Jean Lud Cadet; Christine F. Hohmann

    2007-01-01

    The mesocorticolimbic dopamine (DA) system is implicated in mental health disorders affecting attention, impulse inhibition\\u000a and other cognitive functions. It has also been involved in the regulation of cortical morphogenesis. The present study uses\\u000a focal injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of BALB\\/c mice to examine morphological, behavioral\\u000a and transcriptional responses to selective DA deficit in the

  6. Manganese-Induced Hydroxyl Radical Formation in Rat Striatum Is Not Attenuated by Dopamine Depletion or Iron Chelation in Vivo

    Microsoft Academic Search

    W. N. Sloot; J. Korf; J. F. Koster; L. E. A. de Wit; J. B. P. Gramsbergen

    1996-01-01

    The present studies were aimed at investigating the possible roles of dopamine (DA) and iron in production of hydroxyl radicals (·OH) in rat striatum after Mn2+intoxication. For this purpose, DA depletions were assessed concomitant within vivo2,3- and 2,5-dihydroxybenzoic acid (DHBA) formation from the reaction of salicylate with·OH, of which 2,3-DHBA is a nonenzymatic adduct. Following intrastriatal Mn2+injection, marked 2,3-DHBA increases

  7. Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

    PubMed Central

    Cardinal, R. N.; Rygula, R.; Hong, Y. T.; Fryer, T. D.; Sawiak, S. J.; Ferrari, V.; Cockcroft, G.; Aigbirhio, F. I.; Robbins, T. W.; Roberts, A. C.

    2014-01-01

    Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. PMID:24872570

  8. Substantial telomere shortening in the substantia nigra of telomerase-deficient mice does not increase susceptibility to MPTP-induced dopamine depletion.

    PubMed

    Oeckl, Patrick; Scheffold, Annika; Lechel, André; Rudolph, K Lenhard; Ferger, Boris

    2014-03-26

    The most important risk factor for developing Parkinson's disease (PD) is age. Aging is ascribed to different mechanisms, including telomere shortening. Telomeres consist of repetitive DNA sequences and stabilize chromosome integrity. Currently, however, the data reported on telomere shortening in PD patients are inconsistent. We investigated the effect of telomere shortening in the MPTP mouse model of PD using late-generation telomerase-deficient mice (G3 Terc mice). G3 Terc mice showed a reduction in telomere length in nigral tyrosine hydroxylase-positive neurons by 40%, as indicated by quantitative fluorescence in-situ hybridization. There was no difference in the total motor activity and striatal tissue concentrations of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (4-hydroxy-3-methoxyphenylacetic acid), and 3-MT (3-methoxytyramine) concentrations or dopamine turnover in G3 Terc mice in comparison with controls without MPTP treatment. Low-dose MPTP treatment (four injections, 2 h intervals, 2 × 5 and 2 × 7.5 mg/kg) led to a significant decrease in striatal dopamine concentrations that did not differ in G3 Terc mice compared with control mice (19.15 ± 0.44 to 12.81 ± 1.26 ng/mg in control mice in comparison with 19.51 ± 0.59 to 13.56 ± 1.10 ng/mg in G3 Terc mice). In conclusion, telomere shortening does not increase susceptibility to MPTP-induced dopamine depletion in mice. These data indicate that other age-related mechanisms in the brain may play a more important role in enhancing MPTP-induced dopamine depletion. PMID:24525820

  9. Relationships among rat ultrasonic vocalizations, behavioral measures of striatal dopamine loss, and striatal tyrosine hydroxylase immunoreactivity at acute and chronic time points following unilateral 6-hydroxydopamine-induced dopamine depletion.

    PubMed

    Grant, Laura M; Barnett, David G; Doll, Emerald J; Leverson, Glen; Ciucci, Michelle

    2015-09-15

    Voice deficits in Parkinson disease (PD) emerge early in the disease process, but do not improve with standard treatments targeting dopamine. Experimental work in the rat shows that severe and chronic unilateral nigrostriatal dopamine depletion with 6-OHDA results in decreased intensity, bandwidth, and complexity of ultrasonic vocalizations. However, it is unclear if mild/acute dopamine depletion, paralleling earlier stages of PD, results in vocalization deficits, or to what degree vocalization parameters are correlated with other dopamine-dependent indicators of lesion severity or percent of tyrosine hydroxylase (%TH) loss. Here, we assayed ultrasonic vocalizations, forelimb asymmetry, and apomorphine rotations in rats with a range of unilateral dopamine loss resulting from 6-OHDA or vehicle control infusions to the medial forebrain bundle at acute (72h) and chronic (4 weeks) time points post-infusion. The %TH loss was evaluated at 4 weeks. At 72h, forelimb asymmetry and %TH loss were significantly correlated, while at 4 weeks, all measures of lesion severity were significantly correlated with each other. Call complexity was significantly correlated with all measures of lesion severity at 72h but only with %TH loss at 4 weeks. Bandwidth was correlated with forelimb asymmetry at both time points. Duration was significantly correlated with all dopamine depletion measures at 4 weeks. Notably, not all parameters were affected universally or equally across time. These results suggest that vocalization deficits may be a sensitive index of acute and mild catecholamine loss and further underscores the need to characterize the neural mechanisms underlying vocal deficits in PD. PMID:26026785

  10. Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice.

    PubMed

    Willard, A M; Bouchard, R S; Gittis, A H

    2015-08-20

    Parkinson's disease (PD) is a movement disorder whose cardinal motor symptoms arise due to the progressive loss of dopamine. Although this dopamine loss typically progresses slowly over time, currently there are very few animal models that enable incremental dopamine depletion over time within the same animal. This type of gradual dopamine depletion model would be useful in studies aimed at the prodromal phase of PD, when dopamine levels are pathologically low but motor symptoms have not yet presented. Utilizing the highly characterized neurotoxin 6-hydroxydopamine (6-OHDA), we have developed a paradigm to gradually deplete dopamine levels in the striatum over a user-defined time course - spanning weeks to months - in C57BL/6 mice. Dopamine depletions were achieved by administration of five low-dose injections (0.75?g) of 6-OHDA through an implanted intracranial bilateral cannula targeting the medial forebrain bundle. Levels of dopamine within the striatum declined linearly with successive injections, quantified using tyrosine hydroxylase immunostaining and high-performance liquid chromatography. Behavioral testing was carried out at each time point to study the onset and progression of motor impairments as a function of dopamine loss over time. We found that spontaneous locomotion, measured in an open field, was robust until ?70% of striatal dopamine was lost. Beyond this point, additional dopamine loss caused a sharp decline in motor performance, reaching a final level comparable to that of acutely depleted mice. Similarly, although rearing behavior was more sensitive to dopamine loss and declined linearly as a function of dopamine levels, it eventually declined to levels similar to those seen in acutely depleted mice. In contrast, motor coordination, measured on a vertical pole task, was only moderately impaired in gradually depleted mice, despite severe impairments observed in acutely depleted mice. These results demonstrate the importance of the temporal profile of dopamine loss on the magnitude and progression of behavioral impairments. Our gradual depletion model thus establishes a new paradigm with which to study how circuits respond and adapt to dopamine loss over time, information which could uncover important cellular events during the prodromal phase of PD that ultimately impact the presentation or treatability of behavioral symptoms. PMID:26067595

  11. Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

    PubMed Central

    Sidharthan, Neelima P.; Minchin, Rodney F.; Butcher, Neville J.

    2013-01-01

    Dopamine neurotoxicity is associated with several neurodegenerative diseases, and neurons utilize several mechanisms, including uptake and metabolism, to protect them from injury. Metabolism of dopamine involves three enzymes: monoamine oxidase, catechol O-methyltransferase, and sulfotransferase. In primates but not lower order animals, a sulfotransferase (SULT1A3) is present that can rapidly metabolize dopamine to dopamine sulfate. Here, we show that SULT1A3 and a closely related protein SULT1A1 are highly inducible by dopamine. This involves activation of the D1 and NMDA receptors. Both ERK1/2 phosphorylation and calcineurin activation are required for induction. Pharmacological agents that inhibited induction or siRNA targeting SULT1A3 significantly increased the susceptibility of cells to dopamine toxicity. Taken together, these results show that dopamine can induce its own metabolism and protect neuron-like cells from damage, suggesting that SULT1A3 activity may be a risk factor for dopamine-dependent neurodegenerative diseases. PMID:24136195

  12. Do autoreceptors mediate dopamine agonist — induced yawning and suppression of exploration? A critical review

    Microsoft Academic Search

    Lars Stĺhle

    1992-01-01

    The hypothesis that stimulation of dopamine autoreceptors is the mechanism by which dopamine agonists induce yawning and suppression of exploration is critically examined. It is shown that the relation between reduced extracellular dopamine levels, assessed by microdialysis, and behavioural effects of dopamine agonists, a dopamine synthesis inhibitor and a granule storage blocker is highly inconsistent. The time-course and duration of

  13. Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease

    PubMed Central

    Smith, Michael P.; Cass, Wayne A.

    2007-01-01

    Although the etiology of Parkinson’s disease (PD) is unknown, a common element of most theories is the involvement of oxidative stress, either as a cause or effect of the disease. There have been relatively few studies that have characterized oxidative stress in animal models of PD. In the present study a 6-hydroxydopamine (6-OHDA) rodent model of PD was used to investigate the in vivo production of oxidative stress after administration of the neurotoxin. 6-OHDA was injected into the striatum of young adult rats and the production of protein carbonyls and 4-hydroxynonenal (HNE) was measured at 1, 3, 7, and 14 days after administration. A significant increase in both markers was found in the striatum 1 day after neurotoxin administration, and this increase declined to basal levels by day 7. There was no significant increase found in the substantia nigra at any of the time points investigated. This same lesion paradigm produced dopamine depletions of 90–95% in the striatum and 63–80% in the substantia nigra by 14 to 28 days post 6-OHDA. Protein carbonyl and HNE levels were also measured in middle-aged and aged animals 1 day after striatal 6-OHDA. Both protein carbonyl and HNE levels were increased in the striatum of middle-aged and aged animals treated with 6-OHDA, but the increases were not as great as those observed in the young adult animals. Similar to the young animals, there were no increases in either marker in the substantia nigra of the middle-aged and aged animals. There was a trend for an age-dependent increase in basal amounts of oxidative stress markers when comparing the non-lesioned side of the brains of the three age groups. These results support that an early event in the course of dopamine depletion following intrastriatal 6-OHDA administration is the generation of oxidative stress. PMID:17110046

  14. RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release

    PubMed Central

    Stacey, David; Bilbao, Ainhoa; Maroteaux, Matthieu; Jia, Tianye; Easton, Alanna C.; Longueville, Sophie; Nymberg, Charlotte; Banaschewski, Tobias; Barker, Gareth J.; Büchel, Christian; Carvalho, Fabiana; Conrod, Patricia J.; Desrivičres, Sylvane; Fauth-Bühler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Gallinat, Jürgen; Garavan, Hugh; Bokde, Arun L. W.; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Lourdusamy, Anbarasu; Mann, Karl F.; Martinot, Jean-Luc; Nees, Frauke; Palkovits, Miklós; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Ruggeri, Barbara; Santos, Eugenio; Smolka, Michael N.; Staehlin, Oliver; Jarvelin, Marjo-Riitta; Elliott, Paul; Sommer, Wolfgang H.; Mameli, Manuel; Müller, Christian P.; Spanagel, Rainer; Girault, Jean-Antoine; Schumann, Gunter

    2012-01-01

    The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca2+-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2?/? mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2?/? mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the IA potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse. PMID:23223532

  15. Dopamine alleviates salt-induced stress in Malus hupehensis.

    PubMed

    Li, Chao; Sun, Xiangkai; Chang, Cong; Jia, Dongfeng; Wei, Zhiwei; Li, Cuiying; Ma, Fengwang

    2015-04-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, ion homeostasis and the response to salinity in Malus hupehensis Rehd. Both hydroponics and field-pot experiments were conducted under saline conditions. Salt-stressed plants had reduced growth and a marked decline in their net photosynthetic rates, values for Fv /Fm and chlorophyll contents. However, pretreatment with 100 or 200 ?M dopamine significantly alleviated this inhibition and enabled plants to maintain their photosynthetic capacity. In addition to changing stomatal behavior, supplementation with dopamine positively influenced the uptake of K, N, P, S, Cu and Mn ions but had an inhibitory effect on Na and Cl uptake, the balance of which is responsible for managing the response to salinity by Malus plants. Dopamine pretreatment also controlled the burst of hydrogen peroxide, possibly through direct scavenging and by enhancing the activities of antioxidative enzymes and the capacity of the ascorbate-glutathione cycle. We also investigated whether dopamine might regulate salt overly sensitive pathway genes under salinity. Here, MdHKT1, MdNHX1 and MdSOS1 were greatly upregulated in roots and leaves, which possibly contributed to the maintenance of ion homeostasis and, thus, improved salinity resistance in plants exposed earlier to exogenous dopamine. These results support our conclusion that dopamine alleviates salt-induced stress not only at the level of antioxidant defense but also by regulating other mechanisms of ion homeostasis. PMID:25155951

  16. Abnormal functional connectivity between motor cortex and pedunculopontine nucleus following chronic dopamine depletion

    PubMed Central

    Valencia, Miguel; Chavez, Mario; Artieda, Julio; Bolam, J. Paul

    2013-01-01

    The activity of the basal ganglia is altered in Parkinson's disease (PD) as a consequence of the degeneration of dopamine neurons in the substantia nigra pars compacta. This results in aberrant discharge patterns and expression of exaggerated oscillatory activity across the basal ganglia circuit. Altered activity has also been reported in some of the targets of the basal ganglia, including the pedunculopontine nucleus (PPN), possibly due to its close interconnectivity with most regions of the basal ganglia. However, the nature of the involvement of the PPN in the pathophysiology of PD has not been fully elucidated. Here, we recorded local field potentials in the motor cortex and the PPN in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD under urethane anesthesia. By means of linear and nonlinear statistics, we analyzed the synchrony between the motor cortex and the PPN and the delay in the interaction between these two structures. We observed the presence of coherent activity between the cortex and the PPN in low (5–15 Hz)- and high (25–35 Hz)-frequency bands during episodes of cortical activation. In each case, the cortex led the PPN. Dopamine depletion strengthened the interaction of the low-frequency activities by increasing the coherence specifically in the theta and alpha ranges and reduced the delay of the interaction in the gamma band. Our data show that cortical inputs play a determinant role in leading the coherent activity with the PPN and support the involvement of the PPN in the pathophysiology of PD. PMID:24174651

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

    PubMed

    Ma, Wei; Liu, Hui-Ting; Long, Yi-Tao

    2015-07-01

    Dopamine (DA) quinone-induced dopaminergic neurotoxicity is known to occur due to the interaction between DA quinone and cysteine (Cys) residue, and it may play an important a role in pathological processes associated with neurodegeneration. In this study, we monitored the interaction process of DA to form DA quinone and the subsequent Cys residue using dopamine functionalized quantum dots (QDs). The fluorescence (FL) of the QD bioconjugates changes as a function of the structure transformation during the interaction process, providing a potential FL tool for monitoring dopaminergic neurotoxicity. PMID:26070031

  18. The Expression of the Calcium Binding Protein Calretinin in the Rat Striatum: Effects of Dopamine Depletion and L-DOPA Treatment

    E-print Network

    Verschure, Paul

    The Expression of the Calcium Binding Protein Calretinin in the Rat Striatum: Effects of Dopamine in the neuronal expression of the calcium binding pro- tein calretinin related to dopamine depletion and L-DOPA administration. Immunohistochemical meth- ods were used to assess calretinin in the striatum of rats

  19. Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion

    PubMed Central

    Meerkerk, Dorie (T). J.; Lieben, Cindy K. J.; Blokland, Arjan; Feenstra, Matthijs G. P.

    2007-01-01

    Rationale Acute tryptophan depletion (ATD) is a widely used method to study the role of serotonin (5-HT) in affect and cognition. ATD results in a strong but transient decrease in plasma tryptophan and central 5-HT synthesis and availability. Although its use is widespread, the evidence that the numerous functional effects of ATD are caused by actual changes in 5-HT neuronal release is not very strong. Thus far, decreases in 5-HT efflux (thought to reflect synaptic release) were only reported after chronic tryptophan depletion or when ATD was combined with blockade of 5-HT reuptake. Objective With the current experiment, we aimed to study the validity of the method of ATD by measuring the extent to which it reduces the efflux of 5-HT (and dopamine) in the prefrontal cortex in the absence of reuptake blockage. Materials and methods We simultaneously measured in freely moving animals plasma tryptophan via a catheter in the jugular vein and 5-HT and DA efflux in the medial prefrontal cortex through microdialysis after ATD treatment. Results ATD reduced plasma tryptophan to less than 30% of control, without affecting 5-HT or DA efflux in the prefrontal cortex, indicating that even strong reductions of plasma tryptophan do not necessarily result in decreases in central 5-HT efflux. Conclusion The present experiment showed that reductions in plasma tryptophan, similar to values associated with behavioural effects, do not necessarily reduce 5-HT efflux and suggest that the cognitive and behavioural effects of ATD may not be (exclusively) due to alterations in 5-HT release. PMID:17713760

  20. Dopamine and Pain Sensitivity: Neither Sulpiride nor Acute Phenylalanine and Tyrosine Depletion Have Effects on Thermal Pain Sensations in Healthy Volunteers

    PubMed Central

    Becker, Susanne; Ceko, Marta; Louis-Foster, Mytsumi; Elfassy, Nathaniel M.; Leyton, Marco; Shir, Yoram; Schweinhardt, Petra

    2013-01-01

    Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine’s well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain. PMID:24236199

  1. Dopamine precursor depletion improves punishment prediction during reversal learning in healthy females but not males

    Microsoft Academic Search

    Oliver J. Robinson; Holly R. Standing; Elise E. DeVito; Roshan Cools; Barbara J. Sahakian

    2010-01-01

    Introduction  The neurotransmitter dopamine has frequently been implicated in reward processing but is also, increasingly, implicated in\\u000a punishment processing. We have previously shown that both patients with Parkinson's disease and healthy individuals with low\\u000a dopamine (DA) synthesis are better at reversal learning based on punishment than reward. Here, we extend these prior findings\\u000a by examining the effects of artificially reducing DA

  2. Desynchronization of fast-spiking interneurons reduces ?-band oscillations and imbalance in firing in the dopamine-depleted striatum.

    PubMed

    Damodaran, Sriraman; Cressman, John R; Jedrzejewski-Szmek, Zbigniew; Blackwell, Kim T

    2015-01-21

    Oscillations in the ?-band (8-30 Hz) that emerge in the output nuclei of the basal ganglia during Parkinson's disease, along with an imbalanced activation of the direct and indirect pathways, have been linked to the hypokinetic motor output associated with the disease. Although dopamine depletion causes a change in cellular and network properties in the striatum, it is unclear whether abnormal activity measured in the globus pallidus and substantia nigra pars reticulata is caused by abnormal striatal activity. Here we use a computational network model of medium spiny neurons (MSNs)-fast-spiking interneurons (FSIs), based on data from several mammalian species, and find that robust ?-band oscillations and imbalanced firing emerge from implementation of changes to cellular and circuit properties caused by dopamine depletion. These changes include a reduction in connections between MSNs, a doubling of FSI inhibition to D2 MSNs, an increase in D2 MSN dendritic excitability, and a reduction in D2 MSN somatic excitability. The model reveals that the reduced decorrelation between MSNs attributable to weakened lateral inhibition enables the strong influence of synchronous FSIs on MSN firing and oscillations. Weakened lateral inhibition also produces an increased sensitivity of MSN output to cortical correlation, a condition relevant to the parkinsonian striatum. The oscillations of FSIs, in turn, are strongly modulated by fast electrical transmission between FSIs through gap junctions. These results suggest that pharmaceuticals that desynchronize FSI activity may provide a novel treatment for the enhanced ?-band oscillations, imbalanced firing, and motor dysfunction in Parkinson's disease. PMID:25609629

  3. Rat Globus Pallidus Neurons: Functional Classification and Effects of Dopamine Depletion

    PubMed Central

    Karain, Brad; Xu, Dan; Bellone, John A.; Hartman, Richard E.; Shi, Wei-Xing

    2015-01-01

    The rat globus pallidus (GP) is homologous to the primate GP externus. Studies with injectable anesthetics suggest that GP neurons can be classified into Type-I and Type-II cells based on extracellularly recorded spike shape, or positively coupled (PC), negatively coupled (NC), and uncoupled (UC) cells based on functional connectivity with the cortex. In this study, we examined the electrophysiology of rat GP neurons using the inhalational anesthetic isoflurane which offers more constant and easily regulated levels of anesthesia than injectable anesthetics. In 130 GP neurons recorded using small-tip glass electrodes (<1 ?m), all but one fired Type-II spikes (positive/negative waveform). Type-I cells were unlikely to be inhibited by isoflurane since all GP neurons also fired Type-II spikes under ketamine-induced anesthesia. When recorded with large-tip electrodes (~2 ?m), however, over 70% of GP neurons exhibited Type-I spikes (negative/positive waveform). These results suggest that the spike shape, recorded extracellularly, varies depending on the electrode used and is not reliable in distinguishing Type-I and Type-II neurons. Using dual-site recording, 40% of GP neurons were identified as PC cells, 17.5% NC cells, and 42.5% UC cells. The three subtypes also differed significantly in firing rate and pattern. Lesions of dopamine neurons increased the number of NC cells, decreased that of UC cells, and significantly shifted the phase relationship between PC cells and the cortex. These results support the presence of GP neuron subtypes and suggest that each subtype plays a different role in the pathophysiology of Parkinson’s disease. PMID:25196543

  4. PET imaging of dopamine receptors in MPTP-induced parkinsonism

    SciTech Connect

    Larson, S.M.; DiChiro, G.; Burns, R.S.; Dannals, R.F.; Kopin, I.J.; Brooks, R.A.; Kessler, R.M.; Wagner, R.F.; Eckelman, W.C.; Margolin, R.A.

    1984-01-01

    MPTP(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in animals and man by selectively destroying dopaminergic neurons in the pars compacta of the substantia nigra. The postsynaptic neurons (and presumably the dopamine receptors) are intact. The authors have imaged dopamine receptors in a patient with MPTP induced parkinsonism, using /sup 11/CMS (3-N(/sup 11/C) methylspiperone. Seven and 9 mCi's, respectively, were injected at one week intervals while the patient was first off, and then on, L-dopa. As measured by NeuroPET (NIH), putamen to cerebellum concentration ratios rose progressively to 5.5:1, by 90 min. after injection. At this time the concentration of /sup 11/CMS was 10 picomole/cc (off L-dopa), and 14 picomole/cc (on L-dopa). The Duvoisin scale was used to assess the severity of the patient's parkinsonism immediately prior and at the end of PET imaging. On both occasions, despite the small mass amount of /sup 11/CMS injected, (1.1 g/kg), a transient worsening of symptoms was seen. The effect of L-Dopa was almost completely reversed by the /sup 11/CMS. In contrast, off L-Dopa the patients severe basal state was worsened only slightly. The PET scans suggested that dopamine receptors are not reduced in MPTP-induced parkinsonism. The findings were consistent with the hypotheses that PET may identify patients who will benefit from L-Dopa, and that expression of parkinsonian symptoms reflects desaturation of dopamine receptors in striatum.

  5. Methylphenidate blocks effort-induced depletion of regulatory control in healthy volunteers.

    PubMed

    Sripada, Chandra; Kessler, Daniel; Jonides, John

    2014-06-01

    A recent wave of studies--more than 100 conducted over the last decade--has shown that exerting effort at controlling impulses or behavioral tendencies leaves a person depleted and less able to engage in subsequent rounds of regulation. Regulatory depletion is thought to play an important role in everyday problems (e.g., excessive spending, overeating) as well as psychiatric conditions, but its neurophysiological basis is poorly understood. Using a placebo-controlled, double-blind design, we demonstrated that the psychostimulant methylphenidate (commonly known as Ritalin), a catecholamine reuptake blocker that increases dopamine and norepinephrine at the synaptic cleft, fully blocks effort-induced depletion of regulatory control. Spectral analysis of trial-by-trial reaction times revealed specificity of methylphenidate effects on regulatory depletion in the slow-4 frequency band. This band is associated with the operation of resting-state brain networks that produce mind wandering, which raises potential connections between our results and recent brain-network-based models of control over attention. PMID:24756766

  6. 6-hydroxydopamine-induced degeneration of nigral dopamine neurons: differential effect on nigral and striatal D-1 dopamine receptors

    SciTech Connect

    Porceddu, M.L.; Giorgi, O.; De Montis, G.; Mele, S.; Cocco, L.; Ongini, E.; Biggio, G.

    1987-08-10

    Dopamine-sensitive adenylate cyclase and TH-SCH 23390 binding parameters were measured in the rat substantia nigra and striatum 15 days after the injection of 6-hydroxydopamine into the medial forebrain bundle. The activity of nigral dopamine-sensitive adenylate cyclase and the binding of TH-SCH 23390 to rat nigral D-1 dopamine receptors were markedly decreased after the lesion. On the contrary, 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway enhanced both adenylate cyclase activity and the density of TH-SCH 23390 binding sites in striatal membrane preparations. The changes in TH-SCH 23390 binding found in both nigral and striatal membrane preparations were associated with changes in the total number of binding sites with no modifications in their apparent affinity. The results indicate that: a) within the substantia nigra a fraction (30%) of D-1 dopamine receptors coupled to the adenylate cyclase is located on cell bodies and and/or dendrites of dopaminergic neurons; b) striatal D-1 dopamine receptors are tonically innervated by nigrostriatal afferent fibers. 24 references, 1 figure, 1 table.

  7. Subjective and behavioural consequences of striatal dopamine depletion in schizophrenia — Findings from an in vivo SPECT study

    Microsoft Academic Search

    Lakshmi N. P. Voruganti; A. George Awad

    2006-01-01

    Dysphoria is an integral part of the symptomatology of a variety of clinical states, though there is little empirical data available on the qualitative and quantitative aspects of this phenomenon. The purpose of the study was to administer alphamethyl paratyrosine (AMPT), a catecholamine depleting agent as a chemical probe to induce dysphoria, and document the ensuing changes in mental status.

  8. Testosterone Induces Molecular Changes in Dopamine Signaling Pathway Molecules in the Adolescent Male Rat Nigrostriatal Pathway

    PubMed Central

    Purves-Tyson, Tertia D.; Owens, Samantha J.; Double, Kay L.; Desai, Reena; Handelsman, David J.; Weickert, Cynthia Shannon

    2014-01-01

    Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17?-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence. PMID:24618531

  9. Imaging of Alcohol-Induced Dopamine Release in Rats: Preliminary Findings With

    E-print Network

    Morris, Evan D,

    Imaging of Alcohol-Induced Dopamine Release in Rats: Preliminary Findings With [11 C]Raclopride PET Microdialysis studies report that systemic alcohol increases extracel- lular dopamine (DA) in the rat striatum positron emission tomography (PET). PET images were acquired in 44 alcohol-nai¨ve male Wistar and alcohol

  10. Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons

    PubMed Central

    Berthet, Amandine; Margolis, Elyssa B.; Zhang, Jue; Hsieh, Ivy; Zhang, Jiasheng; Hnasko, Thomas S.; Ahmad, Jawad; Edwards, Robert H.; Sesaki, Hiromi; Huang, Eric J.

    2014-01-01

    Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics—mitochondrial fission—in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose ?-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. PMID:25339743

  11. Relationship between cocaine-induced subjective effects and dopamine transporter occupancy

    SciTech Connect

    Volkow, N.D.; Fischman, M.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1997-05-01

    The ability of cocaine to occupy the dopamine transporter has been linked to its reinforcing properties. However, such a relationship has not been demonstrated in humans. Methods: Positron Emission Tomography and [C-11]cocaine were used to estimate dopamine transporter occupancies after different doses of cocaine in 18 active cocaine abusers. The ratio of the distribution volume of [C-11]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1 and is insensitive to changes in cerebral blood flow, was our measure of dopamine transporter availability. In parallel subjective effects were measured to assess the relationship between dopamine transporter occupancy and cocaines behavioral effects. Intravenous cocaine produced a significant dose,-dependent blockade of dopamine transporters: 73 % for 0.6 mg/kg; 601/6 for 0.3 mg/kg; 48 % for 0.1 mg/kg iv and 40 % for 0.05 mg/kg. In addition, dopamine transporter occupancies were significantly correlated with cocaine plasma concentration (r = 0.55 p < 0.001). Cocaine also produced dose-dependent increases in self-reported ratings of {open_quotes}high{close_quotes} which were significantly correlated with the levels of dopamine transporter blockade. Discussion: These results provide the first documentation in humans that dopamine transporter occupancy is associated with cocaine induced subjective effects. They also suggest that dopamine transporter occupancies equal to or greater than 60% are required to produce significant effects on ratings of {open_quotes}high{close_quotes}.

  12. Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.

    PubMed

    Robinson, John D; Howard, Christopher D; Pastuzyn, Elissa D; Byers, Diane L; Keefe, Kristen A; Garris, Paul A

    2014-08-01

    Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity. PMID:24562969

  13. JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.

    PubMed

    Choi, Won-Seok; Kim, Hyung-Wook; Xia, Zhengui

    2015-02-01

    Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson's disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity. PMID:25496994

  14. Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

    SciTech Connect

    Dewey, S.L.; Straughter-Moore, R.; Chen, R. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series of PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.

  15. The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum.

    PubMed

    Thomas, David M; Angoa Pérez, Mariana; Francescutti-Verbeem, Dina M; Shah, Mrudang M; Kuhn, Donald M

    2010-11-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum. PMID:20722968

  16. Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer's disease.

    PubMed

    Melief, Erica J; Cudaback, Eiron; Jorstad, Nikolas L; Sherfield, Emily; Postupna, Nadia; Wilson, Angela; Darvas, Martin; Montine, Kathleen S; Keene, C Dirk; Montine, Thomas J

    2015-09-01

    Parkinson's disease and Alzheimer's disease (AD) are recognized to coexist on a spectrum of neurodegeneration, and it has been proposed that molecular interactions among pathogenic proteins are a basis for the overlap between these two diseases. We instead hypothesized that degeneration of the nigrostriatal dopaminergic system enhances the clinical penetrance of early-stage AD. To determine the effect of striatal dopamine (DA) on the pathological effects in an experimental model of AD, APPSWE /PS1?E9 mice received striatal injections of the neurotoxin 6-hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and in a water T-maze protocol at different ages to determine the onset of cognitive impairment. APPSWE /PS1?E9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age, APPswe /PS1?E9?+?6OHDA mice demonstrated worse behavioral flexibility than other groups in a task-switch phase of the water T-maze. To determine the neuroprotective effects of dopaminergic neurotransmission against amyloid-?42 (A?42 ) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D1 and D2 receptor agonists before being exposed to oligomerized A?42 . Although there were no differences in A? peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to A?42. Depletion of DA in the striatum exacerbated the cognitive impairment seen in a mouse model of early-stage AD; this may be due to a protective effect of dopaminergic innervation against A? striatal neurotoxicity. © 2015 Wiley Periodicals, Inc. PMID:25824456

  17. Cystamine induces AIF-mediated apoptosis through glutathione depletion.

    PubMed

    Cho, Sung-Yup; Lee, Jin-Haeng; Ju, Mi-Kyeong; Jeong, Eui Man; Kim, Hyo-Jun; Lim, Jisun; Lee, Seungun; Cho, Nam-Hyuk; Park, Hyun Ho; Choi, Kihang; Jeon, Ju-Hong; Kim, In-Gyu

    2015-03-01

    Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting ?-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death. PMID:25549939

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

    PubMed

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

    2014-06-01

    The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50?M) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins. PMID:24743698

  19. Flavonoid-induced glutathione depletion: Potential implications for cancer treatment?

    PubMed Central

    Kachadourian, Remy; Day, Brian J.

    2014-01-01

    The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2?-HC) and the dihydroxychalcones (2?,2-, 2?,3-, 2?,4-, and 2?,5?-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 µM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50–70% of intracellular GSH within 24 h of exposure at 25 µM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2?,5?-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2?,5?-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2?,5?-DHC and chrysin involve mitochondrial dysfunction. PMID:16781454

  20. Basophil depletion downregulates Schistosoma mansoni egg-induced granuloma formation.

    PubMed

    Anyan, William K; Seki, Takenori; Kumagai, Takashi; Obata-Ninomiya, Kazushige; Furushima-Shimogawara, Rieko; Kwansa-Bentum, Bethel; Akao, Nobuaki; Bosompem, Kwabena M; Boakye, Daniel A; Wilson, Michael D; Karasuyama, Hajime; Ohta, Nobuo

    2013-12-01

    Granuloma formation around parasite eggs during schistosomal infection is considered to be controlled by Th2 cytokines. However, it is still controversial which cell populations are responsible for the host Th2 cytokine-dependent granuloma formation. Basophils have recently attracted attention because of their ability to produce large amounts of IL-4. Therefore, we investigated whether basophils play an essential role in the induction of granuloma formation induced by Schistosoma mansoni eggs. Together with our previous observation that basophil numbers increased markedly in the spleen at 7 weeks postinfection, immunohistochemical staining using anti-mMCP8 monoclonal antibody (mAb) showed basophil infiltration in the granulomatous lesions formed around parasite eggs. To examine the roles of basophils more directly, we treated mice with anti-CD200R3 mAb to deplete basophils. Depletion of basophils resulted in a reduction of basophil number with concomitant downregulation of egg granuloma formation at 7 weeks postinfection. Moreover, we observed a significant reduction in the size of egg granulomas formed in basophil-depleted mice in the pulmonary granuloma model. Taken together, these findings indicated that basophils are essential for S. mansoni egg-induced granuloma formation, and this may serve as a novel therapeutic target in ameliorating the pathology of schistosomiasis. PMID:23850838

  1. Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux.

    PubMed

    da Luz, Marcio H M; Peres, Italo T; Santos, Tiago G; Martins, Vilma R; Icimoto, Marcelo Y; Lee, Kil S

    2015-01-01

    Accumulation of protein aggregates is a histopathological hallmark of several neurodegenerative diseases, but in most cases the aggregation occurs without defined mutations or clinical histories, suggesting that certain endogenous metabolites can promote aggregation of specific proteins. One example that supports this hypothesis is dopamine and its metabolites. Dopamine metabolism generates several oxidative metabolites that induce aggregation of ?-synuclein, and represents the main etiology of Parkinson's diseases. Because dopamine and its metabolites are unstable and can be highly reactive, we investigated whether these molecules can also affect other proteins that are prone to aggregate, such as cellular prion protein (PrP(C)). In this study, we showed that dopamine treatment of neuronal cells reduced the number of viable cells and increased the production of reactive oxygen species (ROS) as demonstrated in previous studies. Overall PrP(C) expression level was not altered by dopamine treatment, but its unglycosylated form was consistently reduced at 100 ?M of dopamine. At the same concentration, the level of phosphorylated mTOR and 4EBP1 was also reduced. Moreover, dopamine treatment decreased the solubility of PrP(C), and increased its accumulation in autophagosomal compartments with concomitant induction of LC3-II and p62/SQSTM1 levels. In vitro oxidation of dopamine promoted formation of high-order oligomers of recombinant prion protein. These results suggest that dopamine metabolites alter the conformation of PrP(C), which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrP(C) aggregates is an important feature of prion diseases. Thus, this study brings new insight into the dopamine metabolism as a source of endogenous metabolites capable of altering PrP(C) solubility and its subcellular localization. PMID:25698927

  2. Methamphetamine decreases mouse striatal dopamine transporter activity: roles of hyperthermia and dopamine.

    PubMed

    Sandoval, V; Hanson, G R; Fleckenstein, A E

    2000-12-15

    Multiple methamphetamine administrations rapidly decrease rat striatal dopamine transporter activity. To determine the species specificity of this phenomenon, the present studies examined effects of this stimulant on the dopamine transporter in mice. As in rats, multiple methamphetamine injections rapidly reduced striatal dopamine transporter activity; a decrease that was partially reversed 24 h later. Moreover, methamphetamine decreased binding of the dopamine transporter ligand, WIN35428, but to a lesser degree than the change in dopamine transporter function. These decreases did not appear to result from residual methamphetamine introduced by the original drug treatment. As in rats, hyperthermia contributed to this phenomenon. Unlike in rats, a role for dopamine was not observed in mice as dopamine depletion, resulting from alpha-methyl-p-tyrosine pretreatment, did not prevent this decrease. In addition, unlike in rats, pretreatment with either a dopamine D1 or D2 receptor antagonist (SCH23390 or eticlopride, respectively) did not attenuate the methamphetamine-induced reduction in dopamine uptake. These findings demonstrate both similarities and differences in the acute effects of methamphetamine on dopamine transporter function in mice and rats, and suggest the mouse as an additional model for assessing the acute effects of methamphetamine on the dopamine transporter. PMID:11108820

  3. Dopamine induces neurite retraction in retinal horizontal cells via diacylglycerol and protein kinase C.

    PubMed Central

    Rodrigues, P dos S; Dowling, J E

    1990-01-01

    Dopamine causes a significant retraction of neurites of bull-head catfish horizontal cells maintained in culture. The effects of dopamine are blocked by haloperidol and SCH 23390, a D1 antagonist, but not by sulpiride, a D2 antagonist. The dopamine-induced morphological changes were mimicked by SKF 38393, a D1 agonist, but not by quinpirole, a D2 agonist. Kainate also caused process retraction, but other neuroactive substances tested including glutamate, 5-hydroxytryptamine, N-methyl-D-aspartate, gamma-aminobutyric acid, and glycine caused only minor changes in neurite length. Cyclic AMP analogues do not induce neurite retraction in horizontal cells, indicating that this effect of dopamine is not mediated by cyclic AMP. However, a protein kinase C activator (phorbol 12-myristate 13-acetate) and synthetic diacylglycerol analogs (1-oleoyl-2-acetyl-sn-glycerol and dioctanoglycerol) caused marked neurite retraction. Their effects, as well as the dopamine-induced changes, were blocked by staurosporine, a potent protein kinase antagonist. The results suggest that dopamine causes neurite retraction by the activation of protein kinase C via diacylglycerol. Images PMID:2263620

  4. Selective Effects of Dopamine Depletion and L-DOPA Therapy on Learning-Related Firing Dynamics of Striatal Neurons

    E-print Network

    Hernandez, Ledia F.

    Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by ...

  5. Chronic L-deprenyl-induced up-regulation of the dopamine uptake carrier.

    PubMed

    Wiener, H L; Hashim, A; Lajtha, A; Sershen, H

    1989-04-12

    L-Deprenyl is an inhibitor of monoamine oxidase B and dopamine uptake. Chronic L-deprenyl (10 mg/kg i.p., twice weekly for 4 weeks) was shown to inhibit monoamine oxidase B activity by 89%, and also to induce an up-regulation of the [3H]mazindol binding site associated with the striatal dopamine uptake carrier. Scatchard analysis indicated a 56% increase in the maximal number of [3H]mazindol binding sites in chronic L-deprenyl animals, but no effect on the affinity of these binding sites. The ability of L-deprenyl to up-regulate the [3H]mazindol-associated dopamine uptake carrier appears to be a result of its role as a dopamine uptake inhibitor. PMID:2501102

  6. Role of matrix metalloproteinase and tissue inhibitor of MMP in methamphetamine-induced behavioral sensitization and reward: implications for dopamine receptor down-regulation and dopamine release.

    PubMed

    Mizoguchi, Hiroyuki; Yamada, Kiyofumi; Mouri, Akihiro; Niwa, Minae; Mizuno, Tomoko; Noda, Yukihiro; Nitta, Atsumi; Itohara, Shigeyoshi; Banno, Yoshiko; Nabeshima, Toshitaka

    2007-09-01

    Matrix metalloproteinases (MMPs) and its inhibitors (TIMPs) function to remodel the pericellular environment. We have demonstrated that methamphetamine (METH)-induced behavioral sensitization and reward were markedly attenuated in MMP-2- and MMP-9 deficient [MMP-2-(-/-) and MMP-9-(-/-)] mice compared with those in wild-type mice, suggesting that METH-induced expression of MMP-2 and MMP-9 in the brain plays a role in the development of METH-induced sensitization and reward. In the present study, we investigated the changes in TIMP-2 expression in the brain after repeated METH treatment. Furthermore, we studied a role of MMP/TIMP system in METH-induced behavioral changes and dopamine neurotransmission. Repeated METH treatment induced behavioral sensitization, which was accompanied by an increase in TIMP-2 expression. Antisense TIMP-2 oligonucleotide (TIMP-AS) treatment enhanced the sensitization, which was associated with the potentiation of METH-induced dopamine release in the nucleus accumbens (NAc). On the other hand, MMP-2/-9 inhibitors blocked the METH-induced behavioral sensitization and conditioned place preference, a measure of the rewarding effect, and reduced the METH-increased dopamine release in the NAc. Dopamine receptor agonist-stimulated [(35)S]GTPgammaS binding was reduced in the frontal cortex of sensitized rats. TIMP-AS treatment potentiated, while MMP-2/-9 inhibitor attenuated, the reduction of dopamine D2 receptor agonist-stimulated [(35)S]GTPgammaS binding. Repeated METH treatment also reduced dopamine D2 receptor agonist-stimulated [(35)S]GTPgammaS binding in wild-type mice, but such changes were significantly attenuated in MMP-2-(-/-) and MMP-9-(-/-) mice. These results suggest that the MMP/TIMP system is involved in METH-induced behavioral sensitization and reward, by regulating dopamine release and receptor signaling. PMID:17472698

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

    PubMed

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

    2014-06-01

    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 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

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

    PubMed Central

    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 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

  9. Intracellular methamphetamine prevents the dopamine-induced enhancement of neuronal firing.

    PubMed

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

    2014-08-01

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

  10. Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo

    PubMed Central

    Lamensdorf, Itschak; Porat, Shai; Simantov, Rabi; Finberg, John P M

    1999-01-01

    Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(?)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4?mg?kg?1, i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25?mg?kg?1, s.c.). Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active. PMID:10193780

  11. Dopamine blocks stress mediated ovarian carcinoma growth

    PubMed Central

    Moreno-Smith, Myrthala; Lu, Chunhua; Shahzad, Mian M.K.; Armaiz Pena, Guillermo N.; Allen, Julie K.; Stone, Rebecca L.; Mangala, Lingegowda S.; Han, Hee Dong; Kim, Hye Sun; Farley, Donna; Berestein, Gabriel Lopez; Cole, Steve W.; Lutgendorf, Susan K.; Sood, Anil K.

    2011-01-01

    Purpose Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth. Experimental Design Expression of dopamine receptors (DR1-DR5) was analyzed by real time reverse transcription-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis and migration were examined. For in vivo therapy, murine and human DR2-siRNA’s were incorporated into chitosan nanoparticles (CH). Results In this model of chronic stress, tumoral norepinephrine levels remained elevated while dopamine levels were significantly decreased compared to non-stressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density (MVD) as well as the stimulatory effect on apoptosis, since the DR2-antagonist eticlopride, reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cAMP levels and inhibited norepinephrine and VPF/VEGF induced Src kinase activation. Conclusions Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement. PMID:21531818

  12. Effects of Pharmacologic Dopamine ?-Hydroxylase Inhibition on Cocaine-Induced Reinstatement and Dopamine Neurochemistry in Squirrel Monkeys

    PubMed Central

    Cooper, Debra A.; Kimmel, Heather L.; Manvich, Daniel F.; Schmidt, Karl T.; Weinshenker, David

    2014-01-01

    Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine ?-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies. PMID:24817036

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

    PubMed

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

    2015-07-15

    Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1? expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. PMID:25818600

  14. Evaluating the Role of Neuronal Nitric Oxide Synthase-Containing Striatal Interneurons in Methamphetamine-Induced Dopamine Neurotoxicity

    PubMed Central

    Fricks-Gleason, Ashley N.

    2013-01-01

    Production of nitric oxide (NO) has been implicated in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. The source of this NO has not been clearly delineated, but recent evidence suggests that it arises from activation of neuronal nitric oxide synthase (nNOS), which is selectively expressed in a subpopulation of striatal interneurons. Our objective was to determine whether inhibiting activation of nNOS-containing interneurons in the striatum blocks METH-induced neurotoxicity. These interneurons selectively express the neurokinin-1 (NK-1) receptor, which is activated by substance P. One particular toxin, a conjugate of substance P to the ribosome-inactivating protein saporin (SSP–-SAP), selectively destroys neurons expressing the NK-1 receptor. Thus, we examined the extent to which depletion of the nNOS-containing interneurons alters production of NO and attenuates METH-induced neurotoxicity. The SSP–SAP lesions resulted in significant loss of nNOS-containing interneurons throughout striatum. Surprisingly, this marked deletion did not confer resistance to METH-induced DA neurotoxicity, even in areas devoid of nNOS-positive cells. Furthermore, these lesions did not attenuate NO production, even in areas lacking nNOS. These data suggest that nNOS-containing interneurons either are not necessary for METH-induced DA neurotoxicity or produce NO that can diffuse extensively through striatal tissue and thereby still mediate neurotoxicity. PMID:23575992

  15. Pathological gambling induced by dopamine antagonists: a case report.

    PubMed

    Grötsch, Philipp; Lange, Claudia; Wiesbeck, Gerhard A; Lang, Undine

    2015-03-01

    Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling. PMID:24356928

  16. Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

    PubMed Central

    Park, Ariane; Stacy, Mark

    2011-01-01

    Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease. PMID:21603184

  17. Spatial Learning and Memory Deficits Induced by Dopamine Administration with Decreased Glutathione

    Microsoft Academic Search

    Barbara Shukitt-Hale; Steven A Erat; James A Joseph

    1998-01-01

    Administration of buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) biosynthesis and induces a GSH deficiency. Decreased GSH levels in the brain may result in less oxidative stress (OS) protection, because GSH contributes substantially to intracellular antioxidant defense. Under these conditions, administration of the pro-oxidant, dopamine (DA), which rapidly oxidizes to form reactive oxygen species, may increase OS. To test the

  18. Depletion-induced shape and size selection of gold nanoparticles.

    PubMed

    Park, Kyoungweon; Koerner, Hilmar; Vaia, Richard A

    2010-04-14

    For nanoparticle-based technologies, efficient and rapid approaches that yield particles of high purity with a specific shape and size are critical to optimize the nanostructure-dependent optical, electrical, and magnetic properties, and not bias conclusions due to the existence of impurities. Notwithstanding the continual improvement of chemical methods for shaped nanoparticle synthesis, byproducts are inevitable. Separation of these impurities may be achieved, albeit inefficiently, through repeated centrifugation steps only when the sedimentation coefficient of the species shows sufficient contrast. We demonstrate a robust and efficient procedure of shape and size selection of Au nanoparticles (NPs) through the formation of reversible flocculates by surfactant micelle induced depletion interaction. Au NP flocculates form at a critical surfactant micelle molar concentration, C(m)* where the number of surfactant micelles is sufficient to induce an attractive potential energy between the Au NPs. Since the magnitude of this potential depends on the interparticle contact area of Au NPs, separation is achieved even for the NPs of the same mass with different shape by tuning the surfactant concentration and extracting flocculates from the sediment by centrifugation or gravitational sedimentation. The refined NPs are redispersed by subsequently decreasing the surfactant concentration to reduce the effective attractive potential. These concepts provide a robust method to improve the quality of large scale synthetic approaches of a diverse array of NPs, as well as fine-tune interparticle interactions for directed assembly, both crucial challenges to the continual realization of the broad technological potential of monodispersed NPs. PMID:20349972

  19. Cocaine-Induced Intracellular Signaling and Gene Expression Are Oppositely Regulated by the Dopamine D1 and D3 Receptors

    Microsoft Academic Search

    Lu Zhang; Danwen Lou; Hongyuan Jiao; Dongsheng Zhang; Xinkang Wang; Ying Xia; Jianhua Zhang; Ming Xu

    2004-01-01

    Repeated exposure to cocaine can induce neuroadaptations in the brain. One mechanism by which persistent changes occur involves alterations in gene expression mediated by the dopamine receptors. Both the dopamine D1 and D3 receptors have been shown to mediate gene expression changes. Moreover, the D1 and D3 receptors are also coexpressed in the same neurons, particularly in the nucleus accumbens

  20. Differential involvement of dopamine receptors in conditioned suppression induced by cocaine

    PubMed Central

    Grakalic, Ivana; Panlilio, Leigh V.; Thorndike, Eric B.; Schindler, Charles W.

    2007-01-01

    Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) (0.001–0.03 mg/kg, i.p.), or the dopamine D2-like receptor antagonist eticlopride (0.001–0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2- naphthamide (BP897) (a dopamine D3 partial receptor agonist; 0.1–1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pretreatment with either SCH23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D1- and D2-like receptors underlying these respective processes. PMID:17628537

  1. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens

    PubMed Central

    Danjo, Teruko; Yoshimi, Kenji; Funabiki, Kazuo; Yawata, Satoshi; Nakanishi, Shigetada

    2014-01-01

    Dopamine (DA) transmission from the ventral tegmental area (VTA) is critical for controlling both rewarding and aversive behaviors. The transient silencing of DA neurons is one of the responses to aversive stimuli, but its consequences and neural mechanisms regarding aversive responses and learning have largely remained elusive. Here, we report that optogenetic inactivation of VTA DA neurons promptly down-regulated DA levels and induced up-regulation of the neural activity in the nucleus accumbens (NAc) as evaluated by Fos expression. This optogenetic suppression of DA neuron firing immediately evoked aversive responses to the previously preferred dark room and led to aversive learning toward the optogenetically conditioned place. Importantly, this place aversion was abolished by knockdown of dopamine D2 receptors but not by that of D1 receptors in the NAc. Silencing of DA neurons in the VTA was thus indispensable for inducing aversive responses and learning through dopamine D2 receptors in the NAc. PMID:24737889

  2. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion.

    PubMed

    Morlé, A; Garrido, C; Micheau, O

    2015-01-01

    TRAIL is involved in immune tumor surveillance and is considered a promising anti-cancer agent owing to its limited side effects on healthy cells. However, some cancer cells display resistance, or become resistant to TRAIL-induced cell death. Hyperthermia can enhance sensitivity to TRAIL-induced cell death in various resistant cancer cell lines, including lung, breast, colon or prostate carcinomas. Mild heat shock treatment has been proposed to restore Fas ligand or TRAIL-induced apoptosis through c-FLIP degradation or the mitochondrial pathway. We demonstrate here that neither the mitochondria nor c-FLIP degradation are required for TRAIL-induced cell death restoration during hyperthermia. Our data provide evidence that insolubilization of c-FLIP, alone, is sufficient to enhance apoptosis induced by death receptors. Hyperthermia induced c-FLIP depletion from the cytosolic fraction, without apparent degradation, thereby preventing c-FLIP recruitment to the TRAIL DISC and allowing efficient caspase-8 cleavage and apoptosis. Hyperthermia-induced c-FLIP depletion was independent of c-FLIP DED2 FL chain assembly motif or ubiquitination-mediated c-FLIP degradation, as assessed using c-FLIP point mutants on lysine 167 and 195 or threonine 166, a phosphorylation site known to regulate ubiquitination of c-FLIP. Rather, c-FLIP depletion was associated with aggregation, because addition of glycerol not only prevented the loss of c-FLIP from the cytosol but also enabled c-FLIP recruitment within the TRAIL DISC, thus inhibiting TRAIL-induced apoptosis during hyperthermia. Altogether our results demonstrate that c-FLIP is a thermosensitive protein whose targeting by hyperthermia allows restoration of apoptosis induced by TNF ligands, including TRAIL. Our findings suggest that combining TRAIL agonists with whole-body or localized hyperthermia may be an interesting approach in cancer therapy. PMID:25675293

  3. PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

    PubMed Central

    Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/?) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/?, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

  4. Consistent unmasking of dopamine-induced dilation of the canine femoral vascular bed.

    PubMed

    Listinsky, J J; Kohli, J D; Goldberg, L I

    1980-12-01

    Dopamine (DA) produced dose-related vasodilation in the canine femoral vascular bed after the administration of two alpha adrenergic blocking agents, WR-149,024 (1,18-diamino-6,13-diaza-9,10-dithiaoctadecane) or yohimbine. DA-induced vasodilation unmasked by yohimbine was not antagonized by propranolol, pyrilamine and metiamide, hexamethonium or atropine, but was attenuated selectively by the DA antagonist, sulpiride. The R-enantiomer of sulpiride was more effective than the S-enantiomer in attenuating DA-induced dilation. Phenoxybenzamine produced moderate (apparently nonspecific) attenuation of vasodilator responses to DA. The weaker vascular DA agonist, N,N-di-n-propyl dopamine, was approximately 1/25 as potent as DA in eliciting femoral vasodilation after yohimbine treatment. These findings suggest that DA produces femoral vasodilation after WR-149,024 or yohimbine by activation of vascular DA receptors similar to those proposed to exist in the renal vascular bed. PMID:6108364

  5. Calcium Store Depletion Induces Persistent Perisomatic Increases in the Functional Density

    E-print Network

    Alford, Simon

    Neuron Article Calcium Store Depletion Induces Persistent Perisomatic Increases in the Functional of intracellular calcium by the endo- plasmic reticulum (ER) plays a critical role in neuronal function. While the consequences associated with depleting calcium from the ER have been studied in multiple systems

  6. Design and Automation of an Induced Depletion Experiment on ^108mAg

    Microsoft Academic Search

    I. N. Mills; G. P. Trees; C. J. Sweeney; T. A. Balint; S. A. Karamian; J. J. Carroll

    2009-01-01

    Nuclear isomers may be able to store and provide energy for certain applications. To determine if a particular nuclear isomer is a good candidate for such an application, an experiment must demonstrate an induced depletion. This depletion would bypass the slow decay transitions of the metastable state by exciting the nucleus into a shorter-lived, higher-energy intermediate states with a decay

  7. Positron annihilation studies in the field induced depletion regions of metal-oxide-semiconductor structures

    E-print Network

    Rubloff, Gary W.

    Positron annihilation studies in the field induced depletion regions of metal February 1992) The centroid shifts of positron annihilation spectra are reported from the depletion regions-gaussian positron implantation profile. Inadequacy of the present analysis scheme is evident from the derived

  8. Prior Morphine Exposure Enhances Ibogaine Antagonism of Morphine-induced Dopamine Release in Rats

    Microsoft Academic Search

    SANDRA M PEARL; ISABELLE M MAISONNEUVE; STANLEY D GLICK

    1996-01-01

    The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg\\/kg, i.p.) or saline and given a low dose of ibogaine (10 mg\\/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats

  9. Regulation of NMDA-induced [ 3H]dopamine release from rat hippocampal slices through sigma-1 binding sites

    Microsoft Academic Search

    Shigeyuki Chaki; Shigeru Okuyama; Shin-ichi Ogawa; Kazuyuki Tomisawa

    1998-01-01

    To examine the interaction between ionotropic glutamate receptors and ? binding sites, we made use of [3H]dopamine releasefrom rat hippocampal slices. Agonists for ionotropic glutamate receptors such as N-methyl-d-aspartate (NMDA), ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate evoked release of [3H]dopamine from rat hippocampal slices, in a dose-dependent manner. (+)-Pentazocine, a prototype ?1 agonist, attenuated the NMDA-induced [3H]dopamine release dose-dependently and significantly as

  10. Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase

    Microsoft Academic Search

    Cécile Vindis; Marie-Hélčne Séguélas; Stephen Lanier; Angelo Parini; Claudie Cambon

    2001-01-01

    Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase.BackgroundThe rat renal proximal tubule cells contain a large amount of monoamine oxidase, which catalyzes the oxidative deamination of catecholamines such as dopamine (DA). The aim of this study is to investigate the potential role of hydrogen peroxide (H2O2) produced by monoamine oxidase (MAO) isoform on regulation

  11. Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Effects of diazepam

    Microsoft Academic Search

    J. M. Finlay; M. J. Zigmond; E. D. Abercrombie

    1995-01-01

    We have examined the effects of diazepam on the stress-induced increase in extracellular dopamine and norepinephrine in the medial prefrontal cortex using in vivo microdialysis. In naive rats, acute tail pressure (30 min) elicited an increase in the concentrations of dopamine and norepinephrine in extracellular fluid of medial prefrontal cortex (+54 and +50%, respectively). Diazepam (2.5 mg\\/kg, i.p.) decreased the

  12. Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine

    PubMed Central

    Voulalas, Pamela J.; Schetz, John; Undieh, Ashiwel S.

    2011-01-01

    We investigated the subcellular distribution of dopamine D1, D2 and D5 receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D1 receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D2 receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant membrane fractions, yet were not present in buoyant membranes. Most D5 receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D5 receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D1 receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D5 and D2 receptor subtypes were not significantly altered by cocaine treatment. These data imply that D5 receptors are predominantly cytoplasmic, D2 receptors are diffusely distributed within the cell, whereas D1 receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation. PMID:21236347

  13. BDNF interacts with endocannabinoids to regulate cocaine-induced synaptic plasticity in mouse midbrain dopamine neurons.

    PubMed

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping; Liu, Qing-song

    2015-03-11

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase C? pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB? receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  14. Shock induced multi-mode damage in depleted uranium

    SciTech Connect

    Koller, Darcie D [Los Alamos National Laboratory; Cerreta, Ellen K [Los Alamos National Laboratory; Gray, Ill, George T [Los Alamos National Laboratory

    2009-01-01

    Recent dynamic damage studies on depleted uranium samples have revealed mixed mode failure mechanisms leading to incipient cracking as well as ductile failure processes. Results show that delamination of inclusions upon compression may provide nucleation sites for damage initiation in the form of crack tip production. However, under tension the material propagates cracks in a mixed shear localization and mode-I ductile tearing and cracking. Cracks tips appear to link up through regions of severe, shear dominated plastic flow. Shock recovery experiments were conducted on a 50 mm single stage light gas gun. Serial metallographic sectioning was conducted on the recovered samples to characterize the bulk response of the sample. Experiments show delaminated inclusions due to uniaxial compression without damage propagation. Further results show the propagation of the damage through tensile loading to the incipient state, illustrating ductile processes coupled with mixed mode-I tensile ductile tearing, shear localization, and mode-I cracking in depleted uranium.

  15. Drawdown and stream depletion induced by a nearby pumping well

    NASA Astrophysics Data System (ADS)

    Baalousha, Husam Musa

    2012-10-01

    SummaryThis study derives two dimensional analytical solutions for drawdown and stream depletion resulting from a pumping well near a stream. The solutions were obtained for both line-width and finite-width streams in unconfined/confined aquifers, based on the principle of superposition. These solutions are general enough to be used for different hydrogeological settings within both unconfined and confined aquifers. Results of analytical solutions for both drawdown and stream depletion were checked against results obtained using numerical models for confined/unconfined aquifer. It has been found that both line-width and finite-width stream depletion results are close to numerical results, but the finite-width stream solution has less error. Drawdown results show that the line-width stream solution slightly over-estimates the drawdown, and the finite-width stream solution has a good match with the numerical drawdown results. The error in drawdown results is directly proportional to the increase in stream width, but is higher in the case of a line-width stream.

  16. Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists.

    PubMed

    Hiranita, Takato; Mereu, Maddalena; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

    2013-03-01

    Sigma(1) receptors (?(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective ?(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either ?(1)R agonist. In contrast, after subjects self-administered cocaine ?(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both ?(1)R agonists, extinguished when injections were discontinued, and reconditioned when ?(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of ?(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the ?R antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive ?(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced ?(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. PMID:23187725

  17. Stimulants as Specific Inducers of Dopamine-Independent ? Agonist Self-Administration in Rats

    PubMed Central

    Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.

    2013-01-01

    A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of ? agonists mediated by their selective actions at ?1 receptors (?1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01–0.32 mg/kg per injection), the ?-opioid receptor agonist, heroin (0.001–0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032–1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective ?1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032–1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032–10 mg/kg per injection, each) self-administration. Although the ?1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1–3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32–10.0 µg/kg per injection, for ketamine). The ?R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0–10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10–100 ?g/kg) nor by the opioid antagonist (?)-naltrexone (1.0–10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive ?1R agonists. It is further suggested that induced ?1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

  18. Stimulants as specific inducers of dopamine-independent ? agonist self-administration in rats.

    PubMed

    Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Kopajtic, Theresa A; Katz, Jonathan L

    2013-10-01

    A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of ? agonists mediated by their selective actions at ?1 receptors (?1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg per injection), the ?-opioid receptor agonist, heroin (0.001-0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032-1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective ?1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032-1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg per injection, each) self-administration. Although the ?1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1-3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32-10.0 µg/kg per injection, for ketamine). The ?R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10-100 ?g/kg) nor by the opioid antagonist (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive ?1R agonists. It is further suggested that induced ?1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

  19. Maturation-Dependent Vulnerability of Oligodendrocytes to Oxidative Stress-Induced Death Caused by Glutathione Depletion

    Microsoft Academic Search

    Stephen A. Back; Xiaodong Gan; Ya Li; Paul A. Rosenberg; Joseph J. Volpe

    1998-01-01

    Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation-dependent differences in sur- vival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and

  20. Cyclophosphamide-Induced Apoptosis in COV434 Human Granulosa Cells Involves Oxidative Stress and Glutathione Depletion

    Microsoft Academic Search

    Miyun Tsai-Turton; Brian T. Luong; Youming Tan; Ulrike Luderer

    2007-01-01

    The anticancer drug cyclophosphamide induces granulosa cell apoptosis and is detoxified by glutathione (GSH) conjugation. We previously showed that both cyclophosphamide treatment and GSH depletion induced granulosa cell apoptosis in rats, but the role of GSH in apoptosis in human ovarian cells has not been studied. Using the COV434 human granulosa cell line, we tested the hypotheses that (1) GSH

  1. Repeated resveratrol treatment attenuates methamphetamine-induced hyperactivity and [3H]dopamine overflow in rodents.

    PubMed

    Miller, Dennis K; Oelrichs, Clark E; Sage, Andrew S; Sun, Grace Y; Simonyi, Agnes

    2013-10-25

    Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been investigated for its potential as a prophylactic against degenerative diseases. It is a sirtulin activator that has recently been shown to regulate dopaminergic systems that contribute to the behavioral effects of methamphetamine and cocaine. The present study examined the impact of resveratrol on stimulant neuropsychopharmacology in rodents. Acute resveratrol treatment (20-40mg/kg) was ineffective to alter methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Rodents received resveratrol once-daily for seven days to determine the effect of repeated polyphenolic treatment. Repeated resveratrol treatment (1-20mg/kg) decreased methamphetamine (0.5mg/kg)-induced hyperactivity in mice. Methamphetamine's (0.1-60?M) efficacy to evoke [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was also attenuated by repeated resveratrol (1mg/kg) treatment. Repeated resveratrol treatment (10-20mg/kg) did not affect cocaine-induced hyperactivity in mice. Overall, these data suggest that resveratrol appears to have metaplastic and prophylactic activity to minimize the effects of methamphetamine to increase locomotor activity and evoke dopamine release. These data encourage future research to further investigate the relationship between polyphenolics and psychostimulant abuse and dependence. PMID:24012682

  2. Dopamine induces light-adaptive retinomotor movements in bullfrog cones via D2 receptors and in retinal pigment epithelium via D1 receptors.

    PubMed

    Dearry, A; Edelman, J L; Miller, S; Burnside, B

    1990-04-01

    In the eyes of lower vertebrates, retinal photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) exhibit characteristic retinomotor movements in response to changes in ambient illumination and to signals from an endogenous circadian clock. We previously reported that 3,4-dihydroxyphenylethylamine (dopamine) mimicked the effect of light on these movements in photo-receptors and RPE cells of green sunfish, Lepomis cyanellus, by interacting with D2 dopaminergic receptors. Here, we report that dopamine also mimics the effect of light on cone and RPE retinomotor movements in bullfrogs, Rana catesbeiana, i.e., dopamine induces cone contraction and RPE pigment dispersion. Dopamine induced cone contraction in isolated dark-adapted bullfrog retinas incubated in constant darkness in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). This effect of dopamine was inhibited by a D2 but not a D1 antagonist and mimicked by a D2 but not a D1 agonist. These results suggest that induction of cone contraction by dopamine is mediated by D2 dopaminergic receptors and that cone adenylate cyclase activity is inhibited. Thus, dopamine acts via the same type of receptor in both bullfrog and green sunfish retinas to induce cone contraction. In contrast, dopamine influences RPE retinomotor movement via different receptors in fish and bullfrog. Dopamine induced light-adaptive pigment dispersion in isolated dark-adapted bullfrog RPE-eyecups incubated in constant darkness in normal Ringer's solution. Because the retina was not present, these experiments demonstrate a direct effect of dopamine on bullfrog RPE. This effect of dopamine on bullfrog RPE was inhibited by a D1 but not a D2 antagonist and mimicked by a D1 but not a D2 agonist. Furthermore, agents that increase the concentration of intracellular cyclic AMP also induced pigment dispersion in dark-adapted bullfrog RPE-eyecups incubated in the dark. These results suggest that dopamine induces pigment dispersion in bullfrog RPE via D1 dopaminergic receptors. Thus, dopamine acts via different receptors on bullfrog (D1) versus green sunfish (D2) RPE to induce pigment dispersion. In addition, inhibitor studies indicate that pigment dispersion is actin dependent in teleost but not in bullfrog RPE. Dopamine-induced pigment dispersion was inhibited by cytochalasin D in isolated RPE sheets of green sunfish but not in RPE-eyecups of bullfrogs. Together, these observations indicate that dopamine mimics the effect of light on cone and RPE retinomotor movements in both fish and bullfrogs. However, in the RPE, different receptors mediate the effect of dopamine, and different cytoskeletal mechanisms are used to affect pigment transport.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2156019

  3. Protective effects of metallothionein against dopamine quinone-induced dopaminergic neurotoxicity.

    PubMed

    Miyazaki, Ikuko; Asanuma, Masato; Hozumi, Hiroaki; Miyoshi, Ko; Sogawa, Norio

    2007-10-16

    Dopamine (DA) quinone as DA neuron-specific oxidative stress conjugates with cysteine residues in functional proteins to form quinoproteins. Here, we examined the effects of cysteine-rich metal-binding proteins, metallothionein (MT)-1 and -2, on DA quinone-induced neurotoxicity. MT quenched DA semiquinones in vitro. In dopaminergic cells, DA exposure increased quinoproteins and decreased cell viability; these were ameliorated by pretreatment with MT-inducer zinc. Repeated L-DOPA administration markedly elevated striatal quinoprotein levels and reduced the DA nerve terminals specifically on the lesioned side in MT-knockout parkinsonian mice, but not in wild-type mice. Our results suggested that intrinsic MT protects against L-DOPA-induced DA quinone neurotoxicity in parkinsonian mice by its quinone-quenching property. PMID:17910954

  4. Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism

    PubMed Central

    Kosaraju, Jayasankar; Chinni, Santhivardhan; Roy, Partha Deb; Kannan, Elango; Antony, A. Shanish; Kumar, M. N. Satish

    2014-01-01

    Objective: The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). Materials and Methods: T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 ?g). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed. Results: TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups. Conclusion: Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation. PMID:24741189

  5. Vacuum-ultraviolet-induced charge depletion in plasma-charged patterned-dielectric wafers

    SciTech Connect

    Upadhyaya, G. S.; Shohet, J. L. [Department of Electrical and Computer Engineering and Plasma Processing and Technology Laboratory, University of Wisconsin-Madison, Madison, Wisconsin 53706 (United States); Kruger, J. B. [Stanford Nanofabrication Facility, Stanford University, Stanford, California 94303 (United States)

    2009-03-01

    Plasma-induced charging of patterned-dielectric structures during device fabrication can cause structural and electrical damage to devices. In this work, we report on vacuum-ultraviolet (VUV) radiation-induced charge depletion in plasma-charged patterned-silicon-oxide dielectric wafers. Charge depletion is studied as a function of photon energy and the aspect ratio of hole structures. The wafers were charged in a plasma and subsequently exposed to monochromatic-synchrotron-VUV. Surface-potential measurements after VUV exposure showed that photon energies less than 11 eV were beneficial in depleting the plasma-induced charge from the patterned-dielectric wafers. In addition, for a given photon-flux density and for photon energies less than 11 eV, VUV-induced charge depletion decreases with increasing hole aspect ratio. The results are explained with a physically plausible equivalent-circuit model, which suggests that both electron photoinjection from Si into the oxide and oxide surface conductivity play an important role in the charge-depletion process.

  6. Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia

    PubMed Central

    Taylor, Norman E.; Chemali, Jessica J.; Brown, Emery N.; Solt, Ken

    2012-01-01

    BACKGROUND A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia. METHODS In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiological changes induced by chloro-APB and quinpirole during isoflurane general anesthesia. RESULTS Chloro-APB decreased median time to emergence from 330s to 50s. The median difference in time to emergence between the saline control group (n=6) and the chloro-APB group (n = 6) was 222s (95% CI: 77–534s, Mann-Whitney test). This difference was statistically significant (p = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram delta power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia. CONCLUSIONS Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia, and produces behavioral and neurophysiological evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia. PMID:23221866

  7. S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis

    PubMed Central

    Rodriguez-Menchaca, Aldo A; Solis Jr, Ernesto; Cameron, Krasnodara; De Felice, Louis J

    2012-01-01

    BACKGROUND AND PURPOSE Wherever they are located, dopamine transporters (DATs) clear dopamine (DA) from the extracellular milieu to help regulate dopaminergic signalling. Exposure to amphetamine (AMPH) increases extracellular DA in the synaptic cleft, which has been ascribed to DAT reverse transport. Increased extracellular DA prolongs postsynaptic activity and reinforces abuse and hedonic behaviour. EXPERIMENTAL APPROACH Xenopus laevis oocytes expressing human (h) DAT were voltage-clamped and exposed to DA, R(-)AMPH, or S(+)AMPH. KEY RESULTS At -60mV, near neuronal resting potentials, S(+)AMPH induced a depolarizing current through hDAT, which after removing the drug, persisted for more than 30 min. This persistent leak in the absence of S(+)AMPH was in contrast to the currents induced by R(-)AMPH and DA, which returned to baseline immediately after their removal. Our data suggest that S(+)AMPH and Na+ carry the initial S(+)AMPH-induced current, whereas Na+ and Cl- carry the persistent leak current. We propose that the persistent current results from the internal action of S(+)AMPH on hDAT because the temporal effect was consistent with S(+)AMPH influx, and intracellular S(+)AMPH activated the effect. The persistent current was dependent on Na+ and was blocked by cocaine. Intracellular injection of S(+)AMPH also activated a DA-induced persistent leak current. CONCLUSIONS AND IMPLICATIONS We report a hitherto unknown action of S(+)AMPH on hDAT that potentially affects AMPH-induced DA release. We propose that internal S(+)AMPH acts as a molecular stent that holds the transporter open even after external S(+)AMPH is removed. Amphetamine-induced persistent leak currents are likely to influence dopaminergic signalling, DA release mechanisms, and amphetamine abuse. PMID:22014068

  8. Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

    PubMed Central

    Biskup, Caroline Sarah; Sánchez, Cristina L.; Arrant, Andrew; Van Swearingen, Amanda E. D.; Kuhn, Cynthia; Zepf, Florian Daniel

    2012-01-01

    Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP?) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain- specific effect of ATD Moja-De on anxiety-like behavior. PMID:22629305

  9. Effects of cytisine on hydroxyl radicals in vitro and MPTP-induced dopamine depletion in vivo

    Microsoft Academic Search

    Boris Ferger; Christopher Spratt; Peter Teismann; Gunther Seitz; Klaus Kuschinsky

    1998-01-01

    The potential new iron-chelator cytisine and the radical scavenger N-tert-butyl-?-(2-sulfophenyl) nitrone (S-PBN) were incubated in a Fenton system and hydroxyl radical formation was measured with the salicylate trapping assay. Both cytisine and S-PBN reduced hydroxyl radical formation in a concentration-dependent manner. For in vivo studies, C57BL\\/6 mice were injected repeatedly with cytisine (0.5 mg\\/kg or 2.0 mg\\/kg s.c.) or saline

  10. Measuring cohesion between macromolecular filaments, one pair at a time: Depletion-induced microtubule bundling

    E-print Network

    Feodor Hilitski; Andrew R. Ward; Luis Cajamarca; Michael F. Hagan; Gregory M. Grason; Zvonimir Dogic

    2015-02-11

    In presence of non-adsorbing polymers, colloidal particles experience ubiquitous attractive interactions induced by depletion forces. Here, we measure the depletion interaction between a pair of microtubule filaments using a method that combines single filament imaging with optical trapping. By quantifying the dependence of filament cohesion on both polymer concentration and solution ionic strength, we demonstrate that the minimal model of depletion, based on the Asakura-Oosawa theory, fails to quantitatively describe the experimental data. By measuring the cohesion strength in two- and three- filament bundles we verify pairwise additivity of depletion interactions for the specific experimental conditions. The described experimental technique can be used to measure pairwise interactions between various biological or synthetic filaments and complements information extracted from bulk osmotic stress experiments.

  11. Measuring Cohesion between Macromolecular Filaments One Pair at a Time: Depletion-Induced Microtubule Bundling

    NASA Astrophysics Data System (ADS)

    Hilitski, Feodor; Ward, Andrew R.; Cajamarca, Luis; Hagan, Michael F.; Grason, Gregory M.; Dogic, Zvonimir

    2015-04-01

    In the presence of nonadsorbing polymers, colloidal particles experience ubiquitous attractive interactions induced by depletion forces. Here, we measure the depletion interaction between a pair of microtubule filaments using a method that combines single filament imaging with optical trapping. By quantifying the dependence of filament cohesion on both polymer concentration and solution ionic strength, we demonstrate that the minimal model of depletion, based on the Asakura-Oosawa theory, fails to quantitatively describe the experimental data. By measuring the cohesion strength in two- and three- filament bundles, we verify pairwise additivity of depletion interactions for the specific experimental conditions. The described experimental technique can be used to measure pairwise interactions between various biological or synthetic filaments and complements information extracted from bulk osmotic stress experiments.

  12. Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells

    PubMed Central

    GAO, FENG-HOU; LIU, FENG; WEI, WEI; LIU, LI-BIN; XU, MANG-HUA; GUO, ZHU-YING; LI, WEI; JIANG, BIN; WU, YING-LI

    2012-01-01

    We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated ?-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation. PMID:22294162

  13. Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development

    PubMed Central

    Daquinag, A C; Tseng, C; Salameh, A; Zhang, Y; Amaya-Manzanares, F; Dadbin, A; Florez, F; Xu, Y; Tong, Q; Kolonin, M G

    2015-01-01

    Overgrowth of white adipose tissue (WAT) in obesity occurs as a result of adipocyte hypertrophy and hyperplasia. Expansion and renewal of adipocytes relies on proliferation and differentiation of white adipocyte progenitors (WAP); however, the requirement of WAP for obesity development has not been proven. Here, we investigate whether depletion of WAP can be used to prevent WAT expansion. We test this approach by using a hunter-killer peptide designed to induce apoptosis selectively in WAP. We show that targeted WAP cytoablation results in a long-term WAT growth suppression despite increased caloric intake in a mouse diet-induced obesity model. Our data indicate that WAP depletion results in a compensatory population of adipose tissue with beige adipocytes. Consistent with reported thermogenic capacity of beige adipose tissue, WAP-depleted mice display increased energy expenditure. We conclude that targeting of white adipocyte progenitors could be developed as a strategy to sustained modulation of WAT metabolic activity. PMID:25342467

  14. Genetic Association between Dopamine Transporter Protein Alleles and Cocaine-Induced Paranoia

    Microsoft Academic Search

    Joel Gelernter; Henry R Kranzler; Sally L Satel; Peter A Rao

    1994-01-01

    Paranoia in the context of cocaine abuse is common and potentially dangerous. Several lines of evidence suggest that this phenomenon may be related to function of the dopamine transporter protein (DAT). DAT is the site of presynaptic reuptake of dopamine, an event that terminates its synaptic activity. The gene coding for dopamine transporter protein (DAT1) contains a variable number of

  15. AMPHETAMINE-, SCOPOLAMINE-, AND CAFFEINE-INDUCED LOCOMOTOR ACTIVITY FOLLOWING 6-HYDROXYDOPAMINE LESIONS OF THE MESOLIMBIC DOPAMINE SYSTEM

    EPA Science Inventory

    As previously reported, 6-hydroxydopamine (6-OHDA) lesions to the region of the nucleus accumbens blocked the locomotor activation induced by low doses of d-amphetamine, and produced a supersensitive locomotor response to the dopamine (DA) agonist, apomorphine. This same lesion, ...

  16. Dopamine mediated iron release from ferritin is enhanced at higher temperatures: Possible implications for fever-induced Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Babincová, Melánia; Babinec, Peter

    2005-05-01

    A new molecular mechanism is proposed to explain the pathogenesis of fever-induced Parkinson's disease. This proposal is based on dopamine and 6-hydroxydopamine-mediated free iron release from ferritin magnetic nanoparticles, which is enhanced at higher temperatures, and which may lead to substantial peroxidation and injury of lipid biomembranes of the substantia nigra in the brain.

  17. Depletion from a Hard Wall Induced by Aggregation and Gelation Manuel Rottereau, Taco Nicolai,

    E-print Network

    Paris-Sud XI, Université de

    Depletion from a Hard Wall Induced by Aggregation and Gelation Manuel Rottereau, Taco Nicolai Mans cedex 9, France (Dated: December 12, 2005) Diffusion limited cluster aggregation and gelation-Zernike equation and the Percus-Yevick closure. At high volume fractions ( > 40%) gelation has little influence

  18. EFFECTS OF SYSTEMIC NEUTROPHIL DEPLETION ON LPS-INDUCED AIRWAY DISEASE

    EPA Science Inventory

    Effects of Systemic Neutrophil Depletion on LPS-induced Airway Disease Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, David A. Schwartz Pulmonary and Critical Care Division, Dept of Medicine ? Duke University Medical Center * National Health and E...

  19. Canine distemper virus-induced depletion of uninfected lymphocytes is associated with apoptosis

    Microsoft Academic Search

    Martina Schobesberger; Artur Summerfield; Marcus G. Doherr; Andreas Zurbriggen; Christian Griot

    2005-01-01

    Canine distemper virus (CDV), a negative stranded RNA morbillivirus, causes a multisystemic disease in dogs, which is associated with a severe immune suppression. The aim of the study was to examine the influence of early CDV infection on leukocyte depletion, lymphopenia and virus-induced cell death in dogs infected with a virulent CDV strain. From 10 infected dogs, peripheral blood leukocytes

  20. Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures.

    PubMed

    Gaval-Cruz, Meriem; Schroeder, Jason P; Liles, L Cameron; Javors, Martin A; Weinshenker, David

    2008-06-01

    The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/- mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/- mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/- mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner. PMID:18329701

  1. Dopamine-induced dissociation of BOLD and neural activity in macaque visual cortex.

    PubMed

    Zaldivar, Daniel; Rauch, Alexander; Whittingstall, Kevin; Logothetis, Nikos K; Goense, Jozien

    2014-12-01

    Neuromodulators determine how neural circuits process information during cognitive states such as wakefulness, attention, learning, and memory. fMRI can provide insight into their function and dynamics, but their exact effect on BOLD responses remains unclear, limiting our ability to interpret the effects of changes in behavioral state using fMRI. Here, we investigated the effects of dopamine (DA) injections on neural responses and haemodynamic signals in macaque primary visual cortex (V1) using fMRI (7T) and intracortical electrophysiology. Aside from DA's involvement in diseases such as Parkinson's and schizophrenia, it also plays a role in visual perception. We mimicked DAergic neuromodulation by systemic injection of L-DOPA and Carbidopa (LDC) or by local application of DA in V1 and found that systemic application of LDC increased the signal-to-noise ratio (SNR) and amplitude of the visually evoked neural responses in V1. However, visually induced BOLD responses decreased, whereas cerebral blood flow (CBF) responses increased. This dissociation of BOLD and CBF suggests that dopamine increases energy metabolism by a disproportionate amount relative to the CBF response, causing the reduced BOLD response. Local application of DA in V1 had no effect on neural activity, suggesting that the dopaminergic effects are mediated by long-range interactions. The combination of BOLD-based and CBF-based fMRI can provide a signature of dopaminergic neuromodulation, indicating that the application of multimodal methods can improve our ability to distinguish sensory processing from neuromodulatory effects. PMID:25456449

  2. Involvement of brain ANG II in acute sodium depletion induced salty taste changes.

    PubMed

    Lu, Bo; Yan, Jianqun; Yang, Xuejuan; Li, Jinrong; Chen, Ke

    2012-11-10

    Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion. PMID:22846885

  3. Direct measurements of neutral density depletion by two-photon absorption laser-induced fluorescence spectroscopy

    SciTech Connect

    Aanesland, A.; Liard, L.; Leray, G.; Jolly, J.; Chabert, P. [Laboratoire de Physique et Technologie des Plasmas, Ecole Polytechnique, 91128 Palaiseau Cedex (France)

    2007-09-17

    The ground state density of xenon atoms has been measured by spatially resolved laser-induced fluorescence spectroscopy with two-photon excitation in the diffusion chamber of a magnetized Helicon plasma. This technique allows the authors to directly measure the relative variations of the xenon atom density without any assumptions. A significant neutral gas density depletion was measured in the core of the magnetized plasma, in agreement with previous theoretical and experimental works. It was also found that the neutral gas density was depleted near the radial walls.

  4. Nestin depletion induces melanoma matrix metalloproteinases and invasion

    PubMed Central

    Lee, Chung-Wei; Zhan, Qian; Lezcano, Cecilia; Frank, Markus H.; Huang, John; Larson, Allison; Lin, Jennifer Y.; Wan, Marilyn T.; Lin, Ping-I; Ma, Jie; Kleffel, Sonja; Schatton, Tobias; Lian, Christine G.; Murphy, George F.

    2015-01-01

    Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-?), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence. PMID:25365206

  5. Neutrophil Depletion Attenuates Placental Ischemia-Induced Hypertension in the Rat

    PubMed Central

    Regal, Jean F.; Lillegard, Kathryn E.; Bauer, Ashley J.; Elmquist, Barbara J.; Loeks-Johnson, Alex C.; Gilbert, Jeffrey S.

    2015-01-01

    Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension. PMID:26135305

  6. No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder

    PubMed Central

    Hernaus, D; Collip, D; Kasanova, Z; Winz, O; Heinzel, A; van Amelsvoort, T; Shali, S M; Booij, J; Rong, Y; Piel, M; Pruessner, J; Mottaghy, F M; Myin-Germeys, I

    2015-01-01

    Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [18F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [18F]fallypride displacement and the spatial extent of stress-induced [18F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [18F]fallypride displacement nor the spatial extent of stress-induced [18F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed. PMID:25871972

  7. Disparity between tonic and phasic ethanol-induced dopamine increases in the nucleus accumbens of rats

    PubMed Central

    Robinson, Donita L.; Howard, Elaina C.; McConnell, Scott; Gonzales, Rueben A.; Wightman, R. Mark

    2010-01-01

    BACKGROUND Dopamine concentrations in the nucleus accumbens fluctuate on phasic (subsecond) and tonic (over minutes) timescales in awake rats. Acute ethanol increases tonic concentrations of dopamine, but its effect on subsecond dopamine transients has not been fully explored. METHODS We measured tonic and phasic dopamine fluctuations in the nucleus accumbens of rats in response to ethanol (within-subject cumulative dosing, 0.125 – 2 g/kg, i.v.). RESULTS Microdialysis samples yielded significant tonic increases in dopamine concentrations at 1 – 2 g/kg ethanol in each rat, while repeated saline infusions had no effect. When monitored with fast scan cyclic voltammetry, ethanol increased the frequency of dopamine transients in 6 of 16 recording sites, in contrast to the uniform effect of ethanol as measured with microdialysis. In the remaining 10 recording sites that were unresponsive to ethanol, dopamine transients either decreased in frequency or were unaffected by cumulative ethanol infusions, patterns also observed during repeated saline infusions. The responsiveness of particular recording sites to ethanol was not correlated with either core versus shell placement of the electrodes or the basal rate of dopamine transients. Importantly, the phasic response pattern to a single dose of ethanol at a particular site was qualitatively reproduced when a second dose of ethanol was administered, suggesting that the variable between-site effects reflected specific pharmacology at that recording site. CONCLUSIONS These data demonstrate that the relatively uniform dopamine concentrations obtained with microdialysis can mask a dramatic heterogeneity of phasic dopamine release within the accumbens. PMID:19389195

  8. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model

    PubMed Central

    Choi, Won-Seok; Palmiter, Richard D.

    2011-01-01

    Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4?/? mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease. PMID:21383081

  9. Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.

    PubMed

    Kousik, Sharanya M; Napier, T Celeste; Ross, Ryan D; Sumner, D Rick; Carvey, Paul M

    2014-11-01

    Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1? was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans. PMID:25185214

  10. Generation of a novel mouse model for the inducible depletion of macrophages in vivo.

    PubMed

    Gheryani, Nabeia; Coffelt, Seth B; Gartland, Alison; Rumney, Robin M H; Kiss-Toth, Endre; Lewis, Claire E; Tozer, Gillian M; Greaves, David R; Dear, T Neil; Miller, Gaynor

    2013-01-01

    Macrophages play an essential role in tissue homeostasis, innate immunity, inflammation, and wound repair. Macrophages are also essential during development, severely limiting the use of mouse models in which these cells have been constitutively deleted. Consequently, we have developed a transgenic model of inducible macrophage depletion in which macrophage-specific induction of the cytotoxic diphtheria toxin A chain (DTA) is achieved by administration of doxycycline. Induction of the DTA protein in transgenic animals resulted in a significant 50% reduction in CD68+ macrophages of the liver, spleen, and bone over a period of 6 weeks. Pertinently, the macrophages remaining after doxycycline treatment were substantially smaller and are functionally impaired as shown by reduced inflammatory cytokine production in response to lipopolysaccharide. This inducible model of macrophage depletion can now be utilized to determine the role of macrophages in both development and animal models of chronic inflammatory diseases. PMID:22927121

  11. The probability distribution of the predicted CFM-induced ozone depletion. [Chlorofluoromethane

    NASA Technical Reports Server (NTRS)

    Ehhalt, D. H.; Chang, J. S.; Bulter, D. M.

    1979-01-01

    It is argued from the central limit theorem that the uncertainty in model predicted changes of the ozone column density is best represented by a normal probability density distribution. This conclusion is validated by comparison with a probability distribution generated by a Monte Carlo technique. In the case of the CFM-induced ozone depletion, and based on the estimated uncertainties in the reaction rate coefficients alone the relative mean standard deviation of this normal distribution is estimated to be 0.29.

  12. Progression of Cisplatin-Induced Nephrotoxicity in a Carnitine-Depleted Rat Model

    Microsoft Academic Search

    Mohamed M. Sayed-Ahmed; Maha A. Eissa; Sanaa A. Kenawy; Nadia Mostafa; Menotti Calvani; Abdel-Moneim M. Osman

    2004-01-01

    Background: This study has been initiated to investigate whether endogenous carnitine depletion and\\/or carnitine deficiency is an additional risk factor and\\/or a mechanism in cisplatin-induced nephrotoxicity and to gain insights into the possibility of a mechanism-based protection by L-carnitine against this toxicity. Methods: 60 male Sprague-Dawley rats were divided into six groups of 10 animals each and received one of

  13. Intrinsic vascular dopamine – a key modulator of hypoxia-induced vasodilatation in splanchnic vessels

    PubMed Central

    Pfeil, Uwe; Kuncova, Jitka; Brüggmann, Doerthe; Paddenberg, Renate; Rafiq, Amir; Henrich, Michael; Weigand, Markus A; Schlüter, Klaus-Dieter; Mewe, Marco; Middendorff, Ralf; Slavikova, Jana; Kummer, Wolfgang

    2014-01-01

    Dopamine not only is a precursor of the catecholamines noradrenaline and adrenaline but also serves as an independent neurotransmitter and paracrine hormone. It plays an important role in the pathogenesis of hypertension and is a potent vasodilator in many mammalian systemic arteries, strongly suggesting an endogenous source of dopamine in the vascular wall. Here we demonstrated dopamine, noradrenaline and adrenaline in rat aorta and superior mesenteric arteries (SMA) by radioimmunoassay. Chemical sympathectomy with 6-hydroxydopamine showed a significant reduction of noradrenaline and adrenaline, while dopamine levels remained unaffected. Isolated endothelial cells were able to synthesize and release dopamine upon cAMP stimulation. Consistent with these data, mRNAs coding for catecholamine synthesizing enzymes, i.e. tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase, and dopamine-?-hydroxylase were detected by RT-PCR in cultured endothelial cells from SMA. TH protein was detected by immunohistochemisty and Western blot. Exposure of endothelial cells to hypoxia (1% O2) increased TH mRNA. Vascular smooth muscle cells partially expressed catecholaminergic traits. A physiological role of endogenous vascular dopamine was shown in SMA, where D1 dopamine receptor blockade abrogated hypoxic vasodilatation. Experiments on SMA with endothelial denudation revealed a significant contribution of the endothelium, although subendothelial dopamine release dominated. From these results we conclude that endothelial cells and cells of the underlying vascular wall synthesize and release dopamine in an oxygen-regulated manner. In the splanchnic vasculature, this intrinsic non-neuronal dopamine is the dominating vasodilator released upon lowering of oxygen tension. PMID:24535440

  14. Effects of Kupffer cell depletion on acute alpha-naphthylisothiocyanate-induced liver toxicity in male mice.

    PubMed

    Cullen, John M; Faiola, Brenda; Melich, David H; Peterson, Richard A; Jordan, Holly L; Kimbrough, Carie L; Prescott, Judith S; Miller, Richard T

    2013-01-01

    Depletion of Kupffer cells, known to modulate chemical-induced hepatocellular injury, has not been studied with regard to biliary epithelial injury. Here, the authors investigated the effect of Kupffer cell depletion by clodronate on the toxicity of alpha-naphthylisothiocyanate (ANIT), known to injure biliary epithelium as well as hepatocytes. Up to 99% depletion of Kupffer cells occurred in ANIT and liposome-encapsulated clodronate-treated mice. The effect of Kupffer cell depletion was most evident one day following ANIT treatment. Histologically, there was a modest increase in neutrophil infiltration of the bile ducts, hepatocytic necrosis, and microvesicular vacuolization in the ANIT and clodronate-treated mice, but differences between other groups did not persist. Clinical pathology analytes related to the biliary or hepatocellular injury were significantly elevated in ANIT and clodronate-treated mice compared to mice given clodronate only. This was also true for mice given ANIT and empty liposomes in the case of the biliary analytes. However, group means were typically higher for the ANIT and clodronate-treated group than others on the first 2 days following ANIT injection. These findings suggest that Kupffer cell reduction increases hepatobiliary damage due to ANIT treatment. PMID:22886348

  15. Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia.

    PubMed

    Sarkar, Chandrani; Chakroborty, Debanjan; Dasgupta, Partha Sarathi; Basu, Sujit

    2015-08-01

    The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors. PMID:25556636

  16. Depletion of cellular glutathione modulates LIF-induced JAK1-STAT3 signaling in cardiac myocytes.

    PubMed

    Kurdi, Mazen; Sivakumaran, Vidhya; Duhé, Roy J; Aon, Miguel A; Paolocci, Nazareno; Booz, George W

    2012-12-01

    Previously we reported that the sesquiterpene lactone parthenolide induces oxidative stress in cardiac myocytes, which blocks Janus kinase (JAK) activation by the interleukin 6 (IL-6)-type cytokines. One implication suggested by this finding is that IL-6 signaling is dependent upon cellular anti-oxidant defenses or redox status. Therefore, the present study was undertaken to directly test the hypothesis that JAK1 signaling by the IL-6-type cytokines in cardiac myocytes is impaired by glutathione (GSH) depletion, since this tripeptide is one of the major anti-oxidant molecules and redox-buffers in cells. Cardiac myocytes were pretreated for 6h with l-buthionine-sulfoximine (BSO) to inhibit GSH synthesis. After 24h, cells were dosed with the IL-6-like cytokine, leukemia inhibitory factor (LIF). BSO treatment decreased GSH levels and dose-dependently attenuated activation of JAK1, Signal Transducer and Activator of Transcription 3 (STAT3), and extracellular signal regulated kinases 1 and 2 (ERK1/2). Addition of glutathione monoethyl ester, which is cleaved intracellularly to GSH, prevented attenuation of LIF-induced JAK1 and STAT3 activation, as did the reductant N-acetyl-cysteine. Unexpectedly, LIF-induced STAT1 activation was unaffected by GSH depletion. Evidence was found that STAT3 is more resistant than STAT1 to intermolecular disulfide bond formation under oxidizing conditions and more likely to retain the monomeric form, suggesting that conformational differences explain the differential effect of GSH depletion on STAT1 and STAT3. Overall, our findings indicate that activation of both JAK1 and STAT3 is redox-sensitive and the character of IL-6 type cytokine signaling in cardiac myocytes is sensitive to changes in the cellular redox status. In cardiac myocytes, activation of STAT1 may be favored over STAT3 under oxidizing conditions due to GSH depletion and/or augmented reactive oxygen species production, such as in ischemia-reperfusion and heart failure. PMID:22939972

  17. Serotonin depletion can enhance the cerebrovascular responses induced by cortical spreading depression via the nitric oxide pathway.

    PubMed

    Saengjaroentham, Chonlawan; Supornsilpchai, Weera; Ji-Au, Wilawan; Srikiatkhachorn, Anan; Maneesri-le Grand, Supang

    2015-02-01

    Serotonin (5-HT) is an important neurotransmitter involved in the control of neural and vascular responses. 5-HT depletion can induce several neurological disorders, including migraines. Studies on a cortical spreading depression (CSD) migraine animal model showed that the cortical neurons sensitivity, vascular responses, and nitric oxide (NO) production were significantly increased in 5-HT depletion. However, the involvement of NO in the cerebrovascular responses in 5-HT depletion remains unclear. This study aimed to investigate the role of NO in the CSD-induced alterations of cerebral microvessels in 5-HT depletion. Rats were divided into four groups: control, control with L-NAME treatment, 5-HT depleted, and 5-HT depleted with L-NAME treatment. 5-HT depletion was induced by intraperitoneal injection with para-chlorophenylalanine (PCPA) 3 days before the experiment. The CSD was triggered by KCl application. After the second wave of CSD, N-nitro-l-arginine methyl ester (L-NAME) or saline was intravenously injected into the rats with or without L-NAME treatment groups, respectively. The intercellular adhesion molecules-1 (ICAM-1), cell adhesion molecules-1 (VCAM-1), and the ultrastructural changes of the cerebral microvessels were examined. The results showed that 5-HT depletion significantly increased ICAM-1 and VCAM-1 expressions in the cerebral cortex. The number of endothelial pinocytic vesicles and microvilli was higher in the 5-HT depleted group when compared to the control. Interestingly, L-NAME treatment significantly reduced the abnormalities observed in the 5-HT depleted group. The results of this study demonstrated that an increase of NO production is one of the mechanisms involved in the CSD-induced alterations of the cerebrovascular responses in 5-HT depletion. PMID:24670256

  18. The Role of De Novo Catecholamine Synthesis in Mediating Methylmercury-Induced Vesicular Dopamine Release From Rat Pheochromocytoma (PC12) Cells

    PubMed Central

    Atchison, William D.

    2013-01-01

    The purpose of this study was to characterize methylmercury (MeHg)–induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect. Because DA release induced by 5µM MeHg was associated with a significant percentage of cell death at 60 and 120min, 2µM MeHg was chosen for further characterization of release mechanisms. MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release. Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium. MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release. The tyrosine hydroxylase inhibitor ?-methyltyrosine (300µM, 24h) completely abolished MeHg-induced DA release. MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10µM), revealing that MeHg increases tyrosine hydroxylase activity. Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis. PMID:23425605

  19. Quantification of noradrenaline and dopamine in Portulaca oleracea L. by capillary electrophoresis with laser-induced fluorescence detection

    Microsoft Academic Search

    Ji-you Zhang; Xing-guo Chen; Zhi-de Hu; Xiao Ma

    2002-01-01

    In this paper, a rapid and sensitive method is described for the quantification of noradrenaline (NA) and dopamine (DA) in Portulaca oleracea L. After derivatization in a dark ultrasonic bath for 4h, fluorescein isothiocyanate (FITC) derivatives of NA and DA were separated by capillary zone electrophoresis (CZE) in 5.5min and detected with laser-induced fluorescence. In the concentration range (0.05–2.00?M), the

  20. Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

    Microsoft Academic Search

    Collette Mann; Rodney J Croft; Kirsty E Scholes; Alan Dunne; Barry V O'Neill; Sumie Leung; David Copolov; K Luan Phan; Pradeep J Nathan

    2008-01-01

    Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully

  1. Schizophrenia is Associated with Elevated Amphetamine-Induced Synaptic Dopamine Concentrations: Evidence from a Novel Positron Emission Tomography Method

    Microsoft Academic Search

    A. Breier; T.-P. Su; R. Saunders; R. E. Carson; B. S. Kolachana; A. de Bartolomeis; D. R. Weinberger; N. Weisenfeld; A. K. Malhotra; W. C. Eckelman; D. Pickar

    1997-01-01

    A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outflow. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do

  2. Plasma renin activity and aldosterone concentration in sodium-depleted cattle following ACTH

    E-print Network

    Paris-Sud XI, Université de

    Plasma renin activity and aldosterone concentration in sodium-depleted cattle following ACTH Ceyrat. Summary. Adrenocorticotropic hormone (ACTH) treatment (7!g.kg-' body weight) induced an increase postulate that other factors, such as adrenocorticotropic hormone (ACTH) and/or dopamine (Sowers et al

  3. Endrin-induced depletion of glutathione and inhibition of glutathione peroxidase activity in rats.

    PubMed

    Numan, I T; Hassan, M Q; Stohs, S J

    1990-01-01

    1. Recent studies have shown that endrin induces lipid peroxidation and may produce toxicity through an oxidative stress. We have therefore examined the effect of endrin administration to rats on glutathione content and the activities of glutathione metabolizing enzymes. 2. The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion (90%) occurring in liver at approximately 24 hr post-treatment. 3. Decreases in glutathione content were also observed in lung, brain, spleen and heart. 4. Endrin (4 mg/kg) decreased selenium dependent glutathione peroxidase activity in liver and kidney by 64 and 50%, respectively, while small increases were observed in the activities of glutathione reductase and glutathione S-transferase. 5. The toxicity of endrin may be at least in part related to oxidative tissue damage associated with depletion of glutathione and inhibition of glutathione peroxidase activity. PMID:2276583

  4. Rapid Depletion of Budding Yeast Proteins via the Fusion of an Auxin-Inducible Degron (AID).

    PubMed

    Nishimura, Kohei; Kanemaki, Masato T

    2014-01-01

    The auxin-inducible degron (AID) system allows the rapid and reversible proteolysis of proteins of interest, and enables the generation of conditional mutants of budding yeast. The construction of budding yeast AID mutants is simple, and the effect of depletion of essential proteins on proliferation can be confirmed by analyzing their phenotype. In this protocol, we describe a procedure to generate AID mutants of budding yeast via a simple transformation using PCR-amplified DNA. We also describe methods to confirm the depletion of proteins of interest that are required for proliferation by serial-dilution and liquid-culture assays. Curr. Protoc. Cell Biol. 64:20.9.1-20.9.16. © 2014 by John Wiley & Sons, Inc. PMID:25181302

  5. Measurement of Beta Particles Induced Electron-Hole Pairs Recombination in Depletion Region of GaAs PN Junction

    Microsoft Academic Search

    Hai-Yang Chen; Lan Jiang; Da-Rang Li

    2011-01-01

    PN junctions and schottky diodes are widely employed as electron-hole pair collectors in electron beam induced current (EBIC) techniques and betavoltaic batteries, in which the recombination in depletion regions is ignored. We measured the beta particles induced electron-hole pairs recombination in the depletion region of a GaAs P+PN+ junction, based on comparisons between measured short currents and ideal values. The

  6. Effect of sex chromosome complement on sodium appetite and Fos-immunoreactivity induced by sodium depletion.

    PubMed

    Dadam, Florencia M; Caeiro, Ximena E; Cisternas, Carla D; Macchione, Ana F; Cambiasso, María J; Vivas, Laura

    2014-02-01

    Previous studies indicate a sex chromosome complement (SCC) effect on the angiotensin II-sexually dimorphic hypertensive and bradycardic baroreflex responses. We sought to evaluate whether SCC may differentially modulate sexually dimorphic-induced sodium appetite and specific brain activity due to physiological stimulation of the rennin angiotensin system. For this purpose, we used the "four core genotype" mouse model, in which the effect of gonadal sex and SCC is dissociated, allowing comparisons of sexually dimorphic traits between XX and XY females as well as in XX and XY males. Gonadectomized mice were sodium depleted by furosemide (50 mg/kg) and low-sodium diet treatment; control groups were administered with vehicle and maintained on normal sodium diet. Twenty-one hours later, the mice were divided into two groups: one group was submitted to the water-2% NaCl choice intake test, while the other group was perfused and their brains subjected to the Fos-immunoreactivity (FOS-ir) procedure. Sodium depletion, regardless of SCC (XX or XY), induced a significantly lower sodium and water intake in females than in males, confirming the existence in mice of sexual dimorphism in sodium appetite and the organizational involvement of gonadal steroids. Moreover, our results demonstrate a SCC effect on induced brain FOS-ir, showing increased brain activity in XX-SCC mice at the paraventricular nucleus, nucleus of the solitary tract, and lateral parabrachial nucleus, as well as an XX-SCC augmented effect on sodium depletion-induced brain activity at two circumventricular organs, the subfornical organ and area postrema, nuclei closely involved in fluid and blood pressure homeostasis. PMID:24259464

  7. Effect of IL-1?-Induced Macromolecular Depletion on Residual Quadrupolar Interaction in Articular Cartilage

    PubMed Central

    Borthakur, Arijitt; Shapiro, Erik M.; Beers, Jennifer; Kudchodkar, Sagar; Kneeland, J. Bruce; Reddy, Ravinder

    2010-01-01

    Purpose Sodium multiple-quantum filtered (MQF) NMR spectroscopy may potentially be used to measure proteoglycan (PG) depletion in cartilage caused by osteoarthritis (OA). The purpose of this work was to quantify the effect of interleukin-1 (IL-1?)-induced macromolecule depletion on the residual quadrupolar interaction (RQI) of sodium in bovine cartilage plugs. Materials and Methods Fifteen 8-mm-diameter cartilage plug specimens were cored from the articular surface of fresh bovine patellae. All plugs were kept in culture media and nine of the plugs were subjected to interleukin-1 (IL-1?)-induced degeneration of cartilage for 4, 6, and 7 days. Sodium NMR spectra were obtained from each sample with a 1-cm-diameter solenoid coil in a 2T whole-body magnet interfaced to a custom-built spectrometer. We employed a previously described theoretical model to analyze triple-quantum filtered (TQF) and double-quantum filtered magic angle (DQFMA) spectra obtained from normal cartilage and cartilage treated with IL-1?. The model assumes a static Gaussian distribution of the RQI frequency, ?Q, in the sample. TQF and DQFMA spectra from each sample were fitted with the appropriate signal expressions to determine ? (the root mean square (RMS) ?Q), T2f, and T2s. An inversion-recovery sequence was used to determine T1 of each plug. A spectrophotometric assay was used to determine the amount of PG depleted from each plug. Histology was performed to visualize the PG loss in cartilage plugs. We defined ? as the measure of changes in macroscopic order in the tissue. Results Simulated spectra from the theoretical model were in excellent agreement with the experimental data. We were able to determine the relaxation times as well as ? of each specimen from their corresponding fits. T2f ranged between 2.26–3.50 msec, decreasing with increased PG loss. Over the range of PG depletion investigated, T2s increased from 12.3 msec to 14.9 msec, and T1 increased from 16 msec to 21 msec, while ? decreased from 180 Hz to 120 Hz. The order of macromolecules in the cartilage tissue decreased substantially with PG loss. Histology sections clearly showed qualitative visualization of the PG loss in cartilage following treatment with IL-1?. Conclusion We demonstrated that IL-?-induced macromolecule depletion in cartilage not only changes the relaxation characteristics of sodium but also changes RQI of the tissue. Using MQF sodium spectroscopy we quantified the changes in ? and showed that loss of macromolecules reduces the degree of order in the tissue. PMID:11891977

  8. Involvement of dopamine receptors in diethylpropion-induced conditioning place preference.

    PubMed

    Planeta, C S; DeLucia, R

    1998-04-01

    Diethylpropion (DEP) is an amphetamine-like agent used as an anorectic drug. Abuse of DEP has been reported and some restrictions of its use have been recently imposed. The conditioning place preference (CPP) paradigm was used to evaluate the reinforcing properties of DEP in adult male Wistar rats. After initial preferences were determined, animals weighing 250-300 g (N = 7 per group) were conditioned with DEP (10, 15 or 20 mg/kg). Only the dose of 15 mg/kg produced a significant place preference (358 +/- 39 vs 565 +/- 48 s). Pretreatment with the D1 antagonist SCH 23,390 (0.05 mg/kg, s.c.) 10 min before DEP (15 mg/kg, i.p.) blocked DEP-induced CPP (418 +/- 37 vs 389 +/- 31 s) while haloperidol (0.5 mg/kg, i.p.), a D2 antagonist, 15 min before DEP was ineffective in modifying place conditioning produced by DEP (385 +/- 36 vs 536 +/- 41 s). These results suggest that dopamine D1 receptors mediate the reinforcing effect of DEP. PMID:9698810

  9. Zinc protects human kidney cells from depleted uranium-induced apoptosis.

    PubMed

    Hao, Yuhui; Ren, Jiong; Liu, Cong; Li, Hong; Liu, Jing; Yang, Zhangyou; Li, Rong; Su, Yongping

    2014-03-01

    Depleted uranium (DU) is a weak radioactive heavy metal, and zinc (Zn) is an effective antidote to heavy metal poisoning. However, the effect of Zn on DU-induced cytotoxicity and apoptosis is not completely understood. The purpose of this study was to evaluate the effect of Zn on DU-induced cell apoptosis in human kidney cells (HK-2) and explore its molecular mechanism. Pre-treatment with Zn significantly inhibited DU-induced apoptosis. It reduced the formation of reactive oxygen species in the cells, increased the catalase (CAT) and glutathione (GSH) concentrations, suppressed the DU-induced soluble Fas receptor (sFasR) and soluble Fas ligand (sFasL) overexpression, suppressed the release of cytochrome c and apoptosis inhibitor factor (AIF) from mitochondria to cytoplasm, inhibited the activation of caspase-9, caspase-8 and caspase-3, and induced metallothionein (MT) expression. Furthermore, exogenous MT effectively inhibited DU-induced cell apoptosis. In conclusion, mitochondrial and FasR-mediated apoptosis pathways contribute to DU-induced apoptosis in HK-2 cells. Through independent mechanisms, such as indirect antioxidant effects, inhibition of the activation of caspase-9, caspase-8 and caspase-3, and induction of MT expression, Zn inhibits DU-induced apoptosis. PMID:24330236

  10. 5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.

    PubMed

    Simon, P; Guardiola, B; Bizot-Espiard, J; Schiavi, P; Costentin, J

    1992-01-01

    The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections. PMID:1357709

  11. Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons

    PubMed Central

    Beckley, Jacob T.; Evins, Caitlin E.; Fedarovich, Hleb; Gilstrap, Meghin J.; Woodward, John J.

    2013-01-01

    Toluene is a volatile solvent that is intentionally inhaled by children, adolescents and adults for its intoxicating effects. While voluntary use of toluene suggests that it possesses rewarding properties and abuse potential, it is unknown whether toluene alters excitatory synaptic transmission in reward sensitive dopamine neurons like other drugs of abuse. Here, using a combination of retrograde labeling and slice electrophysiology, we show that a brief in vivo exposure of rats to a behaviorally relevant concentration of toluene vapor enhances glutamatergic synaptic strength of dopamine (DA) neurons projecting to nucleus accumbens core and medial shell neurons. This effect persisted for up to 3 days in mesoaccumbens core DA neurons and for at least 21 days in those projecting to the medial shell. In contrast, toluene vapor exposure had no effect on synaptic strength of DA neurons that project to the medial prefrontal cortex (mPFC). Furthermore, infusion of GABAergic modulators into the mPFC prior to vapor exposure to pharmacologically manipulate output, inhibited or potentiated toluene's action on mesoaccumbens DA neurons. Taken together, the results of these studies indicate that toluene induces a target-selective increase in mesolimbic DA neuron synaptic transmission and strongly implicates the mPFC as an important regulator of drug-induced plasticity of mesolimbic dopamine neurons. PMID:23303956

  12. Sedimentation rapidly induces an immune response and depletes energy stores in a hard coral

    NASA Astrophysics Data System (ADS)

    Sheridan, C.; Grosjean, Ph.; Leblud, J.; Palmer, C. V.; Kushmaro, A.; Eeckhaut, I.

    2014-12-01

    High sedimentation rates have been linked to reduced coral health within multiple systems; however, whether this is a direct result of compromised coral immunity has not been previously investigated. The potential effects of sedimentation on immunity of the hard coral Montipora patula were examined by comparing physiological responses of coral fragments inoculated with sterilized marine sediments and those under control conditions. Sediments were collected from terrestrial runoff-affected reefs in SW Madagascar and applied cyclically for a total of 24 h at a rate observed during precipitation-induced sedimentation events. Coral health was determined 24 h after the onset of the sedimentation stress through measuring metabolic proxies of O2 budget and lipid ratios. Immune response of the melanin synthesis pathway was measured by quantifying phenoloxidase activity and melanin deposits. Sedimentation induced both immune and metabolic responses in M. patula. Both phenoloxidase activity and melanin deposition were significantly higher in the sediment treatment compared to controls, indicating an induced immune response. Sediment-treated corals also showed a tendency towards increased respiration (during the night) and decreased photosynthesis (during the day) and a significant depletion of energy reserves as compared to controls. These data highlight that short-term (24 h) sedimentation, free of live microorganisms, compromises the health of M. patula. The energetically costly immune response, potentially elicited by residual endotoxins and other inflammatory particles associated with the sterile sediments, likely contributes to the energy depletion. Overall, exposure to sedimentation adversely affects coral health and continued exposure may lead to resource depletion and an increased susceptibility to disease.

  13. Mesenchymal stem cells prevent restraint stress-induced lymphocyte depletion via interleukin-4.

    PubMed

    Cao, Gang; Yang, Qian; Zhang, Siyu; Xu, Chunliang; Roberts, Arthur I; Wang, Ying; Shi, Yufang

    2014-05-01

    Chronic stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including cancer, immune disorders, and infections. Recent studies in animals and humans have demonstrated that mesenchymal stem cells (MSCs) significantly modulate the immune system. Here we show that administration of MSCs in vivo prevents lymphocyte depletion induced by physical restraint stress (12:12-h stress-rest, 2 repetitions) in mice. This effect was found to be exerted not through modulation of glucocorticoid levels in the circulation, but rather through direct effects on lymphocyte apoptosis. By testing various possible protective mechanisms, we found that IL-4 provides a strong anti-apoptosis signal to lymphocytes in the presence of dexamethasone. When neutralizing antibody against IL-4 was co-administered with MSCs to restraint-stressed mice, the protective effect of MSCs was diminished. Furthermore, in mice deficient in STAT6, a key molecule in IL-4 receptor-mediated signaling, MSCs had no effect on restraint stress-induced lymphocyte depletion. Additionally, MSCs administered to stressed mice promoted IL-4 production by splenocytes. This study reveals that MSCs can effectively prevent stress-induced lymphocyte apoptosis in an IL-4-dependent manner and provides novel information for the development of countermeasures against the deleterious effects of stress on the immune system. PMID:24480719

  14. Purine-induced alterations of dopamine metabolism in rat pheochromocytoma PC12 cells

    Microsoft Academic Search

    D. A Loeffler; D. M Camp; P. L Juneau; E Harel; P. A LeWitt

    2000-01-01

    Studies with cerebrospinal fluid from subjects with Parkinson’s disease suggest that purine abnormalities may be present in this disorder. The effects of purines on dopamine metabolism have not been characterized, though adenosine is known to inhibit dopaminergic neurotransmission. In this study, dopamine, its precursor 3,4-dihydroxyphenylalanine (DOPA), and its degradation products 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in

  15. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects.

    PubMed

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naďve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  16. D-2 dopamine receptor activation reduces free ( sup 3 H)arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells

    SciTech Connect

    Canonico, P.L. (Univ. of Catania School of Medicine (Italy))

    1989-09-01

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

  17. Pumping-induced drawdown and stream depletion in a leaky aquifer system.

    PubMed

    Butler, James J; Zhan, Xiaoyong; Zlotnik, Vitaly A

    2007-01-01

    The impact of ground water pumping on nearby streams is often estimated using analytic models of the interconnected stream-aquifer system. A common assumption of these models is that the pumped aquifer is underlain by an impermeable formation. A new semianalytic solution for drawdown and stream depletion has been developed that does not require this assumption. This solution shows that pumping-induced flow (leakage) through an underlying aquitard can be an important recharge mechanism in many stream-aquifer systems. The relative importance of this source of recharge increases with the distance between the pumping well and the stream. The distance at which leakage becomes the primary component of the pumping-induced recharge depends on the specific properties of the aquifer, aquitard, and streambed. Even when the aquitard is orders of magnitude less transmissive than the aquifer, leakage can be an important recharge mechanism because of the large surface area over which it occurs. Failure to consider aquitard leakage can lead to large overestimations of both the drawdown produced by pumping and the contribution of stream depletion to the pumping-induced recharge. The ramifications for water resources management and water rights adjudication can be significant. A hypothetical example helps illustrate these points and demonstrates that more attention should be given to estimating the properties of aquitards underlying stream-aquifer systems. The solution presented here should serve as a relatively simple but versatile tool for practical assessments of pumping-induced stream-aquifer interactions. However, this solution should not be used for such assessments without site-specific data that indicate pumping has induced leakage through the aquitard. PMID:17335482

  18. Pumping-induced drawdown and stream depletion in a leaky aquifer system

    USGS Publications Warehouse

    Butler, J.J., Jr.; Zhan, X.; Zlotnik, V.A.

    2007-01-01

    The impact of ground water pumping on nearby streams is often estimated using analytic models of the interconnected stream-aquifer system. A common assumption of these models is that the pumped aquifer is underlain by an impermeable formation. A new semianalytic solution for drawdown and stream depletion has been developed that does not require this assumption. This solution shows that pumping-induced flow (leakage) through an underlying aquitard can be an important recharge mechanism in many stream-aquifer systems. The relative importance of this source of recharge increases with the distance between the pumping well and the stream. The distance at which leakage becomes the primary component of the pumping-induced recharge depends on the specific properties of the aquifer, aquitard, and streambed. Even when the aquitard is orders of magnitude less transmissive than the aquifer, leakage can be an important recharge mechanism because of the large surface area over which it occurs. Failure to consider aquitard leakage can lead to large overestimations of both the drawdown produced by pumping and the contribution of stream depletion to the pumping-induced recharge. The ramifications for water resources management and water rights adjudication can be significant. A hypothetical example helps illustrate these points and demonstrates that more attention should be given to estimating the properties of aquitards underlying stream-aquifer systems. The solution presented here should serve as a relatively simple but versatile tool for practical assessments of pumping-induced stream-aquifer interactions. However, this solution should not be used for such assessments without site-specific data that indicate pumping has induced leakage through the aquitard. ?? 2006 National Ground Water Association.

  19. Effect of the adenosine A 2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat

    Microsoft Academic Search

    Mariana Pereira; Andrew M. Farrar; Jörg Hockemeyer; Christa E. Müller; John D. Salamone; Joan I. Morrell

    2011-01-01

    Rationale  Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness.\\u000a DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most\\u000a forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that\\u000a there is a functional interaction between DA D2 and adenosine A2A receptors in striatal

  20. Glutathione Depletion Due to Copper-Induced Phytochelatin Synthesis Causes Oxidative Stress in Silene cucubalus

    PubMed Central

    De Vos, C. H. Ric; Vonk, Marjolein J.; Vooijs, Riet; Schat, Henk

    1992-01-01

    The relation between loss of glutathione due to metal-induced phytochelatin synthesis and oxidative stress was studied in the roots of copper-sensitive and tolerant Silene cucubalus (L.) Wib., resistant to 1 and 40 micromolar Cu, respectively. The amount of nonprotein sulfhydryl compounds other than glutathione was taken as a measure of phytochelatins. At a supply of 20 micromolar Cu, which is toxic for sensitive plants only, phytochelatin synthesis and loss of total glutathione were observed only in sensitive plants within 6 h of exposure. When the plants were exposed to a range of copper concentrations for 3 d, a marked production of phytochelatins in sensitive plants was already observed at 0.5 micromolar Cu, whereas the production in tolerant plants was negligible at 40 micromolar or lower. The highest production in tolerant plants was only 40% of that in sensitive plants. In both varieties, the synthesis of phytochelatins was coupled to a loss of glutathione. Copper at toxic concentrations caused oxidative stress, as was evidenced by both the accumulation of lipid peroxidation products and a shift in the glutathione redox couple to a more oxidized state. Depletion of glutathione by pretreatment with buthionine sulfoximine significantly increased the oxidative damage by copper. At a comparably low glutathione level, cadmium had no effect on either lipid peroxidation or the glutathione redox couple in buthionine sulfoximine-treated plants. These results indicate that copper may specifically cause oxidative stress by depletion of the antioxidant glutathione due to phytochelatin synthesis. We conclude that copper tolerance in S. cucubalus does not depend on the production of phytochelatins but is related to the plant's ability to prevent glutathione depletion resulting from copper-induced phytochelatin production, e.g. by restricting its copper uptake. PMID:16668756

  1. Alantolactone Induces Apoptosis in HepG2 Cells through GSH Depletion, Inhibition of STAT3 Activation, and Mitochondrial Dysfunction

    PubMed Central

    Khan, Muhammad; Li, Ting; Ahmad Khan, Muhammad Khalil; Rasul, Azhar; Nawaz, Faisal; Sun, Meiyan; Zheng, Yongchen; Ma, Tonghui

    2013-01-01

    Signal transducer and activator of transcription 3 (STAT3) constitutively expresses in human liver cancer cells and has been implicated in apoptosis resistance and tumorigenesis. Alantolactone, a sesquiterpene lactone, has been shown to possess anticancer activities in various cancer cell lines. In our previous report, we showed that alantolactone induced apoptosis in U87 glioblastoma cells via GSH depletion and ROS generation. However, the molecular mechanism of GSH depletion remained unexplored. The present study was conducted to envisage the molecular mechanism of alantolactone-induced apoptosis in HepG2 cells by focusing on the molecular mechanism of GSH depletion and its effect on STAT3 activation. We found that alantolactone induced apoptosis in HepG2 cells in a dose-dependent manner. This alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine (NAC). The data demonstrate clearly that intracellular GSH plays a central role in alantolactone-induced apoptosis in HepG2 cells. Thus, alantolactone may become a lead chemotherapeutic candidate for the treatment of liver cancer. PMID:23533997

  2. Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity.

    PubMed

    Vazquez-DeRose, Jacqueline; Stauber, Gregory; Khroyan, Taline V; Xie, Xinmin Simon; Zaveri, Nurulain T; Toll, Lawrence

    2013-01-15

    Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0?M, 10?M, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction. PMID:23219985

  3. Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity

    PubMed Central

    Vazquez-DeRose, Jacqueline; Stauber, Gregory; Khroyan, Taline V.; Xie, Xinmin (Simon); Zaveri, Nurulain T.; Toll, Lawrence

    2012-01-01

    Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0µM, 10µM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(?)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction. PMID:23219985

  4. Photo-induced environmental depletion processes of beta-blockers in river waters.

    PubMed

    Liu, Qin-Tao; Cumming, Rob I; Sharpe, Alan D

    2009-06-01

    In order to improve the understanding of the fate and behaviour of pharmaceuticals in the environment there is a need to investigate in-stream depletion mechanisms, e.g. phototransformation of active pharmaceutical ingredients (APIs) in natural surface waters. In this study, abiotic and biotic degradation of selected beta-blockers was measured simultaneously in non-sterilised and sterilised river waters and deionised water (DIW) under simulated sunlight (lambda: 295-800 nm) and dark conditions, and at environmentally relevant concentrations, i.e.induced or reactive transient mediated oxidation mechanisms in river waters. Phototransformation was the main depletion mechanism for the beta-blockers tested over a 2 to 7 day period. Slow hydrolysis was observed for metoprolol only. Loss due to biodegradation in river waters was not observed for propranolol but was found for metoprolol and atenolol at a very slow rate within the study period. However, biodegradation of metoprolol was accelerated under the light conditions, implying that photo-induced intermediates could be more easily biodegraded in river waters. PMID:19492104

  5. Studies of Nuclear Structure Related to an Induced Depletion of Isomers

    SciTech Connect

    Carroll, James J. [Department of Physics and Astronomy, Youngstown State University One University Plaza, Youngstown, OH 44555 (United States)

    2009-03-31

    Nuclear isomers have served as important touchstones in the development of nuclear models. In addition, those metastable excited states whose lifetimes reach decades or longer present intriguing possibilities as high-energy-density media. Together, these aspects have motivated considerable research on whether some isomeric nuclides might allow an induced release of the stored energy upon demand. Targeted studies of nuclear structure aimed at this question are a rather recent development, providing a parallel approach to direct tests of induced depletion on isomeric samples. This paper will discuss the relationship between these dual research tracks, as exemplified by experiments conducted on isomeric nuclei in {sup 108}Ag, {sup 178}Hf and {sup 180}Ta.

  6. p53 Induces skin aging by depleting Blimp1+ sebaceous gland cells.

    PubMed

    Kim, J; Nakasaki, M; Todorova, D; Lake, B; Yuan, C-Y; Jamora, C; Xu, Y

    2014-01-01

    p53 is an important inducer of organismal aging. However, its roles in the aging of skin remain unclear. Here we show that mice with chronic activation of p53 develop an aging phenotype in the skin associated with a reduction of subcutaneous fat and loss of sebaceous gland (SG). The reduction in the fat layer may result from the decrease of mammalian TOR complex 1 (mTORC1) activity accompanied by elevated expression of energy expenditure genes, and possibly as compensatory effects, leading to the elevation of peroxisome proliferator-activated receptor (PPAR)?, an inducer of sebocyte differentiation. In addition, Blimp1(+) sebocytes become depleted concomitantly with an increase in cellular senescence, which can be reversed by PPAR? antagonist (BADGE) treatment. Therefore, our results indicate that p53-mediated aging of the skin involves not only thinning through the loss of subdermal fat, but also xerosis or drying of the skin through declining sebaceous gland activity. PMID:24675459

  7. Measurement of Beta Particles Induced Electron-Hole Pairs Recombination in Depletion Region of GaAs PN Junction

    NASA Astrophysics Data System (ADS)

    Chen, Hai-Yang; Jiang, Lan; Li, Da-Rang

    2011-05-01

    PN junctions and schottky diodes are widely employed as electron-hole pair collectors in electron beam induced current (EBIC) techniques and betavoltaic batteries, in which the recombination in depletion regions is ignored. We measured the beta particles induced electron-hole pairs recombination in the depletion region of a GaAs P+PN+ junction, based on comparisons between measured short currents and ideal values. The results show that only 20% electron-hole pairs in the depletion can be collected, causing the short current. This indicates an electron-hole pair diffusion length of 0.2?m in the depletion region. Hence, it is necessary to evaluate the recombination in the EBIC techniques and betavoltaic design.

  8. Dopamine transporter inhibition is necessary for cocaine-induced increases in dendritic spine density in the nucleus accumbens

    PubMed Central

    Martin, Bradley; Naughton, Bartholomew; Thirtamara-Rajamani, Keerthi; Yoon, Daniel; Han, Dawn; Devries, A. Courtney; Gu, Howard

    2010-01-01

    Repeated exposure to cocaine produces changes in the nervous system that facilitate drug-seeking behaviors. These drug-seeking behaviors have been studied with animal models, such as cocaine-induced locomotor sensitization. Cocaine is hypothesized to induce locomotor sensitization by neural changes, including an increase in the density of spines on the dendrites of neurons in the nucleus accumbens (NAC). However, how cocaine increases dendritic spine density in the NAC has been difficult to discern because cocaine inhibits the function of multiple targets, including the transporters for dopamine, serotonin, and norepinephrine. Previously, our lab created a tool that is useful for determining how inhibiting the dopamine transporter (DAT) contributes to the effects of cocaine by generating mice that express a cocaine-insensitive DAT (DAT-CI mice). In this study, we used DAT-CI mice to determine the contribution of DAT inhibition in cocaine-induced increases in dendritic spine density in the NAC. We repeatedly injected DAT-CI mice with either cocaine or saline, and measured both dendritic spine density in the NAC and locomotor activity. Unlike wild-type mice, DAT-CI mice did not show an increase in dendritic spine density in the NAC or in locomotor activity in response to repeated injections of cocaine. These data show that cocaine-induced increases in dendritic spine density in the NAC require DAT inhibition. Thus, DAT-inhibition may play a role in mediating the long-lasting neural changes associated with drug addiction. PMID:20936687

  9. Effects of 18-methoxycoronaridine on ghrelin-induced increases in sucrose intake and accumbal dopamine overflow in female rats

    PubMed Central

    Taraschenko, Olga D.; Hathaway, Ethan R.; Vincent, Melanie Y.; Glick, Stanley D.

    2013-01-01

    Rationale 18-Methoxycoronaridine (18-MC), a selective antagonist of ?3?4 nicotinic receptors, has been previously shown, in rats, to reduce the self-administration of several drugs of abuse, reduce operant responding for sucrose, and prevent the development of sucrose-induced obesity. It has become increasingly apparent that there is a significant overlap between the systems regulating drug reward and food intake, therefore, we investigated whether 18-MC might modulate the effects of ghrelin, one of several orexigenic peptides recently implicated in both feeding and drug reward. Objectives In female Sprague–Dawley rats, we determined whether acute 18-MC treatment would reduce both ghrelin-induced increases in sucrose intake and ghrelin-elicited increases in accumbal dopamine levels. Results Pretreatment with 18-MC (20 mg/kg, i.p.), given prior to the administration of ghrelin (1 µg, lateral ventricle), blocked ghrelin-induced increases in sucrose (5%) intake in a two-bottle open access paradigm. Using in vivo microdialysis, 18-MC (both 20 and 40 mg/kg) prevented ghrelin (2 µg, intraventral tegmental area)-induced increases in extracellular dopamine in the nucleus accumbens. 18-MC had no effect on deposition of fat or on serum levels of glucose, triglycerides, and cholesterol in ghrelin-treated rats. Conclusions The present results suggest that one potential mechanism by which 18-MC exerts its effects on palatable food consumption is via modulation of ghrelin’s effects. PMID:21210086

  10. Maitotoxin-induced myocardial cell injury: Calcium accumulation followed by ATP depletion precedes cell death

    SciTech Connect

    Santostasi, G.; Kutty, R.K.; Bartorelli, A.L.; Yasumoto, T.; Krishna, G. (National Heart, Lung and Blood Institute, Bethesda, MD (USA))

    1990-01-01

    Maitotoxin, the most potent marine toxin, is known to increase the uptake and the accumulation of Ca2+ into cells, and was used in the present study to investigate the mechanisms of myocardial cell damage induced by Ca2+ overload. In cultured cardiomyocytes, isolated from 2-day-old rats, maitotoxin affected cell viability, as indicated by the leakage of the cytosolic enzyme lactate dehydrogenase (LDH) and of radiolabeled adenine nucleotides into the extracellular medium. Maitotoxin-induced leakage of LDH steadily increased between 30 min and 24 hr, and was preceded by a marked depletion of intracellular ATP. Addition of maitotoxin resulted in a rapid influx of extracellular Ca2+, as detected by preincubating the cells in the presence of 45Ca; this effect evolved in a few minutes, thus preceding the signs of cell death. Cytosolic levels of free Ca2+ ((Ca2+)i) were monitored by loading freshly isolated, suspended cardiomyocytes with the intracellular fluorescent probe fura-2; in these cells, maitotoxin induced a dose-dependent increase in (Ca2+)i, with a lag phase of less than a minute. All these effects of maitotoxin were inhibited by reducing Ca2+ concentration in the culture medium or by incubating the cells with the calcium-channel blocking drug verapamil. It is thus demonstrated that maitotoxin-induced cardiotoxicity is secondary to an inordinate influx of Ca2+ into the cells. It is also suggested that, in those conditions that lead to an inordinate accumulation of Ca2+ into myocardial cells, the unmatched demands of energy and the depletion of ATP play a primary role in the irreversible stage of cell damage.

  11. THE METAL TRANSPORTER SMF-3/DMT-1 MEDIATES ALUMINUM-INDUCED DOPAMINE NEURON DEGENERATION

    PubMed Central

    VanDuyn, Natalia; Settivari, Raja; LeVora, Jennifer; Zhou, Shaoyu; Unrine, Jason; Nass, Richard

    2012-01-01

    Aluminum (Al3+) is the most prevalent metal in the earth's crust, and is a known human neurotoxicant. Al3+ has been shown to accumulate in the substantia nigra of Parkinson's disease (PD) patients, and epidemiological studies suggest correlations between Al3+ exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al3+ exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al3+ transport in neurons and subsequent cellular death has remained elusive. In this study we show that a brief exposure to Al3+ decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode Caenorhabditis elegans (C. elegans). Al3+ exposure also exacerbates DA neuronal death conferred by the human PD-associated protein ?-synuclein. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. We also show that SMF-3 is expressed in DA neurons, Al3+ exposure results in a significant decrease in protein levels, and the neurodegeneration is partially dependent on the PD-associated transcription factor Nrf2/SKN-1 and caspase Apaf1/CED-4. Furthermore we provide evidence that the deletion of SMF-3 confers Al3+-resistance due to sequestration of Al3+ into an intracellular compartment. This study describes a novel model for Al3+-induced DA neurodegeneration and provides the first molecular evidence of an animal Al3+ transporter. PMID:23106139

  12. Neurosteroid Agonist at GABAA receptor induces persistent neuroplasticity in VTA dopamine neurons.

    PubMed

    Vashchinkina, Elena; Manner, Aino K; Vekovischeva, Olga; den Hollander, Bjřrnar; Uusi-Oukari, Mikko; Aitta-Aho, Teemu; Korpi, Esa R

    2014-02-01

    The main fast-acting inhibitory receptors in the mammalian brain are ?-aminobutyric acid type-A (GABAA) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABAA receptors, with a preference for ?-subunit-containing receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids. We studied the effects of ganaxolone (GAN)-a synthetic analog of endogenous allopregnanolone that lacks activity on nuclear steroid receptors-on the mesolimbic dopamine (DA) system involved in emotions and motivation. A single dose of GAN in young mice induced a dose-dependent, long-lasting neuroplasticity of glutamate synapses of DA neurons ex vivo in the ventral tegmental area (VTA). Increased ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate ratio and rectification of AMPA receptor responses even at 6 days after GAN administration suggested persistent synaptic targeting of GluA2-lacking AMPA receptors. This glutamate neuroplasticity was not observed in GABAA receptor ?-subunit-knockout (?-KO) mice. GAN (500?nM) applied locally to VTA selectively increased tonic inhibition of GABA interneurons and triggered potentiation of DA neurons within 4?h in vitro. Place-conditioning experiments in adult wild-type C57BL/6J and ?-KO mice revealed aversive properties of repeated GAN administration that were dependent on the ?-subunits. Prolonged neuroadaptation to neurosteroids in the VTA might contribute to both the physiology and pathophysiology underlying processes and changes in motivation, mood, cognition, and drug addiction. PMID:24077066

  13. GABAAergic inhibition or dopamine denervation of the A11 hypothalamic nucleus induces trigeminal analgesia.

    PubMed

    Abdallah, Khaled; Monconduit, Lénaic; Artola, Alain; Luccarini, Philippe; Dallel, Radhouane

    2015-04-01

    Descending pain-modulatory systems, either inhibitory or facilitatory, play a critical role in both acute and chronic pain. Compared with serotonin and norepinephrine, little is known about the function of dopamine (DA). We characterized the anatomical organization of descending DA pathways from hypothalamic A11 nuclei to the medullary dorsal horn (MDH) and investigated their role in trigeminal pain. Immunochemistry analysis reveals that A11 is a heterogeneous nucleus that contains at least 3 neuronal phenotypes, DA, GABA, and alpha-calcitonin gene-related peptide (?-CGRP) neurons, exhibiting different distribution patterns, with a large proportion of GABA relative to DA neurons. Using fluorogold, we show that descending pathways from A11 nuclei to MDH originate mainly from DA neurons and are bilateral. Facial nociceptive stimulation elevates Fos immunoreactivity in both ipsilateral and contralateral A11 nuclei. Fos immunoreactivity is not detected in DA or projecting neurons but, interestingly, in GABA neurons. Finally, inactivating A11, using muscimol, or partially lesioning A11 DA neurons, using the neurotoxin 6-hydroxydopamine, inhibits trigeminal pain behavior. These results show that A11 nuclei are involved in pain processing. Interestingly, however, pain seems to activate GABAergic neurons within A11 nuclei, which suggests that pain inhibits rather than activates descending DA controls. We show that such inhibition produces an antinociceptive effect. Pain-induced inhibition of descending DA controls and the resulting reduced DA concentration within the dorsal horn may inhibit the transfer of nociceptive information to higher brain centers through preferential activation of dorsal horn D2-like receptors. PMID:25790455

  14. Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

    PubMed Central

    Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud

    2011-01-01

    Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. PMID:22174933

  15. Increased physical activity severely induces osteoarthritic changes in knee joints with papain induced sulfate-glycosaminoglycan depleted cartilage

    PubMed Central

    2014-01-01

    Introduction Articular cartilage needs sulfated-glycosaminoglycans (sGAGs) to withstand high pressures while mechanically loaded. Chondrocyte sGAG synthesis is regulated by exposure to compressive forces. Moderate physical exercise is known to improve cartilage sGAG content and might protect against osteoarthritis (OA). This study investigated whether rat knee joints with sGAG depleted articular cartilage through papain injections might benefit from moderate exercise, or whether this increases the susceptibility for cartilage degeneration. Methods sGAGs were depleted from cartilage through intraarticular papain injections in the left knee joints of 40 Wistar rats; their contralateral joints served as healthy controls. Of the 40 rats included in the study, 20 rats remained sedentary, and the other 20 were subjected to a moderately intense running protocol. Animals were longitudinally monitored for 12 weeks with in vivo micro-computed tomography (?CT) to measure subchondral bone changes and single-photon emission computed tomography (SPECT)/CT to determine synovial macrophage activation. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced ?CT and histology to measure sGAG content and cartilage thickness. Results All outcome measures were unaffected by moderate exercise in healthy control joints of running animals compared with healthy control joints of sedentary animals. Papain injections in sedentary animals resulted in severe sGAG-depleted cartilage, slight loss of subchondral cortical bone, increased macrophage activation, and osteophyte formation. In running animals, papain-induced sGAG-depleted cartilage showed increased cartilage matrix degradation, sclerotic bone formation, increased macrophage activation, and more osteophyte formation. Conclusions Moderate exercise enhanced OA progression in papain-injected joints and did not protect against development of the disease. This was not restricted to more-extensive cartilage damage, but also resulted in pronounced subchondral sclerosis, synovial macrophage activation, and osteophyte formation. PMID:24472689

  16. Experimentally induced depletion of germ cells in sub-adult Patagonian pejerrey (Odontesthes hatcheri).

    PubMed

    Majhi, S K; Hattori, R S; Rahman, Sk M; Suzuki, T; Strüssmann, C A

    2009-04-15

    Germ cell (GC) transplantation (GCT) is a novel reproductive technology with application in seed production and conservation of endangered species. This study examined the suitability of treatment with Busulfan, a cytotoxic agent, and warm water, known to cause GC degeneration, for depletion of endogenous GCs in sub-adult Patagonia pejerrey Odontesthes hatcheri intended as hosts in GCT. In two experiments, fish were treated with six combinations of temperature (intermediate and high, 20 and 25 degrees C, respectively) and Busulfan (0, 20, and 40 mg/kg body weight), given intraperitoneally (ip) as a single (0 week) or repeated (0 and 4 week) dose. The effectiveness of the treatments was assessed by gonado-somatic index, histology, and (germ cell-specific) vasa gene expression after 8 weeks. Fish were allowed to recover at 17 degrees C for 4-8 weeks after the treatments to ascertain the permanency of the effects. The high temperature (25 degrees C) alone induced only incipient gonadal degeneration and germ cell loss, but was highly effective in combination with double administration of 40 mg/kg Busulfan. Males tolerated Busulfan better and were more easily depleted of germ cells than females. Animals treated for 8 weeks were severely devoid of germ cells, but were still capable of gametogenesis. Thus, the combination of Busulfan and high water temperature appeared to be efficient for depletion of GCs in adult fish; and the treated gonads retained the ability to support GC proliferation and differentiation. Furthermore, quantitative analysis of vasa transcript levels was found to be an useful to monitor the degree of gonad sterility during treatment. PMID:19168208

  17. Mutations at Tyrosine 88, Lysine 92 and Tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport

    PubMed Central

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

    2015-01-01

    HIV-1 transactivator of transcription (Tat) protein disrupts the dopamine (DA) neurotransmission by inhibiting DA transporter (DAT) function, leading to increased neurocognitive impairment in HIV-1 infected individuals. Through integrated computational modeling and pharmacological studies, we have demonstrated that mutation of tyrosine470 (Y470H) of human DAT (hDAT) attenuates Tat-induced inhibition of DA uptake by changing the transporter conformational transitions. The present study examined the functional influences of other substitutions at tyrosine470 (Y470F and Y470A) and tyrosine88 (Y88F) and lysine92 (K92M), two other relevant residues for Tat binding to hDAT, in Tat-induced inhibitory effects on DA transport. Y88F, K92M and Y470A attenuated Tat-induced inhibition of DA transport, implicating the functional relevance of these residues for Tat binding to hDAT. Compared to wild type hDAT, Y470A and K92M but not Y88F reduced the maximal velocity of [3H]DA uptake without changes in the Km. Y88F and K92M enhanced IC50 values for DA inhibition of [3H]DA uptake and [3H]WIN35,428 binding but decreased IC50 for cocaine and GBR12909 inhibition of [3H]DA uptake, suggesting that these residues are critical for substrate and these inhibitors. Y470F, Y470A, Y88F and K92M attenuated zinc-induced increase of [3H]WIN35,428 binding. Moreover, only Y470A and K92M enhanced DA efflux relative to wild type hDAT, suggesting mutations of these residues differentially modulate transporter conformational transitions. These results demonstrate Tyr88 and Lys92 along with Tyr470 as functional recognition residues in hDAT for Tat-induced inhibition of DA transport and provide mechanistic insights into identifying target residues on the DAT for Tat binding. PMID:25604666

  18. Type I Interferon Contributes to CD4+ T Cell Depletion Induced by Infection with HIV-1 in the Human Thymus?

    PubMed Central

    Sivaraman, Vijay; Zhang, Liguo; Su, Lishan

    2011-01-01

    Persistent induction of type 1 interferon (IFN) is associated with human immunodeficiency virus type 1 (HIV-1) infection. We report here that the pathogenic HIV strain R3A (HIV-R3A) induced high levels of type 1 IFN, while the nonpathogenic HIV-R3B showed no significant induction in human fetal thymus organ culture (HFTOC). We found that IFN contributed to the depletion of human T cells by HIV-R3A in a fusion-independent fashion. The R3B recombinant with the R3A Env V1V2 domain (R3B/A-V1V2) was able to induce type 1 IFN, which contributed to the increased depletion of T cells. Therefore, type 1 IFN induction plays a significant role in HIV-induced T cell depletion in the human thymus. PMID:21697497

  19. Experimental system to search for induced depletion of 108mAg

    NASA Astrophysics Data System (ADS)

    Mills, Isaac; Harle, Thomas; Trees, Geoffrey; Carroll, James

    2008-10-01

    Nuclear isomers may provide high density energy storage media for specialized batteries. The key would be to identify a way to release the stored energy when desired, by depleting the isomer population. Existing nuclear data [1] suggest that an induced depletion of the 418 year isomer ^108mAg may be possible, caused by providing an input of 255 keV or 413 keV. The result would be production of additional ground state nuclei with a half-life of 2.37 minutes, leading to beta decay. An experiment has been designed to measure beta decay of ^108mAg after exposure of an isomeric sample to 450 keV bremsstrahlung. Because beta particles are attenuated by air, a clean vacuum chamber was assembled with which to use a Si(Li) detector. The aim of this experiment is to observe an increased rate of beta decay after several minutes of direct exposure to bremsstrahlung radiation. [1] F. R. Espinoza-Quinones, et al., Phys. Rev. C 52, 104 (1995).

  20. Phagocyte depletion inhibits AA amyloid accumulation in AEF-induced huIL-6 transgenic mice

    PubMed Central

    Kennel, Stephen J.; Macy, Sallie; Wooliver, Craig; Huang, Ying; Richey, Tina; Heidel, Eric; Wall, Jonathan S.

    2014-01-01

    OBJECTIVE Determine the role of phagocytosis in the deposition of acute phase SAA protein in peripheral organs as AA amyloid. METHODS AA amyloidosis was induced by injection of amyloid enhancing factor (AEF) in huIL-6 transgenic mice. Clodronate liposomes were injected at different times, and the amyloid load evaluated by Congo red birefringence staining and monitoring with the amyloid specific probe 125I-labeled peptide p5R. RESULTS Injection of clodronate containing liposomes depleted Iba-1 positive and F4/80 positive phagocytic cells in liver and spleen for up to 5 days. Treatment prior to administration of intravenous AEF did not alter the pattern of deposition of the AEF in spleen, but inhibited the catabolism of the 125I-labeled AEF. Clodronate treatment 1 day before or 1 day after AEF administration had little effect on AA amyloid accumulation at 2 weeks; however, mice treated with clodronate liposomes 5 days after AEF induction and evaluated at 2 weeks post AEF induction showed reduced amyloid load relative to controls. At 6 weeks post-AEF there was no significant effect on amyloid load following a single clodronate treatment. CONCLUSION Macrophages have been shown to be instrumental in both accumulation and clearance of AA amyloid after cessation of inflammation. Our data indicate that when SAA protein is continuously present, depletion of phagocytic cells during the early course of the disease progression temporarily reduces amyloid load. PMID:24446872

  1. Dopamine denervation does not alter in vivo /sup 3/H-spiperone binding in rat striatum: implications for external imaging of dopamine receptors in Parkinson's disease

    SciTech Connect

    Bennett, J.P. Jr.; Wooten, G.F.

    1986-04-01

    Striatal particulate preparations, both from rats with lesion-induced striatal dopamine (DA) loss and from some striatal dopamine (DA) loss and from some patients with Parkinson's disease, exhibit increased /sup 3/H-neuroleptic binding, which is interpreted to be the mechanism of denervation-induced behavioral supersensitivity to dopaminergic compounds. After intravenous /sup 3/H-spiperone (/sup 3/H-SP) administration to rats with unilateral nigral lesions, we found no differences in accumulation of total or particulate-bound /sup 3/H-SP in dopamine-denervated compared with intact striata. /sup 3/H-SP in vivo binds to less than 10% of striatal sites labeled by /sup 3/H-SP incubated with striatal particulate preparations in vitro. Quantitative autoradiography of /sup 3/H-SP binding to striatal sections in vitro also failed to reveal any effects of dopamine denervation. /sup 3/H-SP bound to striatal sites in vivo dissociates more slowly than that bound to striatal particulate preparations labeled in vitro. Striatal binding properties of /sup 3/H-SP administered in vivo are quite different from the same kinetic binding parameters estimated in vitro using crude membrane preparations of striatum. In addition, striatal binding of in vivo-administered 3H-SP is not affected by prior lesion of the substantia nigra, which results in profound ipsilateral striatal dopamine depletion. Thus, behavioral supersensitivity to dopaminergic compounds may not be associated with altered striatal binding properties for dopamine receptor ligands in vivo.

  2. Dopamine agonist-induced penile erection and yawning: a comparative study in outbred Roman high- and low-avoidance rats.

    PubMed

    Sanna, Fabrizio; Corda, Maria Giuseppa; Melis, Maria Rosaria; Piludu, Maria Antonietta; Löber, Stefan; Hübner, Harald; Gmeiner, Peter; Argiolas, Antonio; Giorgi, Osvaldo

    2013-08-01

    The effects on penile erection and yawning of subcutaneous (SC) injections of the mixed dopamine D1/D2-like agonist apomorphine (0.02-0.2 mg/kg) were studied in outbred Roman high- (RHA) and low-avoidance (RLA) male rats, two lines selectively bred for their respectively rapid versus poor acquisition of the active avoidance response in the shuttle-box, and compared with the effects observed in male Sprague-Dawley (SD) rats. Apomorphine dose-response curves were bell-shaped in all rat lines/strains. Notably, more penile erections and yawns were recorded mainly in the ascending part of these curves (e.g., apomorphine 0.02-0.08 mg/kg) in both RLA and RHA rats compared to SD rats, with RLA rats showing the higher response (especially for yawning) with respect to RHA rats. Similar results were found with PD-168,077 (0.02-0.2 mg/kg SC), a D4 receptor agonist, which induced penile erection but not yawning. In all rat lines/strains, apomorphine responses were markedly reduced by the D2 antagonist L-741,626, but not by the D3 antagonist, SB277011A, whereas the D4 antagonists L-745,870 and FAUC213 elicited a partial, yet statistically significant, inhibitory effect. In contrast, the pro-erectile effect of PD-168,077 was completely abolished by L-745,870 and FAUC213, as expected. The present study confirms and extends previously reported differences in dopamine transmission between RLA and RHA rats and between the SD strain and the Roman lines. Moreover, it confirms previous studies supporting the view that dopamine receptors of the D2 subtype play a predominant role in the pro-yawning and pro-erectile effect of apomorphine, and that the selective stimulation of D4 receptors induces penile erection. PMID:23664901

  3. Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography Study

    PubMed Central

    Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M. A.; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

    2013-01-01

    Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by ?9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of ?9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after ?9-THC administration, reflecting dopamine release. While ?9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by ?9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to ?9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID:23936196

  4. Prepulses Inhibit Startle-Induced Reductions of Extracellular Dopamine in the Nucleus Accumbens of Rat

    Microsoft Academic Search

    Trevor Humby; Lawrence S. Wilkinson; Trevor W. Robbins; Mark A. GeyeP

    1996-01-01

    In viva brain microdialysis was used to monitor extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of rats during exposure to startling acoustic stimuli. Ten rats were prepared with guide cannulae into which dialysis probes were inserted 1 d before testing. Two to three hours after the start of perfusion, rats were placed into the startle chamber and

  5. Light-induced dopamine release from teleost retinas acts as a light-adaptive signal to the retinal pigment epithelium.

    PubMed

    Dearry, A; Burnside, B

    1989-09-01

    In the retinal pigment epithelium (RPE) of lower vertebrates, melanin pigment granules migrate in and out of the cells' long apical projections in response to changes in light condition. When the RPE is in its normal association with the retina, light onset induces pigment granules to disperse into the apical projections; dark onset induces pigment granules to aggregate into the cell bodies. However, when the RPE is separated from the retina, pigment granule movement in the isolated RPE is insensitive to light onset. It thus seems likely that a signal from the retina communicates light onset to the RPE to initiate pigment dispersion. We have examined the nature of this retina-to-RPE signal in green sunfish, Lepomis cyanellus. In isolated retinas with adherent RPE, light-induced pigment dispersion in the RPE is blocked by treatments known to block Ca2+-dependent transmitter release in the retina. In addition, the medium obtained from incubating previously dark-adapted retinas in the light induces light-adaptive pigment dispersion when added to isolated RPE. In contrast, the medium obtained from incubating dark-adapted retinas in constant darkness does not affect pigment distribution when added to isolated RPE. These results are consistent with the idea that RPE pigment dispersion is triggered by a substance that diffuses from the retina at light onset. The capacity of the conditioned medium from light-incubated retinas to induce pigment dispersion in isolated RPE is inhibited by a D2 dopamine antagonist, but not by D1 or alpha-adrenergic antagonists. Light-induced pigment dispersion in whole RPE-retinas is also blocked by a D2 dopamine antagonist.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2547905

  6. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

    PubMed Central

    Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from ? (0.1–4 Hz) to ? (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes significant neurophysiological changes, but does not promote behavioral arousal during general anesthesia. We hypothesize that dextroamphetamine is more likely than atomoxetine to be clinically useful for restoring consciousness in anesthetized patients, mainly due to its stimulation of dopaminergic neurotransmission. PMID:26148114

  7. Depletion induced clustering in mixtures of colloidal spheres and fd-virus.

    PubMed

    Guu, D; Dhont, J K G; Vliegenthart, G A; Lettinga, M P

    2012-11-21

    We determined the phase boundary of an ideal rod-sphere mixture consisting of fd-virus, which is an established model system for mono-disperse colloidal rods, and density matched mono-disperse polystyrene beads employing diffuse wave spectroscopy. The low volume fraction of fd needed to induce a phase separation at relatively low ionic strength exemplifies the fact that slender rods are very effective depletion agents. Confocal microscopy showed that stable clusters are formed during phase separation. Relaxation after shear deformation of these clusters showed that the phase separation is gas-liquid-like and that the interfacial tension involved is very low as in colloid-polymer mixtures. PMID:23114036

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

    SciTech Connect

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

    1996-05-01

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

  9. Cannabidiol hydroxyquinone-induced apoptosis of splenocytes is mediated predominantly by thiol depletion.

    PubMed

    Wu, Hsin-Ying; Jan, Tong-Rong

    2010-05-19

    Cannabidiol, the major nonpsychotropic phytocannabinoid, has been recently demonstrated to induce apoptosis in primary lymphocytes via an oxidative stress-dependent mechanism. Cannabidiol can be converted by microsomal enzymes to the hydroxyquinone metabolite HU-331 that forms adducts with glutathione. The present study tested the hypothesis that HU-331 could cause apoptosis via the depletion of thiols in splenocytes. Our results showed that HU-331 treatment significantly enhanced splenocyte apoptosis in a time- and concentration-dependent manner. Concordantly, a gradual diminishment in the cellular thiols and glutathione was detected in HU-331-treated splenocytes. The apoptosis and thiol diminishment induced by HU-331 were abrogated in the presence of thiol antioxidants, including N-acetyl-(L)-cysteine and N-(2-mercaptopropionyl) glycine, whereas the non-thiol antioxidants catalase and pyruvate were ineffective. In comparison, both thiol and non-thiol antioxidants were capable of attenuating H(2)O(2)-induced thiol diminishment and reactive oxygen species generation in splenocytes. Collectively, these results suggest that HU-331 might be an active metabolite of cannabidiol potentially contributing to the induction of apoptosis in splenocytes, and that the apoptosis is primarily mediated by the loss of cellular thiols. PMID:20184945

  10. Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease.

    PubMed

    Sgambato-Faure, Véronique; Cenci, Maria Angela

    2012-01-01

    Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia. PMID:22075179

  11. The Dopamine Metabolite 3-Methoxytyramine Is a Neuromodulator

    PubMed Central

    Sotnikova, Tatyana D.; Beaulieu, Jean-Martin; Espinoza, Stefano; Masri, Bernard; Zhang, Xiaodong; Salahpour, Ali; Barak, Larry S.; Caron, Marc G.; Gainetdinov, Raul R.

    2010-01-01

    Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia. PMID:20976142

  12. The dopamine metabolite 3-methoxytyramine is a neuromodulator.

    PubMed

    Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Espinoza, Stefano; Masri, Bernard; Zhang, Xiaodong; Salahpour, Ali; Barak, Larry S; Caron, Marc G; Gainetdinov, Raul R

    2010-01-01

    Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia. PMID:20976142

  13. Depleted uranium–uranyl chloride induces apoptosis in mouse J774 macrophages

    Microsoft Academic Search

    John F Kalinich; Narayani Ramakrishnan; Vilmar Villa; David E McClain

    2002-01-01

    Depleted uranium entering the body as a result of inhalation or embedded fragments becomes associated to a great extent with macrophages. As part of our continuing studies on the health effects of internalized depleted uranium, we investigated the effect of soluble depleted uranium–uranyl chloride on the mouse macrophage cell line, J774. Using a cytochemical staining protocol specific for uranium, we

  14. Coronin 1A depletion protects endothelial cells from TNF?-induced apoptosis by modulating p38? expression and activation.

    PubMed

    Kim, Geun-Young; Kim, Hanna; Lim, Hyun-Joung; Park, Hyun-Young

    2015-09-01

    Coronins are conserved actin-binding proteins that regulate various cellular processes such as migration and endocytosis. Among coronin family members, coronin 1A is highly expressed in hematopoietic lineage cells where it regulates cell homeostasis. However, the expression and function of coronin 1A in endothelial cells have not yet been elucidated. We found that coronin 1A is expressed in the human umbilical vein endothelial cell (HUVEC) and human brain microvascular endothelial cell (HBMVEC). In HUVEC depleted of coronin 1A by siRNA transfection, tumor necrosis factor ? (TNF?)+cyclohexamide (CHX) treatment resulted in a decrease in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells. Coronin 1A depletion also resulted in the suppression of caspase 3 and poly(ADP-ribose) polymerase cleavage and a reduction in caspase 3 activity. Next, we examined TNF?-induced activation of several pro- and anti-apoptotic signaling molecules to find the target molecule of coronin 1A and found that p38 phosphorylation was enhanced by TNF? stimulation in coronin 1A-depleted HUVEC. Among the p38 isoforms, the expression of p38? was significantly upregulated after coronin 1A depletion, suggesting that the expression and phosphorylation of anti-apoptotic p38? were significantly induced in coronin 1A-depleted HUVEC. Inhibition of p38? upregulation in coronin 1A-depleted HUVEC restored the cleavage of caspase 8 and caspase 3 and induced more apoptosis than in coronin 1A-depleted HUVEC in response to TNF?+CHX. These findings suggest that coronin 1A modulates endothelial cell apoptosis by regulating p38? expression and activation. PMID:25936522

  15. Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen–glucose depletion

    PubMed Central

    Wu, X; Kihara, T; Hongo, H; Akaike, A; Niidome, T; Sugimoto, H

    2010-01-01

    BACKGROUND AND PURPOSE Several clinical trials and in vivo animal experiments have suggested that blockade of angiotensin receptor type 1 (AT1) improves ischaemic outcomes. However, the mechanism(s) underlying these effects has not been elucidated. Here, we have investigated the protective effects of pretreatment with AT1 receptor antagonists, losartan or telmisartan, against ischaemic insult to neurons in vitro. EXPERIMENTAL APPROACH Primary rat neuron–astrocyte co-cultures and astrocyte-defined medium (ADM)-cultured pure astrocyte cultures were prepared. Ischaemic injury was modelled by oxygen–glucose depletion (OGD) and lactate dehydrogenase release after OGD was measured with or without AT1 receptor antagonists or agonists (L162313), AT2 receptor antagonist (PD123319) or agonist (CGP-42112A) pretreatment, for 48 h. Activity of glutamate transporter 1 (GLT-1) was evaluated by [3H]-glutamate uptake assays, after AT1 receptor agonists or antagonists. Immunoblot and real-time PCR were used for analysis of protein and mRNA levels of GLT-1. KEY RESULTS AT1 receptor agonists augmented OGD-induced cellular damage, which was attenuated by AT1 receptor antagonists. AT1 receptor antagonists also suppressed OGD-induced extracellular glutamate release, reactive oxygen species production and nitric oxide generation. GLT-1 expression and glutamate uptake activity were significantly enhanced by AT1 receptor antagonists and impaired by AT1 receptor agonists. AT1 receptor stimulation suppressed both ADM-induced GLT-1 protein expression and mRNA levels. AT1b receptor knock-down with siRNA enhanced GLT-1 expression. In postnatal (P1–P21) rat brains, protein levels of GLT-1 and AT1 receptors were inversely correlated. CONCLUSIONS AND IMPLICATIONS Suppression of AT1 receptor stimulation induced GLT-1 up-regulation, which ameliorated effects of ischaemic injury. PMID:20718738

  16. Depletion-induced Oligomerization of Stromal Interaction Molecule 1 (STIM1) via the EF-SAM Region

    E-print Network

    Ikura, Mitsuhiko

    ). The molecular mecha- nisms initiating ER STIM1 redistribution and plasma mem- brane CRAC activity are not well initiating STIM1 punctae formation via large conformational changes. The low Ca2 affinity of EFStored Ca2 Depletion-induced Oligomerization of Stromal Interaction Molecule 1 (STIM1) via the EF

  17. Glutathione depletion or radiation treatment alters respiration and induces apoptosis in R3230Ac mammary carcinoma.

    PubMed

    Biaglow, John E; Lee, Intae; Donahue, Jerry; Held, Kathy; Mieyal, John; Dewhirst, Mark; Tuttle, Steve

    2003-01-01

    Glutathione depletion by L-buthionine sulfoximine inhibits the growth of Ehrlich mouse mammary carcinoma, R3230Ac rat mammary carcinoma and the PC3 human prostrate carcinoma cells, in vitro. Inhibition of growth occurs within the first 24 hours after exposure to the drug. The cell density does not increase over the initial cell density over 7 days. A549 human lung carcinoma and the DU145 human prostrate carcinoma cells show no inhibition of growth under the same treatment conditions. A comparative study of the R323OAc and A549 cells demonstrated a marked increase in apoptosis following L-BSO treatment in R3230Ac, which was dependent on L-BSO concentration and incubation time. L-BSO did not induce apoptosis in A549 cells at any of the concentrations tested. The incidence of apoptosis for R323OAc cells following exposure to 0.1 mM L-BSO was similar to the incidence of radiation-induced apoptosis observed after exposure to 10 Gy. Treatment with L-BSO or radiation alone inhibited O2 utilization in of R323Oac, while no effect on O2 utilization was observed in A549 cells. LBSO altered the bioreductive capacity of both the R323OAc and A549 cells. These results suggest that the ability of L-BSO to block mitochondrial O2 utilization may be involved in the apoptotic response in R3230Ac cells. PMID:14562713

  18. Delta-tocotrienol induces apoptotic cell death via depletion of intracellular squalene in ED40515 cells.

    PubMed

    Yamasaki, Masao; Nishimura, Misato; Sakakibara, Yoichi; Suiko, Masahito; Morishita, Kazuhiro; Nishiyama, Kazuo

    2014-11-01

    Here, we examined the effect of tocotrienols (T3) on the growth of adult T-cell leukemia (ATL) cells. All three forms (?-, ?-, and ?-T3) inhibited cell proliferation in a dose-dependent manner; ?-T3 showed the strongest growth-inhibitory effect. ?-T3 increased the G1, G2/M, and subG1 populations and induced internucleosomal DNA fragmentation. ?-T3 treatment also increased the levels of cleaved caspase-3, -6, -7, -9, and poly-ADP ribose polymerase (PARP), and this was accompanied by downregulation of Bcl-2, Bcl-xL, and XIAP. Moreover, ?-T3 decreased nuclear p65 NF-?B levels, indicating downregulation of NF-?B activity. This cytotoxic effect of ?-T3 was abrogated by squalene (SQL) but not mevalonate (MVL), farnesyl diphosphate (FPP), geranylgeranyl diphosphate (GGPP), or cholesterol (CL). ?-T3 decreased intracellular SQL levels, and inhibition of de novo cholesterol synthesis did not affect the action of SQL. Furthermore, ?-T3 significantly decreased farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. Taken together, it is evident that ?-T3, due to its ability to potently induce apoptosis via the depletion of intracellular SQL, shows the potential to be considered a therapeutic agent in patients with ATL. PMID:25225850

  19. Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

    Microsoft Academic Search

    Dongsheng Zhang; Lu Zhang; Yang Tang; Qi Zhang; Danwen Lou; Frank R Sharp; Jianhua Zhang; Ming Xu; M Xu

    2005-01-01

    Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects

  20. Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen

    PubMed Central

    Weitemier, Adam; Inoue, Masato

    2015-01-01

    In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses. PMID:26110516

  1. Suppression of Ethanol-Reinforced Behavior by Naltrexone Is Associated with Attenuation of the Ethanol-Induced Increase in Dialysate Dopamine Levels in the Nucleus Accumbens

    Microsoft Academic Search

    Rueben A. Gonzales; Friedbert Weiss

    The opiate antagonist naltrexone suppresses ethanol- reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simulta- neous measures of the effects

  2. Reduction of Reactive Oxygen Species Prevents Hypoxia-Induced CREB Depletion in Pulmonary Artery Smooth Muscle Cells

    PubMed Central

    Klemm, Dwight J.; Majka, Susan M.; Crossno, Joseph T.; Psilas, John C.; Reusch, Jane E.B.; Garat, Chrystelle V.

    2011-01-01

    Hypoxia-induced pulmonary arterial hypertension (PAH) is a deadly disease characterized by progressive remodeling and persistent vasoconstriction of the pulmonary arterial (PA) system. Remodeling of the PA involves smooth muscle cell (SMC) proliferation, hypertrophy, migration and elevated extracellular matrix (ECM) production elicited by mitogens and oxidants produced in response to hypoxic insult. We previously reported that the transcription factor CREB is depleted in medial PA SMCs in remodeled, hypertensive vessels in rats or calves exposed to chronic hypoxia. In culture, CREB loss can be induced in PA SMCs by exogenous oxidants or PDGF. Forced depletion of CREB with siRNA in PA SMCs is sufficient to induce their proliferation, hypertrophy, migration, dedifferentiation and ECM production. This suggests that oxidant and/or mitogen-induced loss of CREB in medial SMCs is, in part, responsible for PA thickening. Here we tested whether oxidant scavengers could prevent loss of CREB in PA SMCs, and inhibit SMC proliferation, migration and ECM production using in vitro and in vivo models. Exposure of PA SMCs to hypoxia induced H2O2 production and loss of CREB. Treatment of SMCs with exogenous H2O2 or a second oxidant, Sin-1, elicited CREB depletion under normoxic conditions. Exogenous H2O2 also induced SMC proliferation, migration and increased elastin levels as did forced depletion of CREB. In vivo, hypoxia-induced thickening of PA wall was suppressed by the superoxide dismutase mimetic, Tempol, which also prevented loss of CREB in medial SMCs. Tempol also reduced hypoxia-induced SMC proliferation and elastin deposition in the PA. The data indicate that CREB levels in the arterial wall are regulated in part by oxidants produced in response to hypoxia, and that CREB plays a crucial role in regulating SMC phenotype and PA remodeling. PMID:21562428

  3. Acetaminophen-Induced Hepatic Necrosis V. Correlation of Hepatic Necrosis, Covalent Binding and Glutathione Depletion in Hamsters

    Microsoft Academic Search

    W. Z. Potter; S. S. Thorgeirsson; D. J. Jollow; J. R. Mitchell

    1974-01-01

    We previously postulated that acetaminophen-induced hepatic necrosis in mice results from the formation of a reactive metabolite that arylates vital cellular macro-molecules. While studying species differences in susceptibility to acetaminophen-induced hepatic necrosis, hamsters were found to be particularly vulnerable. We now report the relationships between hepatic glutathione depletion, arylation of hepatic macromolecules in vivo and in vitro and hepatic necrosis

  4. Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease

    PubMed Central

    Sahin, Gurdal; Thompson, Lachlan H.; Lavisse, Sonia; Ozgur, Merve; Rbah-Vidal, Latifa; Dollé, Frédéric

    2014-01-01

    Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease. PMID:24614598

  5. Human Neural Stem Cells Survive Long Term in the Midbrain of Dopamine-Depleted Monkeys After GDNF Overexpression and Project Neurites Toward an Appropriate Target

    PubMed Central

    Wakeman, Dustin R.; Dodiya, Hemraj B.; Sladek, John R.; Leranth, Csaba; Teng, Yang D.; Samulski, R. Jude

    2014-01-01

    Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%–5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression of a developmentally critical molecule, glial cell-derived neurotrophic factor (GDNF), in the host striatum could enhance DA differentiation of hfNSCs injected into the substantia nigra and elicit growth of their axons to the GDNF-expressing target. hfNSCs were transplanted into the midbrain of 10 green monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. GDNF was delivered concomitantly to the striatum via an adeno-associated virus serotype 5 vector, and the fate of grafted cells was assessed after 11 months. Donor cells remained predominantly within the midbrain at the injection site and sprouted numerous neurofilament-immunoreactive fibers that appeared to course rostrally toward the striatum in parallel with tyrosine hydroxylase-immunoreactive fibers from the host substantia nigra but did not mature into DA neurons. This work suggests that hfNSCs can generate neurons that project long fibers in the adult primate brain. However, in the absence of region-specific signals and despite GDNF overexpression, hfNSCs did not differentiate into mature DA neurons in large numbers. It is encouraging, however, that the adult primate brain appeared to retain axonal guidance cues. We believe that transplantation of stem cells, specifically instructed ex vivo to yield DA neurons, could lead to reconstruction of some portion of the nigrostriatal pathway and prove beneficial for the parkinsonian condition. PMID:24744393

  6. Protective effects of flavonol isoquercitrin, against 6-hydroxy dopamine (6-OHDA) - induced toxicity in PC12 cells

    PubMed Central

    2014-01-01

    Background Free radicals-induced neurodegeneration is one of the many causes of Parkinson’s disease (PD). This study investigated the neuroprotective effects of flavonol isoquercitrin against toxicity induced by 6-hydroxy-dopamine (6-OHDA) in rat pheochromocytoma (PC12) cells. Methods PC12 cells were pretreated with different concentrations of isoquercitrin for 4, 8 and 12 hours and incubated with 6-OHDA for 24 hours to induce oxidative cell damage. Results A significant cytoprotective activity was observed in isoquercitrin pre-treated cells in a dose-dependent manner. There was a significant increase (P < 0.01) in the antioxidant enzymes namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione in isoquercitrin pretreated cells compared to cells incubated with 6-OHDA alone. Isoquercitrin significantly reduced (P < 0.01) lipid peroxidation in 6-OHDA treated cells. These results suggested that isoquercitrin protects PC 12 cells against 6-OHDA–induced oxidative stress. Conclusions The present study suggests the protective role of isoquercitrin on 6-hydroxydopamine-induced toxicity by virtue of its antioxidant potential. Isoquercitrin could be a potential therapeutic agent against neurodegeneration in Parkinson’s disease. PMID:24443837

  7. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: ?-ketoamphetamine modulation of neurotoxicity by the dopamine transporter.

    PubMed

    Anneken, John H; Angoa-Pérez, Mariana; Kuhn, Donald M

    2015-04-01

    Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as ?-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the ?-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The ?-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that ?-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release DA from cytoplasmic pools selectively. When METH is combined with METHY or MEPH (c), DA efflux and neurotoxicity are enhanced. MDPV (d), which is a non-substrate blocker of the DAT, prevents METH uptake and efflux of DA. Therefore, bath salts that are substrates for the DAT and release DA (METHY, MEPH) accentuate METH neurotoxicity, whereas those that are non-substrate blockers of the DAT (MDPV) are neuroprotective. PMID:25626880

  8. Lycopene Pretreatment Ameliorates Acute Ethanol Induced NAD+ Depletion in Human Astroglial Cells

    PubMed Central

    Guest, Jade; Heng, Benjamin; Grant, Ross

    2015-01-01

    Excessive alcohol consumption is associated with reduced brain volume and cognition. While the mechanisms by which ethanol induces these deleterious effects in vivo are varied most are associated with increased inflammatory and oxidative processes. In order to further characterise the effect of acute ethanol exposure on oxidative damage and NAD+ levels in the brain, human U251 astroglioma cells were exposed to physiologically relevant doses of ethanol (11?mM, 22?mM, 65?mM, and 100?mM) for ? 30 minutes. Ethanol exposure resulted in a dose dependent increase in both ROS and poly(ADP-ribose) polymer production. Significant decreases in total NAD(H) and sirtuin 1 activity were also observed at concentrations ? 22?mM. Similar to U251 cells, exposure to ethanol (?22?mM) decreased levels of NAD(H) in primary human astrocytes. NAD(H) depletion in primary astrocytes was prevented by pretreatment with 1??M of lycopene for 3.5 hours. Unexpectedly, in U251 cells lycopene treatment at concentrations ? 5??M resulted in significant reductions in [NAD(H)]. This study suggests that exposure of the brain to alcohol at commonly observed blood concentrations may cause transitory oxidative damage which may be at least partly ameliorated by lycopene.

  9. Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

    Microsoft Academic Search

    Hanna S Lindgren; K Elisabet Ohlin; M Angela Cenci

    2009-01-01

    Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis

  10. Depletion of SMN by RNA interference in HeLa cells induces defects in Cajal body formation

    PubMed Central

    Girard, Cyrille; Neel, Henry; Bertrand, Edouard; Bordonné, Rémy

    2006-01-01

    Neuronal degeneration in spinal muscular atrophy (SMA) is caused by reduced expression of the survival of motor neuron (SMN) protein. The SMN protein is ubiquitously expressed and is present both in the cytoplasm and in the nucleus where it localizes in Cajal bodies. The SMN complex plays an essential role for the biogenesis of spliceosomal U-snRNPs. In this article, we have used an RNA interference approach in order to analyse the effects of SMN depletion on snRNP assembly in HeLa cells. Although snRNP profiles are not perturbed in SMN-depleted cells, we found that SMN depletion gives rise to cytoplasmic accumulation of a GFP-SmB reporter protein. We also demonstrate that the SMN protein depletion induces defects in Cajal body formation with coilin being localized in multiple nuclear foci and in nucleolus instead of canonical Cajal bodies. Interestingly, the coilin containing foci do not contain snRNPs but appear to co-localize with U85 scaRNA. Because Cajal bodies represent the location in which snRNPs undergo 2?-O-methylation and pseudouridylation, our results raise the possibility that SMN depletion might give rise to a defect in the snRNA modification process. PMID:16738131

  11. Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria.

    PubMed

    Shaki, Fatemeh; Hosseini, Mir-Jamal; Ghazi-Khansari, Mahmoud; Pourahmad, Jalal

    2013-06-01

    Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 ?M) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome. PMID:23629690

  12. Performance of movement in hemiparkinsonian rats influences the modifications induced by dopamine agonists in striatal efferent dynorphinergic neurons.

    PubMed

    Frau, Lucia; Morelli, Micaela; Simola, Nicola

    2013-09-01

    A previous study of our group demonstrated that movement performance induced by dopamine agonist drugs in hemiparkinsonian rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA), governs the occurrence of a sensitized motor response to a subsequent dopaminergic challenge (priming model). In the present study, we examined the influence of movement performance (rotational behavior) on the molecular events induced by priming in the striatum. To this end, unilaterally 6-OHDA-lesioned rats were primed with apomorphine (0.2 mg/kg) in immobilized or freely moving conditions (priming induction) and 3 days later the D1 receptor agonist SKF 38393 was administered (priming expression). Evaluation of striatal mRNA for enkephalin and dynorphin, markers of the indirect and direct striatonigral pathways, and of GAD67 showed an increase in dynorphin in primed SKF 38393-treated rats, no matter whether immobilized or freely moving during priming induction, whilst enkephalin and GAD67 did not show any changes. In contrast, evaluation of mRNA for the early gene zif-268 in the striatum showed a generalized increase after administration of SKF 38393, in both primed and unprimed rats. However, examination of zif-268 mRNA at the single-cell level, showed that only dynorphin(+) neurons of primed not immobilized rats displayed a significantly higher number of zif-268-positive silver grains in response to the SKF 38393 challenge. This selective activation of zif-268 in dynorphinergic striatonigral efferent neurons demonstrates that movement performance in response to dopaminergic drug administration under conditions of dopamine denervation is critical for the emergence of neurochemical modifications in selected striatal efferent neurons. Furthermore, these results may provide information on the first initial molecular events taking place in the complex processes that lead to dyskinetic movements in Parkinson's disease. PMID:23499830

  13. Quantum dots and etch-induced depletion of a silicon two-dimensional electron gas

    NASA Astrophysics Data System (ADS)

    Klein, L. J.; Lewis, K. L. M.; Slinker, K. A.; Goswami, Srijit; van der Weide, D. W.; Blick, R. H.; Mooney, P. M.; Chu, J. O.; Coppersmith, S. N.; Friesen, Mark; Eriksson, M. A.

    2006-01-01

    The controlled depletion of electrons in semiconductors is the basis for numerous devices. Reactive-ion etching provides an effective technique for fabricating both classical and quantum devices. However, Fermi-level pinning must be carefully considered in the development of small devices, such as quantum dots. Because of depletion, the electrical size of the device is reduced in comparison with its physical dimension. To investigate this issue in modulation-doped silicon single-electron transistors, we fabricate several types of devices in silicon-germanium heterostructures using two different etches, CF4 and SF6. We estimate the depletion width associated with each etch by two methods: (i) conductance measurements in etched wires of decreasing thickness (to determine the onset of depletion), and (ii) capacitance measurements of quantum dots (to estimate the size of the active region). We find that the SF6 etch causes a much smaller depletion width, making it more suitable for device fabrication.

  14. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    PubMed

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. PMID:25053279

  15. Peripheral nerve-dopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems.

    PubMed

    Collier, T J; Elsworth, J D; Taylor, J R; Sladek, J R; Roth, R H; Redmond, D E

    1994-08-01

    Previous studies of rats in our laboratory indicate that a molecule or molecules released by Schwann cells exert survival and growth-promoting effects on mesencephalic dopamine neurons. In the present study, we have begun to investigate the potential for Schwann cell augmentation of host dopamine fiber systems and embryonic dopamine neuron grafts in non-human primates. Ten adult male St Kitts African Green monkeys treated with the dopaminergic neurotoxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine one year previously, but behaviorally asymptomatic, served as hosts for implant studies. A segment of young adult monkey saphenous nerve was collected to serve as an implanted tissue source of Schwann cell-derived growth factors. Nerve was enclosed in a hollow semi-permeable polymer fiber for implantation into the lateral ventricle, with embryonic ventral mesencephalic tissue co-grafts containing developing dopamine neurons aimed at nearby locations in the caudate nucleus. Control implants consisted of an empty polymer fiber co-grafted with embryonic ventral mesencephalon. Our morphological observations indicate that while no clear augmentation of the morphology of grafted dopamine neurons attributable to co-grafted nerve was observed, this lack of influence may be related to the spatial separation of the co-grafted tissues. In contrast, some monkeys with nerve segments in the lateral ventricle exhibited increased tyrosine hydroxylase-positive fiber staining in the immediately adjacent lateral septal area and the ventricular wall of the caudate nucleus. This enhancement was not associated with empty polymer implants. Levels of dopamine and its metabolite homovanillic acid derived from tissue punches in the caudate nucleus and septal area support the view that monkeys exhibiting morphological enhancement of host dopamine systems also show biochemical increases in dopamine levels and changes in the direction of normalization of the homovanillic acid/dopamine ratio. Biochemical values from a single septal area tissue punch in one animal were an exception to this rule. This study suggests that while the utility of peripheral nerve as a source of dopamine graft augmentation in non-human primates remains to be demonstrated, grafted nerve has a stimulatory effect on host brain dopamine systems in adult, dopamine-depleted monkeys, and that this morphological effect can be dissociated from previously hypothesized injury-induced regeneration. PMID:7838385

  16. Agonist-induced desensitization of dopamine D1 receptor-stimulated adenylyl cyclase activity is temporally and biochemically separated from D1 receptor internalization.

    PubMed Central

    Ng, G Y; Trogadis, J; Stevens, J; Bouvier, M; O'Dowd, B F; George, S R

    1995-01-01

    The regulation of the dopamine D1 receptor was investigated by using c-myc epitope-tagged D1 receptors expressed in Sf9 (fall armyworm ovary) cells. Treatment of D1 receptors with 10 microM dopamine for 15 min led to a loss of the dopamine-detected high-affinity state of the receptor accompanying a 40% reduction in the ability of the receptor to mediate maximal dopamine stimulation of adenylyl cyclase activity. After 60 min of agonist exposure, 45 min after the occurrence of desensitization, 28% of the cell surface receptors were internalized into an intracellular light vesicular membrane fraction as determined by radioligand binding and supported by photoaffinity labeling, immunocytochemical staining, and immunoblot analysis. Pretreatment of cells with concanavalin A or sucrose completely blocked agonist-induced D1 receptor internalization without preventing agonist-induced desensitization, indicating a biochemical separation of these processes. Collectively, these findings indicate that the desensitization of D1 receptor-coupled adenylyl cyclase activity and D1 receptor internalization are temporarily and biochemically distinct mechanisms regulating D1 receptor function following agonist activation. Images Fig. 2 Fig. 3 PMID:7479745

  17. Blockade of D1-like dopamine receptors within the ventral tegmental area and nucleus accumbens attenuates antinociceptive responses induced by chemical stimulation of the lateral hypothalamus.

    PubMed

    Moradi, Marzieh; Fatahi, Zahra; Haghparast, Abbas

    2015-07-10

    It was established that stimulation of the lateral hypothalamus (LH) can induce antinociception. Previous studies showed a role for the ventral tegmental area (VTA) and nucleus accumbens (NAc) in antinociception induced by LH stimulation through the orexinergic system. In this study, we tried to assess the involvement of dopamine D1-like receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA or intra-accumbal infusion of SCH-23390, as a D1-like dopamine receptor antagonist (0.125, 0.25, 1 and 4?g/rat), 2min before intra-LH administration of carbachol (125nM/rat). The antinociceptive effects of SCH-23390 were measured by using a tail-flick analgesiometer and represented as maximal possible effect (%MPE). Results showed that intra-VTA and/or accumbal administration of SCH-23390 could prevent carbachol-induced antinociception. These findings revealed that D1-like dopamine receptors within the VTA and NAc play an important role in antinociceptive effect induced by chemical stimulation of the LH. PMID:26022630

  18. N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats

    Microsoft Academic Search

    S. Y. Yeh

    1999-01-01

    The present study examined the effect of N-tert-butyl-alpha-phenylni- trone (PBN) on 3,4-methylenedioxmathamphetamine (MDMA)-induced depletion of serotonin in the CNS. Rats were treated with two concurrent injections of MDMA (20 mg\\/kg, s.c.), PBN (50-400 mg\\/kg dissolved in ethanol, 50 mg\\/ml of 25% ethanol, i.p.), saline or 25% ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later. Rectal

  19. Scanned gate microscopy of surface-acoustic-wave-induced current through a depleted one-dimensional GaAs channel

    Microsoft Academic Search

    R. Crook; R. J. Schneble; M. Kataoka; H. E. Beere; D. A. Ritchie; D. Anderson; G. A. C. Jones; C. G. Smith; C. J. B. Ford; C. H. W. Barnes

    2010-01-01

    We present scanned gate microscopy images of the surface-acoustic-wave (SAW)-induced current through a depleted GaAs one-dimensional channel. The images show a crescent-shaped feature, which splits into two fragments when the tip bias is taken more negative. This is consistent with depopulation of the SAW minima when the electron energy is out of equilibrium with the source two-dimensional electron system, where

  20. Combined depletion and electrostatic forces in polymer-induced membrane adhesion: A theoretical model

    NASA Astrophysics Data System (ADS)

    Raudino, Antonio; Pannuzzo, Martina; Karttunen, Mikko

    2012-02-01

    We develop a semi-quantitative analytical theory to describe adhesion between two identical planar charged surfaces embedded in a polymer-containing electrolyte solution. Polymer chains are uncharged and differ from the solvent by their lower dielectric permittivity. The solution mimics physiological fluids: It contains 0.1 M of monovalent ions and a small number of divalent cations that form tight bonds with the headgroups of charged lipids. The components have heterogeneous spatial distributions. The model was derived self-consistently by combining: (a) a Poisson-Boltzmann like equation for the charge densities, (b) a continuum mean-field theory for the polymer profile, (c) a solvation energy forcing the ions toward the polymer-poor regions, and (d) surface interactions of polymers and electrolytes. We validated the theory via extensive coarse-grained Molecular Dynamics (MD) simulations. The results confirm our analytical model and reveal interesting details not detected by the theory. At high surface charges, polymer chains are mainly excluded from the gap region, while the concentration of ions increases. The model shows a strong coupling between osmotic forces, surface potential and salting-out effects of the slightly polar polymer chains. It highlights some of the key differences in the behaviour of monomeric and polymeric mixed solvents and their responses to Coulomb interactions. Our main findings are: (a) the onset of long-ranged ion-induced polymer depletion force that increases with surface charge density and (b) a polymer-modified repulsive Coulomb force that increases with surface charge density. Overall, the system exhibits homeostatic behaviour, resulting in robustness against variations in the amount of charges. Applications and extensions of the model are briefly discussed.

  1. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter.

    PubMed

    Fachinetto, Roselei; Villarinho, Jardel G; Wagner, Caroline; Pereira, Romaiana P; Avila, Daiana Silva; Burger, Marilise E; Calixto, Joăo Batista; Rocha, Joăo B T; Ferreira, Juliano

    2007-10-01

    Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study. PMID:17669571

  2. Modulation of acrylonitrile-induced embryotoxicity in vitro by glutathione depletion

    Microsoft Academic Search

    Anne-Marie Saillenfait; Jean-Paul Payan; Isabelle Langonné; Dominique Beydon; Marie-Christine Grandclaude; Jean-Philippe Sabaté; Jacques de Ceaurriz

    1993-01-01

    The effects of glutathione (GSH) depletion on the embryotoxicity of acrylonitrile were assessed in vitro using the rat whole-embryo culture system. Day 10 rat embryos were cultured in rat serum medium for 6 h in the presence of 250 ?Ml-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of GSH synthesis, to deplete GSH in both embryo and visceral yolk sac. Following pretreatment, conceptuses

  3. Mechanism of glucocorticoid-induced depletion of human CD14+CD16+ monocytes

    Microsoft Academic Search

    Farshid Dayyani; Kai-Uwe Belge; Marion Frankenberger; Matthias Mack; Timea Berki; Loems Ziegler-Heitbrock

    2003-01-01

    Healthy donors infused with high doses of glucocorticoids (GCs; methyl-prednisolone (MP); 500 mg\\/day for 3 days) suffer a selective depletion of the CD14CD16 monocytes such that these cells are reduced by 95% on day 5. In vitro studies revealed that at 11 h of culture in the presence of 105 M MP, no depletion was ob- served as yet, but

  4. Age dependence of myosin heavy chain transitions induced by creatine depletion in rat skeletal muscle

    NASA Technical Reports Server (NTRS)

    Adams, Gregory R.; Baldwin, Kenneth M.

    1995-01-01

    This study was designed to test the hypothesis that myosin heavy chain (MHC) plasticity resulting from creatine depletion is an age-dependent process. At weaning (age 28 days), rat pups were placed on either standard rat chow (normal diet juvenile group) or the same chow supplemented with 1% wt/wt of the creatine analogue beta-guanidinopropionic acid (creatine depletion juvenile (CDJ) group). Two groups of adult rats (age approximately 8 wk) were placed on the same diet regimens (normal diet adult and creatine depletion adult (CDA) groups). After 40 days (CDJ and normal diet juvenile groups) and 60 days (CDA and normal diet adult groups), animals were killed and several skeletal muscles were removed for analysis of creatine content or MHC ditribution. In the CDJ group, creatine depletion (78%) was accompanied by significant shifts toward expression of slower MHC isoforms in two slow and three fast skeletal muscles. In contrast, creatine depletion in adult animals did not result in similar shifts toward slow MHC isoform expression in either muscle type. The results of this study indicate that there is a differential effect of creatine depletion on MHC tranitions that appears to be age dependent. These results strongly suggest that investigators contemplating experimental designs involving the use of the creatine analogue beta-guanidinopropionic acid should consider the age of the animals to be used.

  5. Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect ?-Oxidation

    PubMed Central

    von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gĺfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2?/?) that progressively loses its mtDNA. The TK2?/? mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2?/? mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2?/? mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2?/? mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial ?-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2?/? mice causes impaired mitochondrial function that leads to defect ?-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies. PMID:23505564

  6. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect ?-oxidation.

    PubMed

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gĺfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial ?-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect ?-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies. PMID:23505564

  7. Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator.

    PubMed

    Yoshimi, Noriko; Futamura, Takashi; Hashimoto, Kenji

    2015-03-01

    Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin-dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine). Dosing with dizocilpine (0.1mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1mg/kg, p.o.) significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03mg/kg, p.o.) nor olanzapine (0.03mg/kg, p.o.) altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits via 5-HT1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders. PMID:25600995

  8. Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence

    PubMed Central

    2013-01-01

    Background Methamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter-mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter. Findings Bupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV?>?methylphenidate?>?bupropion). Conclusions Bupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV?>?methylphenidate?>?bupropion). PMID:23734766

  9. Involvement of dopamine receptors within the dorsal hippocampus in suppression of the formalin-induced orofacial pain.

    PubMed

    Shamsizadeh, Ali; Pahlevani, Pouyan; Haghparast, Amir; Moslehi, Maryam; Zarepour, Leila; Haghparast, Abbas

    2013-12-01

    It is widely established that the dopaminergic system has profound effects on pain modulation in different regions of the brain including the hippocampus, the salient area for brain functions. The orofacial region is one of the most densely innervated (by the trigeminal nerves) areas of the body susceptible to acute and chronic pains. In this study, we tried to examine the effects of dopamine receptors located in the dorsal hippocampus (CA1) region upon the modulation of orofacial pain induced by the formalin test. To induce orofacial pain in male Wistar rats, 50?l of 1% formalin was subcutaneously injected into the upper lip. In control and experimental groups, two guide cannulae were stereotaxically implanted in the CA1, and SKF-38393 (0.25, 0.5, 1 and 2?g/0.5?l saline) as a D1-like receptor agonist, SCH-23390 (1?g/0.5?l saline) as a D1-like receptor antagonist, Quinpirole (0.5, 1, 2 and 4?g/0.5?l saline) as a D2-like receptor agonist and Sulpiride(3?g/0.5?l DMSO) as a D2-like receptor antagonist or vehicles were microinjected. For induction of orofacial pain, 50?l of 1% formalin was subcutaneously injected into the left side of the upper lip. Results indicated that SKF-38393 at the dose of 1 and 2?g significantly reduced pain during the first and second phases of observed pain while SCH-23390 reversed such analgesic effect. Moreover, there is a significant difference between groups in which animals received 2 and 4?g quinpirole or vehicle in the first phase (early phase) of pain. The three high doses of this compound (1, 2 and 4?g) appeared to have an analgesic effect during the second (late) phase. Furthermore, Sulpiride could potentially reverse the observed analgesic effects already induced by an agonist. Current findings suggest that the dorsal hippocampal dopamine receptors exert an analgesic effect during the orofacial pain test. PMID:24201047

  10. Striatal dopamine level contributes to hydroxyl radical generation and subsequent neurodegeneration in the striatum in 3-nitropropionic acid-induced Huntington's disease in rats.

    PubMed

    Pandey, Mritunjay; Borah, Anupom; Varghese, Merina; Barman, Pijus Kanti; Mohanakumar, Kochupurackal P; Usha, Rajamma

    2009-11-01

    We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical (OH)-induced striatal neurotoxicity caused by 3-nitropropionic acid (3-NP) in a rat model of Huntington's disease. Dopamine (10-100 microM) or 3-NP (10-1000 microM) individually caused a significant increase in the generation of hydroxyl radical (OH) in the mitochondria, which was synergistically enhanced when the lowest dose of the neurotoxin (10 microM) and dopamine (100 microM) were present together. Similarly, systemic administration of l-DOPA (100-250 mg/kg) and a low dose of 3-NP (10 mg/kg) potentiated OH generation in the striatum, and the rats exhibited significant decrease in stride length, a direct indication of neuropathology. The pathology was also evident in striatal sections subjected to NeuN immunohistochemistry. The significant changes in stride length, the production of striatal OH and neuropathological features due to administration of a toxic dose of 3-NP (20 mg/kg) were significantly attenuated by treating the rats with tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine prior to 3-NP administration. These results strongly implicate a major contributory role of striatal dopamine in increased generation of OH, which leads to striatal neurodegeneration and accompanied behavioral changes, in 3-NP model of Huntington's disease. PMID:19410615

  11. Salsolinol modulation of dopamine neurons

    PubMed Central

    Xie, Guiqin; Krnjevi?, Krešimir; Ye, Jiang-Hong

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic (DA) system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens (NAc). However, the underlying neuronal mechanisms are unclear. Here we present an overview of some of the recent research on this topic. Electrophysiological studies reveal that DA neurons in the pVTA are a target of salsolinol. In acute brain slices from rats, salsolinol increases the excitability and accelerates the ongoing firing of dopamine neurons in the pVTA. Intriguingly, this action of salsolinol involves multiple pre- and post-synaptic mechanisms, including: (1) depolarizing dopamine neurons; (2) by activating ? opioid receptors on the GABAergic inputs to dopamine neurons – which decreases GABAergic activity – dopamine neurons are disinhibited; and (3) enhancing presynaptic glutamatergic transmission onto dopamine neurons via activation of dopamine type 1 receptors, probably situated on the glutamatergic terminals. These novel mechanisms may contribute to the rewarding/reinforcing properties of salsolinol observed in vivo. PMID:23745110

  12. Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice

    PubMed Central

    Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, JA; Colado, MI; O'Shea, E

    2010-01-01

    Background and purpose: 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Experimental approach: Mice received a course of cocaine (20 mg·kg?1, ×2 for 3 days) followed by MDMA (20 mg·kg?1, ×2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Key results: Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Conclusions and implications: Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA. PMID:20015297

  13. Comparative effects of scopolamine and quinpirole on the striatal fos expression induced by stimulation of D 1 dopamine receptors in the rat

    Microsoft Academic Search

    David Wirtshafter; Karen E. Asin

    2001-01-01

    Treatment of intact rats with the full D1 dopamine agonist A-77636 induced Fos-like immunoreactivity in the medial and, to a lesser extent, the lateral portions of the striatum. Pretreatment with the muscarinic antagonist scopolamine hydrobromide (1.5–6 mg\\/kg) potentiated the response to A-77636 and eliminated the mediolateral staining gradient seen after A-77636 alone. Similar effects were not produced by scopolamine methylbromide,

  14. Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens

    Microsoft Academic Search

    A. Del Arco; F. Mora; A. H. Mohammed; K. Fuxe

    2007-01-01

    Summary.  The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC)\\u000a on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects\\u000a of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and\\u000a HVA in the nucleus accumbens were

  15. UV Radiation Induces the Epidermal Recruitment of Dendritic Cells that Compensate for the Depletion of Langerhans Cells in Human Skin.

    PubMed

    Achachi, Amine; Vocanson, Marc; Bastien, Philippe; Péguet-Navarro, Josette; Grande, Sophie; Goujon, Catherine; Breton, Lionel; Castiel-Higounenc, Isabelle; Nicolas, Jean-François; Gueniche, Audrey

    2015-08-01

    UVR causes skin injury and inflammation, resulting in impaired immune function and increased skin cancer risk. Langerhans cells (LCs), the immune sentinels of the epidermis, are depleted for several days following a single UVR exposure and can be reconstituted from circulating monocytes. However, the differentiation pathways leading to the recovery of a normal pool of LCs is still unclear. To study the dynamic changes in human skin with UV injury, we exposed a cohort of 29 healthy human volunteers to a clinically relevant dose of UVR and analyzed sequential epidermal biopsies for changes in leukocyte and dendritic cell (DC) subsets. UV-induced depletion of CD1a(high) LC was compensated by sequential appearance of various epidermal leukocytes. CD14(+) monocytes were recruited as early as D1 post exposure, followed by recruitment of two inflammatory DC subsets that may represent precursors of LCs. These CD1a(low) CD207(-) and the heretofore unknown CD1a(low) CD207(+) DCs appeared at day 1 and day 4 post UVR, respectively, and were endowed with T-cell-activating properties similar to those of LCs. We conclude that recruitment of monocytes and inflammatory DCs appear as a physiological response of the epidermis in order to repair UVR-induced LC depletion associated with immune suppression. PMID:25806853

  16. Genetic Variance Contributes to Dopamine Receptor Antagonist-Induced Inhibition of Sucrose Intake in Inbred and Outbred Mouse Strains

    PubMed Central

    Dym, Cheryl T.; Pinhas, Alexander; Robak, Magdalena; Sclafani, Anthony; Bodnar, Richard J.

    2009-01-01

    Preference and intake of sucrose varies across inbred and outbred strains of mice. Pharmacological analyses revealed that the greatest sensitivity to naltrexone-induced inhibition of sucrose (10%) intake was observed in C57BL10/J and C57BL/6J strains, whereas 129P3/J, SWR/J and SJL/J strains displayed far less sensitivity to naltrexone-induced inhibition of sucrose intake. Given that dopamine D1 (SCH23390) and D2 (raclopride) receptor antagonism potently reduce sucrose intake in outbred rat and mouse strains, the present study examined the possibility of genetic variance in the dose-dependent (50–1600 nmol/kg) and time-dependent (5–120 min) effects of these antagonists upon sucrose (10%) intake in the eight inbred (BALB/cJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains previously tested with naltrexone. SCH23390 significantly reduced sucrose intake across all five doses in 129P3/J and SJL/J mice, across four doses in C57BL/6J and BALB/cJ mice, across three doses in DBA/2J, SWR/J, C3H/HeJ and C57BL/10J mice, but only at the two highest doses in CD-1 mice. SCH23390 was 2–3-fold more potent in inhibiting sucrose intake in 129P3/J and SJL/J mice relative to CD-1 mice. In contrast, only the highest equimolar 1600 nmol/kg dose of raclopride significantly reduced sucrose intake in the BALB/cJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J and 129P3/J, but not the SWR/J and CD-1 strains. The present and previous data demonstrate specific and differential patterns of genetic variability in inhibition of sucrose intake by dopamine and opioid antagonists, suggesting that distinct neurochemical mechanisms control sucrose intake across different mouse strains. PMID:19135035

  17. K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration

    PubMed Central

    Schiemann, Julia; Schlaudraff, Falk; Klose, Verena; Bingmer, Markus; Seino, Susumu; Magill, Peter J; Zaghloul, Kareem A; Schneider, Gaby; Liss, Birgit; Roeper, Jochen

    2014-01-01

    Phasic activation of the dopamine (DA) midbrain system in response to unexpected reward or novelty is critical for adaptive behavioral strategies. This activation of DA midbrain neurons occurs via a synaptically triggered switch from low-frequency background spiking to transient high-frequency burst firing. We found that, in medial DA neurons of the substantia nigra (SN), activity of ATP-sensitive potassium (K-ATP) channels enabled NMDA-mediated bursting in vitro as well as spontaneous in vivo burst firing in anesthetized mice. Cell-selective silencing of K-ATP channel activity in medial SN DA neurons revealed that their K-ATP channel-gated burst firing was crucial for novelty-dependent exploratory behavior. We also detected a transcriptional upregulation of K-ATP channel and NMDA receptor subunits, as well as high in vivo burst firing, in surviving SN DA neurons from Parkinson’s disease patients, suggesting that burst-gating K-ATP channel function in DA neurons affects phenotypes in both disease and health. PMID:22902720

  18. Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex

    PubMed Central

    Glovaci, Iulia; Chapman, C. Andrew

    2015-01-01

    The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine. PMID:26133167

  19. Decreased ER-associated degradation of alpha-TCR induced by Grp78 depletion with the SubAB cytotoxin.

    PubMed

    Lass, Agnieszka; Kujawa, Marek; McConnell, Elizabeth; Paton, Adrienne W; Paton, James C; Wójcik, Cezary

    2008-01-01

    HeLa cells stably expressing the alpha chain of T-cell receptor (alphaTCR), a model substrate of ER-associated degradation (ERAD), were used to analyze the effects of BiP/Grp78 depletion by the SubAB cytotoxin. SubAB induced XBP1 splicing, followed by JNK phosphorylation, eIF2alpha phosphorylation, upregulation of ATF3/4 and partial ATF6 cleavage. Other markers of ER stress, including elements of ERAD pathway, as well as markers of cytoplasmic stress, were not induced. SubAB treatment decreased absolute levels of alphaTCR, which was caused by inhibition of protein synthesis. At the same time, the half-life of alphaTCR was extended almost fourfold from 70 min to 210 min, suggesting that BiP normally facilitates ERAD. Depletion of p97/VCP partially rescued SubAB-induced depletion of alphaTCR, confirming the role of VCP in ERAD of alphaTCR. It therefore appears that ERAD of alphaTCR is driven by at least two different ATP-ase systems located at two sides of the ER membrane, BiP located on the lumenal side, while p97/VCP on the cytoplasmic side. While SubAB altered cell morphology by inducing cytoplasm vacuolization and accumulation of lipid droplets, caspase activation was partial and subsided after prolonged incubation. Expression of CHOP/GADD153 occurred only after prolonged incubation and was not associated with apoptosis. PMID:18611445

  20. L-tetrahydropalmatine inhibits methamphetamine-induced locomotor activity via regulation of 5-HT neuronal activity and dopamine D3 receptor expression.

    PubMed

    Yun, Jaesuk

    2014-09-25

    Methamphetamine (METH) is a psychomotor stimulant that produces hyperlocomotion in rodents. l-tetrahydropalmatine (l-THP) is an active ingredient found in Corydalis ternata which has been used as a traditional herbal preparation in Asian countries for centuries, however, the effect of l-THP on METH-induced phenotypes largely unknown. In this study, to evaluate the effect of l-THP on METH-induced psychotropic effects, rats were pretreated with l-THP (10 and 15 mg/kg) before acute METH injection, following which the total distance the rats moved in an hour was measured. To clarify a possible mechanism underlying the effect of l-THP on METH-induced behavioral changes, dopamine receptor mRNA expression levels in the striatum of the rats was measured following the locomotor activity study. In addition, the effect of l-THP (10 and 15 mg/kg) on serotonergic (5-HTergic) neuronal pathway activation was studied by measurement of 5-HT (80 ?g/10?l/mouse)-induced head twitch response (HTR) in mice. l-THP administration significantly inhibited both hyperlocomotion in rats and HTR in mice. l-THP inhibited climbing behavior-induced by dopaminergic (DAergic) neuronal activation in mice. Furthermore, l-THP attenuated the decrease in dopamine D3 receptor mRNA expression levels in the striatum of the rats induced by METH. These results suggest that l-THP can ameliorate behavioral phenotype induced by METH through regulation of 5-HT neuronal activity and dopamine D3 receptor expression. PMID:25172791

  1. Band to Band Tunneling (BBT) Induced Leakage Current Enhancement in Irradiated Fully Depleted SOI Devices

    NASA Technical Reports Server (NTRS)

    Adell, Phillipe C.; Barnaby, H. J.; Schrimpf, R. D.; Vermeire, B.

    2007-01-01

    We propose a model, validated with simulations, describing how band-to-band tunneling (BBT) affects the leakage current degradation in some irradiated fully-depleted SOI devices. The dependence of drain current on gate voltage, including the apparent transition to a high current regime is explained.

  2. Antagonist-induced conformational changes in dopamine transporter extracellular loop two involve residues in a potential salt bridge.

    PubMed

    Gaffaney, Jon D; Shetty, Madhur; Felts, Bruce; Pramod, Akula-Bala; Foster, James D; Henry, L Keith; Vaughan, Roxanne A

    2014-07-01

    Ligand-induced changes in the conformation of extracellular loop (EL) 2 in the rat (r) dopamine transporter (DAT) were examined using limited proteolysis with endoproteinase Asp-N and detection of cleavage products by epitope-specific immunoblotting. The principle N-terminal fragment produced by Asp-N was a 19kDa peptide likely derived by proteolysis of EL2 residue D174, which is present just past the extracellular end of TM3. Production of this fragment was significantly decreased by binding of cocaine and other uptake blockers, but was not affected by substrates or Zn(2+), indicating the presence of a conformational change at D174 that may be related to the mechanism of transport inhibition. DA transport activity and cocaine analog binding were decreased by Asp-N treatment, suggesting a requirement for EL2 integrity in these DAT functions. In a previous study we demonstrated that ligand-induced protease resistance also occurred at R218 on the C-terminal side of rDAT EL2. Here using substituted cysteine accessibility analysis of human (h) DAT we confirm cocaine-induced alterations in reactivity of the homologous R219 and identify conformational sensitivity of V221. Focused molecular modeling of D174 and R218 based on currently available Aquifex aeolicus leucine transporter crystal structures places these residues within 2.9Ĺ of one another, suggesting their proximity as a structural basis for their similar conformational sensitivities and indicating their potential to form a salt bridge. These findings extend our understanding of DAT EL2 and its role in transport and binding functions. PMID:24269640

  3. Diffraction barrier breakthrough in coherent anti-Stokes Raman scattering microscopy by additional probe-beam-induced phonon depletion

    SciTech Connect

    Liu Wei [College of Precison Instrument and Opto-electronics Engineering, Tianjin University, Tianjin 300072 (China); Institute of Optoelectronics, Key Laboratory of Optoelectronic Deviced and Systems of Education Ministry, Shenzhen University, Shenzhen 518060 (China); Niu Hanben [Institute of Optoelectronics, Key Laboratory of Optoelectronic Deviced and Systems of Education Ministry, Shenzhen University, Shenzhen 518060 (China)

    2011-02-15

    We provide an approach to significantly break the diffraction limit in coherent anti-Stokes Raman scattering (CARS) microscopy via an additional probe-beam-induced photon depletion (APIPD). The additional probe beam, whose profile is doughnut shaped and whose wavelength is different from the Gaussian probe beam, depletes the phonons to yield an unwanted anti-Stokes signal within a certain bandwidth at the rim of the diffraction-limited spot. When the Gaussian probe beam that follows immediately arrives, no anti-Stokes signal is generated in this region, resembling stimulated emission depletion (STED) microscopy, and the spot-generating useful anti-Stokes signals by this beam are substantially suppressed to a much smaller dimension. Scanning the spot renders three-dimensional, label-free, and chemically selective CARS images with subdiffraction resolution. Also, resolution-enhanced images of the molecule, specified by its broadband even-total CARS spectral signals not only by one anti-Stokes signal for its special chemical bond, can be obtained by employing a supercontinuum source.

  4. Comparative study of femtosecond and nanosecond laser-induced breakdown spectroscopy of depleted uranium

    SciTech Connect

    Emmert, Luke A.; Chinni, Rosemarie C.; Cremers, David A.; Jones, C. Randy; Rudolph, Wolfgang

    2011-01-20

    We present spectra of depleted uranium metal from laser plasmas generated by nanosecond Nd:YAG (1064 nm) and femtosecond Ti:sapphire (800 nm) laser pulses. The latter pulses produce short-lived and relatively cool plasmas in comparison to the longer pulses, and the spectra of neutral uranium atoms appear immediately after excitation. Evidence for nonequilibrium excitation with femtosecond pulses is found in the dependence of spectral line intensities on the pulse chirp.

  5. Mechanisms of deformation-induced grain boundary chromium depletion (sensitization) development in type 316 stainless steels

    Microsoft Academic Search

    A. H. Advani; L. E. Murr; D. G. Atteridge; R. Chelakara

    1991-01-01

    Deformation accelerates the development of grain boundary chromium depletion (GBCD), or sensitization, in type 316 austenitic\\u000a stainless steels (SS). Quantitative assessment of the degree of sensitization (DOS) using the electrochemical potentiokinetic\\u000a reactivation (EPR) test indicates that the acceleration in GBCD is a function of the amount of strain in the material and\\u000a temperature of isothermal sensitization treatment. A systematic increase

  6. Virulent Salmonella typhimurium-induced lymphocyte depletion and immunosuppression in chickens.

    PubMed Central

    Hassan, J O; Curtiss, R

    1994-01-01

    The effect of experimental Salmonella infection on chicken lymphoid organs, immune responses, and fecal shedding of salmonellae were assessed following oral inoculation of 1-day-old chicks or intra-air-sac infection of 4-week-old chickens with virulent S. typhimurium wild-type chi 3761 or avirulent S. typhimurium delta cya delta crp vaccine strain chi 3985. Some 4-week-old chickens infected intra-air-sac with chi 3761 or chi 3985 were challenged with Bordetella avium to determine the effect of Salmonella infection on secondary infection by B. avium. S. typhimurium chi 3761 caused lymphocyte depletion, atrophy of lymphoid organs, and immunosuppression 2 days after infection in 1-day-old chicks and 4-week-old chickens. The observed lymphocyte depletion or atrophy of lymphoid organs was transient and dose dependent. Lymphocyte depletion and immunosuppression were associated with prolonged fecal shedding of S. typhimurium chi 3761. No lymphocyte depletion, immunosuppression, or prolonged Salmonella shedding was observed in groups of chickens infected orally or intra-air-sac with chi 3985. Infection of chickens with salmonellae before challenge with B. avium did not suppress the specific antibody response to B. avium. However, B. avium isolation was higher in visceral organs of chickens infected with chi 3761 and challenged with B. avium than in chickens infected with B. avium only. Infection of chickens with chi 3985 reduced B. avium colonization. We report a new factor in Salmonella pathogenesis and reveal a phenomenon which may play a critical role in the development of Salmonella carrier status in chickens. We also showed that 10(8) CFU of chi 3985, which is our established oral vaccination dose for chickens, did not cause immunosuppression or enhance the development of Salmonella carrier status in chickens. Images PMID:8168969

  7. Methamphetamine Induces Dopamine D1 Receptor-Dependent Endoplasmic Reticulum Stress-Related Molecular Events in the Rat Striatum

    PubMed Central

    Jayanthi, Subramaniam; McCoy, Michael T.; Beauvais, Genevieve; Ladenheim, Bruce; Gilmore, Kristi; Wood, William; Becker, Kevin; Cadet, Jean Lud

    2009-01-01

    Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain. PMID:19564919

  8. Methamphetamine induces dopamine D1 receptor-dependent endoplasmic reticulum stress-related molecular events in the rat striatum.

    PubMed

    Jayanthi, Subramaniam; McCoy, Michael T; Beauvais, Genevieve; Ladenheim, Bruce; Gilmore, Kristi; Wood, William; Becker, Kevin; Cadet, Jean Lud

    2009-01-01

    Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain. PMID:19564919

  9. Micelle-induced depletion interaction and resultant structure in charged colloidal nanoparticle system

    NASA Astrophysics Data System (ADS)

    Ray, D.; Aswal, V. K.; Kohlbrecher, J.

    2015-04-01

    The evolution of the interaction and the resultant structure in the mixed system of anionic silica nanoparticles (Ludox LS30) and non-ionic surfactant decaethylene glycol monododecylether (C12E10), undergoing phase separation, have been studied using small-angle neutron scattering and dynamic light scattering. The measurements have been carried out for a fixed concentration of nanoparticle (1 wt. %) with varying concentration of surfactant (0 to 1 wt. %), in the absence and presence of an electrolyte. It is found that the micelles of non-ionic surfactant adsorb on the nanoparticle in the absence of electrolyte (form stable system), whereas these micelles become non-adsorbing in the presence of electrolyte (show phase separation). The phase separation arises because of C12E10 micelles, causing depletion interaction between nanoparticles and leading to their aggregation. The interaction is modeled by double Yukawa potential accounting for attractive depletion as well as repulsive electrostatic forces. Both the interactions (attraction and repulsion) are found to be of long-range. The nanoparticle aggregation (phase separation) is governed by the increase in the magnitude and the range of the depletion attraction with the increase in the surfactant concentration. The nanoparticle aggregates formed are quite large in size (order of micron) and are characterized by the surface fractal having simple cubic packing of nanoparticles within the aggregates.

  10. The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization

    Microsoft Academic Search

    C. Velázquez-Sánchez; A. Ferragud; J. Murga; M. Cardá; J. J. Canales

    2010-01-01

    The discovery and evaluation of high affinity dopamine transport inhibitors with low abuse liability is an important step toward the development of efficacious medications for cocaine addiction. We examined in mice the behavioural effects of (N-(n-butyl)-3?-[bis(4?-fluorophenyl)methoxy]-tropane) (JHW 007), a benztropine (BZT) analogue that blocks dopamine uptake, and assessed its potential to influence the actions of cocaine in clinically-relevant models of

  11. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

    Microsoft Academic Search

    Kent C. Berridge; Terry E. Robinson

    1998-01-01

    What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is `no'. Rather, dopamine systems may

  12. Vaccine-Induced CD107a+ CD4+ T Cells Are Resistant to Depletion following AIDS Virus Infection

    PubMed Central

    Terahara, Kazutaka; Ishii, Hiroshi; Nomura, Takushi; Takahashi, Naofumi; Takeda, Akiko; Shiino, Teiichiro; Tsunetsugu-Yokota, Yasuko

    2014-01-01

    ABSTRACT CD4+ T-cell responses are crucial for effective antibody and CD8+ T-cell induction following virus infection. However, virus-specific CD4+ T cells can be preferential targets for human immunodeficiency virus (HIV) infection. HIV-specific CD4+ T-cell induction by vaccination may thus result in enhancement of virus replication following infection. In the present study, we show that vaccine-elicited CD4+ T cells expressing CD107a are relatively resistant to depletion in a macaque AIDS model. Comparison of virus-specific CD107a, macrophage inflammatory protein-1?, gamma interferon, tumor necrosis factor alpha, and interleukin-2 responses in CD4+ T cells of vaccinated macaques prechallenge and 1 week postchallenge showed a significant reduction in the CD107a? but not the CD107a+ subset after virus exposure. Those vaccinees that failed to control viremia showed a more marked reduction and exhibited significantly higher viral loads at week 1 than unvaccinated animals. Our results indicate that vaccine-induced CD107a? CD4+ T cells are depleted following virus infection, suggesting a rationale for avoiding virus-specific CD107a? CD4+ T-cell induction in HIV vaccine design. IMPORTANCE Induction of effective antibody and/or CD8+ T-cell responses is a principal vaccine strategy against human immunodeficiency virus (HIV) infection. CD4+ T-cell responses are crucial for effective antibody and CD8+ T-cell induction. However, virus-specific CD4+ T cells can be preferential targets for HIV infection. Here, we show that vaccine-induced virus-specific CD107a? CD4+ T cells are largely depleted following infection in a macaque AIDS model. While CD4+ T-cell responses are important in viral control, our results indicate that virus-specific CD107a? CD4+ T-cell induction by vaccination may not lead to efficient CD4+ T-cell responses following infection but rather be detrimental and accelerate viral replication in the acute phase. This suggests that HIV vaccine design should avoid virus-specific CD107a? CD4+ T-cell induction. Conversely, this study found that vaccine-induced CD107a+ CD4+ T cells are relatively resistant to depletion following virus challenge, implying that induction of these cells may be an alternative approach toward HIV control. PMID:25275131

  13. Mesolimbic Dopamine Transients in Motivated Behaviors: Focus on Maternal Behavior

    PubMed Central

    Robinson, Donita L.; Zitzman, Dawnya L.; Williams, Sarah K.

    2011-01-01

    Phasic activity of the mesolimbic dopamine pathway – burst-firing of dopamine neurons and the resulting dopamine release events at striatal targets – have been associated with a variety of motivational events, such as novelty, salient stimuli, social interaction, and reward prediction. Over the past decade, advances in electrochemical techniques have allowed measurement of naturally occurring dopamine release events, or dopamine transients, in awake animals during ongoing behavior. Thus, a growing body of studies has revealed dynamic dopamine input to ventral striatum during motivated behavior in a variety of experimental paradigms. We propose that dopamine transients may be important neural signals in pup-directed aspects of maternal behavior, as preliminary data suggest that dopamine transients in dams are associated with pup cues. Measurements of dopamine transients may be useful to investigate not only typical maternal behavior but also maternal inattention induced by drug exposure or stress. PMID:21629844

  14. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells

    Microsoft Academic Search

    Houbo Jiang; Yong Ren; Eunice Y. Yuen; Ping Zhong; Mahboobe Ghaedi; Zhixing Hu; Gissou Azabdaftari; Kazuhiro Nakaso; Zhen Yan; Jian Feng

    2012-01-01

    Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate

  15. Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation

    PubMed Central

    Vosper, Jonathan; Masuccio, Alessia; Kullmann, Michael; Ploner, Christian; Geley, Stephan; Hengst, Ludger

    2015-01-01

    Statins, such as lovastatin, can induce a cell cycle arrest in the G1 phase. This robust antiproliferative activity remains intact in many cancer cells that are deficient in cell cycle checkpoints and leads to an increased expression of CDK inhibitor proteins p27Kip1 and p21Cip1. The molecular details of this statin-induced growth arrest remains unclear. Here we present evidence that lovastatin can induce the degradation of Skp2, a subunit of the SCFSkp2 ubiquitin ligase that targets p27Kip1 and p21Cip1 for proteasomal destruction. The statin-induced degradation of Skp2 is cell cycle phase independent and does not require its well characterised degradation pathway mediated by APC/CCdh1- or Skp2 autoubiquitination. An N-terminal domain preceding the F-box of Skp2 is both necessary and sufficient for its statin mediated degradation. The degradation of Skp2 results from statin induced depletion of geranylgeranyl isoprenoid intermediates of cholesterol biosynthesis. Inhibition of geranylgeranyl-transferase-I also promotes APC/CCdh1-independent degradation of Skp2, indicating that de-modification of a geranylgeranylated protein triggers this novel pathway of Skp2 degradation. PMID:25605247

  16. Norepinephrine transporter inhibition with desipramine exacerbates L-DOPA-induced dyskinesia: role for synaptic dopamine regulation in denervated nigrostriatal terminals.

    PubMed

    Chotibut, Tanya; Fields, Victoria; Salvatore, Michael F

    2014-12-01

    Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI + L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI + L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI + L-DOPA group compared with the L-DOPA- and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism. PMID:25208966

  17. Apoptosis induced by NAD depletion is inhibited by KN-93 in a CaMKII-independent manner.

    PubMed

    Takeuchi, Mikio; Yamamoto, Tomoko

    2015-07-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme that catalyzes the synthesis of nicotinamide mononucleotide from nicotinamide (Nam) in the salvage pathway of mammalian NAD biosynthesis. Several potent NAMPT inhibitors have been identified and used to investigate the role of intracellular NAD and to develop therapeutics. NAD depletion induced by NAMPT inhibitors depolarizes mitochondrial membrane potential and causes apoptosis in a range of cell types. However, the mechanisms behind this depolarization have not been precisely elucidated. We observed that apoptosis of THP-1 cells in response to NAMPT inhibitors was reduced by the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 via an unknown mechanism. The inactive analog of KN-93, KN-92, exhibited the same activity, but the CaMKII-inhibiting cell-permeable autocamtide-2-related inhibitory peptide II did not, indicating that the inhibition of THP-1 cell apoptosis was not dependent on CaMKII. In evaluating the mechanism of action, we confirmed that KN-93 did not inhibit decreases in NAD levels but did inhibit decreases in mitochondrial membrane potential, indicating that KN-93 exerts inhibition upstream of the mitochondrial pathway of apoptosis. Further, qPCR analysis of the Bcl-2 family of proteins showed that Bim is efficiently expressed following NAMPT inhibition and that KN-92 did not inhibit this expression. The L-type Ca(2+) channel blockers verapamil and nimodipine partially inhibited apoptosis, indicating that part of this effect is dependent on Ca(2+) channel inhibition, as both KN-93 and KN-92 are reported to inhibit L-type Ca(2+) channels. On the other hand, KN-93 and KN-92 did not markedly inhibit apoptosis induced by anti-cancer agents such as etoposide, actinomycin D, ABT-737, or TW-37, indicating that the mechanism of inhibition is specific to apoptosis induced by NAD depletion. These results demonstrate that NAD depletion induces a specific type of apoptosis that is effectively inhibited by the KN-93 series of compounds. PMID:26024774

  18. Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson's disease.

    PubMed

    Lindgren, Hanna S; Ohlin, K Elisabet; Cenci, M Angela

    2009-11-01

    Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1- or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1- but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response. PMID:19606087

  19. N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia

    PubMed Central

    Stamellou, Eleni; Fontana, Johann; Wedel, Johannes; Ntasis, Emmanouil; Sticht, Carsten; Becker, Anja; Pallavi, Prama; Wolf, Kerstin; Krämer, Bernhard K.; Hafner, Mathias; van Son, Willem J.; Yard, Benito A.

    2014-01-01

    Aim N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour. Methods Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC. Results NOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. Conclusions We provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy. PMID:24926788

  20. Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

    PubMed Central

    Villarroya, Joan; Dorado, Beatriz; Vilŕ, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

    2011-01-01

    Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

  1. RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer.

    PubMed

    Guo, Chengcheng; Hao, Chuncheng; Shao, RuPing; Fang, Bingliang; Correa, Arlene M; Hofstetter, Wayne L; Roth, Jack A; Behrens, Carmen; Kalhor, Neda; Wistuba, Ignacio I; Swisher, Stephen G; Pataer, Apar

    2015-05-10

    We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2? are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinaseT172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKK? pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation. PMID:25798539

  2. RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer

    PubMed Central

    Guo, Chengcheng; Hao, Chuncheng; Shao, RuPing; Fang, Bingliang; Correa, Arlene M.; Hofstetter, Wayne L.; Roth, Jack A.; Behrens, Carmen; Kalhor, Neda; Wistuba, Ignacio I.; Swisher, Stephen G.; Pataer, Apar

    2015-01-01

    We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2? are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinaseT172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKK? pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation. PMID:25798539

  3. Depletion of Securin Induces Senescence After Irradiation and Enhances Radiosensitivity in Human Cancer Cells Regardless of Functional p53 Expression

    SciTech Connect

    Chen Wenshu; Yu Yichu [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Lee Yijang [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Chen, J.-H. [Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan (China); Hsu, H.-Y. [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Chiu, S.-J., E-mail: chiusj@mail.tcu.edu.t [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan (China)

    2010-06-01

    Purpose: Radiotherapy is one of the best choices for cancer treatment. However, various tumor cells exhibit resistance to irradiation-induced apoptosis. The development of new strategies to trigger cancer cell death besides apoptosis is necessary. This study investigated the role of securin in radiation-induced apoptosis and senescence in human cancer cells. Methods and Materials: Cell survival was determined using clonogenic assays. Western blot analysis was used to analyze levels of securin, caspase-3, PARP, p53, p21, Rb, gamma-H2AX, and phospho-Chk2. Senescent cells were analyzed using a beta-galactosidase staining assay. A securin-expressed vector (pcDNA-securin) was stably transfected into securin-null HCT116 cells. Securin gene knockdown was performed by small interfering RNA and small hairpin RNA in HCT116 and MDA-MB-231 cells, respectively. Results: Radiation was found to induce apoptosis in securin wild type HCT116 cells but induced senescence in securin-null cells. Restoration of securin reduced senescence and increased cell survival in securin-null HCT116 cells after irradiation. Radiation-induced gamma-H2AX and Chk2 phosphorylation were induced transiently in securin-wild-type cells but exhibited sustained activation in securin-null cells. Securin gene knockdown switches irradiation-induced apoptosis to senescence in both HCT116 p53-null and MDA-MB-231 cells. Conclusions: Our results demonstrated that the level of securin expression plays a determining role in the radiosensitivity and fate of cells. Depletion of securin impairs DNA repair after irradiation, increasing DNA damage and promoting senescence in the residual surviving cells regardless of functional p53 expression. The knockdown of securin may contribute to a novel radiotherapy protocol for the treatment of human cancer cells that are resistant to irradiation.

  4. Spirafolide from bay leaf ( Laurus nobilis ) prevents dopamine-induced apoptosis by decreasing reactive oxygen species production in human neuroblastoma SH-SY5Y cells

    Microsoft Academic Search

    Ahrom Ham; Bora Kim; Uk Koo; Kung-Woo Nam; Sung-Jin Lee; Kyeong Ho Kim; Jongheon Shin; Woongchon Mar

    2010-01-01

    Reactive oxygen species (ROS) are important mediators in many neurodegenerative diseases including Alzheimer’s disease and\\u000a Parkinson’s disease. This study tested the neuroprotective effects of spirafolide, a compound purified from the leaves of\\u000a Laurus nobilis L. (Lauraceae), against dopamine (DA)-induced apoptosis in human neuroblastoma SH-SY5Y cells. Following a 24-h exposure of\\u000a cells to DA (final conc., 0.6 mM), we observed a

  5. Intracellular Metabolite Pool Changes in Response to Nutrient Depletion Induced Metabolic Switching in Streptomyces coelicolor

    PubMed Central

    Wentzel, Alexander; Sletta, Havard; Consortium, Stream; Ellingsen, Trond E.; Bruheim, Per

    2012-01-01

    A metabolite profiling study of the antibiotic producing bacterium Streptomyces coelicolor A3(2) has been performed. The aim of this study was to monitor intracellular metabolite pool changes occurring as strains of S. coelicolor react to nutrient depletion with metabolic re-modeling, so-called metabolic switching, and transition from growth to secondary metabolite production phase. Two different culture media were applied, providing depletion of the key nutrients phosphate and L-glutamate, respectively, as the triggers for metabolic switching. Targeted GC-MS and LC-MS methods were employed to quantify important primary metabolite groups like amino acids, organic acids, sugar phosphates and other phosphorylated metabolites, and nucleotides in time-course samples withdrawn from fully-controlled batch fermentations. A general decline, starting already in the early growth phase, was observed for nucleotide pools and phosphorylated metabolite pools for both the phosphate and glutamate limited cultures. The change in amino acid and organic acid pools were more scattered, especially in the phosphate limited situation while a general decrease in amino acid and non-amino organic acid pools was observed in the L-glutamate limited situation. A phoP deletion mutant showed basically the same metabolite pool changes as the wild-type strain M145 when cultivated on phosphate limited medium. This implies that the inactivation of the phoP gene has only little effect on the detected metabolite levels in the cell. The energy charge was found to be relatively constant during growth, transition and secondary metabolite production phase. The results of this study and the employed targeted metabolite profiling methodology are directly relevant for the evaluation of precursor metabolite and energy supply for both natural and heterologous production of secondary metabolites in S. coelicolor. PMID:24957373

  6. Intracellular Metabolite Pool Changes in Response to Nutrient Depletion Induced Metabolic Switching in Streptomyces coelicolor.

    PubMed

    Wentzel, Alexander; Sletta, Havard; Consortium, Stream; Ellingsen, Trond E; Bruheim, Per

    2012-01-01

    A metabolite profiling study of the antibiotic producing bacterium Streptomyces coelicolor A3(2) has been performed. The aim of this study was to monitor intracellular metabolite pool changes occurring as strains of S. coelicolor react to nutrient depletion with metabolic re-modeling, so-called metabolic switching, and transition from growth to secondary metabolite production phase. Two different culture media were applied, providing depletion of the key nutrients phosphate and L-glutamate, respectively, as the triggers for metabolic switching. Targeted GC-MS and LC-MS methods were employed to quantify important primary metabolite groups like amino acids, organic acids, sugar phosphates and other phosphorylated metabolites, and nucleotides in time-course samples withdrawn from fully-controlled batch fermentations. A general decline, starting already in the early growth phase, was observed for nucleotide pools and phosphorylated metabolite pools for both the phosphate and glutamate limited cultures. The change in amino acid and organic acid pools were more scattered, especially in the phosphate limited situation while a general decrease in amino acid and non-amino organic acid pools was observed in the L-glutamate limited situation. A phoP deletion mutant showed basically the same metabolite pool changes as the wild-type strain M145 when cultivated on phosphate limited medium. This implies that the inactivation of the phoP gene has only little effect on the detected metabolite levels in the cell. The energy charge was found to be relatively constant during growth, transition and secondary metabolite production phase. The results of this study and the employed targeted metabolite profiling methodology are directly relevant for the evaluation of precursor metabolite and energy supply for both natural and heterologous production of secondary metabolites in S. coelicolor. PMID:24957373

  7. Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area.

    PubMed

    Xiao, Cheng; Shao, Xuesi Max; Olive, M Foster; Griffin, William C; Li, Ke-Yong; Krnjevi?, Kresimir; Zhou, Chunyi; Ye, Jiang-Hong

    2009-01-01

    The cellular mechanisms underlying alcohol addiction are poorly understood. In several brain areas, ethanol depresses glutamatergic excitatory transmission, but how it affects excitatory synapses on dopamine neurons of the ventral tegmental area (VTA), a crucial site for the development of drug addiction, is not known. We report here that in midbrain slices from rats, clinically relevant concentrations of ethanol (10-80 mM) increase the amplitude of evoked EPSCs and reduce their paired-pulse ratio in dopamine neurons in the VTA. The EPSCs were mediated by glutamate alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. In addition, ethanol increases the frequency but not the amplitude of spontaneous EPSCs. Furthermore, ethanol increases extracellular glutamate levels in the VTA of midbrain slices. The effects of ethanol are mimicked by SKF 38393, a dopamine D(1) receptor agonist, and by GBR 12935, a dopamine reuptake inhibitor, and they are blocked by SKF 83566, a D(1) antagonist, or by reserpine, which depletes dopamine stores. The enhancement of sEPSC frequency reaches a peak with 40 mM ethanol and declines with concentrations >or=80 mM ethanol, which is quite likely a result of D(2) receptor activation as raclopride, a D(2) receptor blocker, significantly enhanced 80 mM ethanol-induced enhancement of sEPSCs. Finally, 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), an AMPA receptor antagonist, attenuates ethanol-induced excitation of VTA DA neurons. We therefore conclude that, acting via presynaptic D(1) receptors, ethanol at low concentrations increases glutamate release in the VTA, thus raising somatodendritic dopamine release, which further activates the presynaptic D(1) receptors. Enhancement of this positive feedback loop may significantly contribute to the development of alcohol addiction. PMID:18596684

  8. Similar l-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation.

    PubMed

    Li, Li; Sagot, Ben; Zhou, Fu-Ming

    2015-07-30

    The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease. PMID:25960345

  9. D2 autoreceptor inhibition reveals oxygen-glucose deprivation-induced release of dopamine in guinea-pig cochlea.

    PubMed

    Halmos, G; Doleviczényi, Z; Répássy, G; Kittel, A; Vizi, E S; Lendvai, B; Zelles, T

    2005-01-01

    Dopamine (DA), released from the lateral olivocochlear (LOC) efferent terminals, the efferent arm of the short-loop feedback in the cochlea, is considered as a protective factor in the inner ear since it inhibits auditory nerve dendrite firing in ischemia- or noise-induced excitotoxicity leading to sensorineural hearing loss (SNHL). In the present study we investigated the effect of oxygen-glucose deprivation (OGD), an in vitro ischemia model, on guinea-pig cochlear [(3)H]DA release in a microvolume superfusion system. We found that OGD alone failed to induce a detectable elevation of [(3)H]DA level, but in the presence of specific D(2) receptor antagonists, sulpiride and L-741,626, it evoked a significant increase in the extracellular concentration of [(3)H]DA. D(2) negative feedback receptors are involved not exclusively in the regulation of synthesis and vesicular release of DA, but also in the activation of its reuptake. Thus, D(2) receptor antagonism interferes with the powerful reuptake of DA from the extracellular space. To explore the underlying mechanism of this DA-releasing effect we applied nomifensine and found that the effect of OGD on cochlear DA release in the presence of D(2) antagonists could be inhibited by this selective DA uptake inhibitor. This finding indicates that the OGD-evoked DA release was mainly mediated through the reverse operation of the DA transporter. The two structurally different D(2) antagonists also augmented the electrical field stimulation-evoked release of DA proving the presence of D(2) autoreceptors on dopaminergic LOC terminals. Our results confirm the presence and role of D(2) DA autoreceptors in the regulation of DA release from LOC efferents, and suggest a protective local mechanism during ischemia which involves the direct transporter-mediated release of DA. Increasing the release of the protective transmitter DA locally in the inner ear may form the basis of future new therapeutic strategies in patients suffering from SNHL. PMID:15837140

  10. MPTP-induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice.

    PubMed

    Costa, Giulia; Frau, Lucia; Wardas, Jadwiga; Pinna, Annalisa; Plumitallo, Antonio; Morelli, Micaela

    2013-12-01

    Clinical observations report a greater propensity to develop Parkinson's disease (PD) in amphetamine users. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is an amphetamine-related drug that is largely consumed by adolescents and young adults, which may have neuroinflammatory and neurotoxic effects. Here, the objective was to evaluate in mice whether consumption of MDMA during adolescence might influence the neuroinflammatory and neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin known to induce PD in humans. The activation of astroglia and microglia by glial fibrillary acidic protein (GFAP) and complement receptor type 3 (CD11b) immunohistochemistry and the degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry were evaluated. MPTP (20 mg/kg × 4) was administered to mice treated from ages 8 weeks to 17 weeks with MDMA (10 mg/kg twice daily, two times a week). In mice that were chronically treated with MDMA, administration of MPTP induced a higher microglial and astroglial response in both the striatum and the substantia nigra pars compacta (SNc) compared with vehicle-treated or vehicle?+?MPTP-treated mice. Inflammatory changes were associated with a decrease in TH immunoreactivity in the SNc of MDMA-treated mice and with a further decrease in the striatum and the SNc of MDMA?+?MPTP-treated mice compared with vehicle-treated, MDMA-treated, and MPTP-treated mice. The results demonstrate that chronic administration of MDMA during late adolescence in mice exacerbates the neurodegeneration and neuroinflammation caused by MPTP, suggesting that MDMA may constitute a risk factor for dopaminergic neuron degeneration. PMID:24108425

  11. Heavy-ion-induced digital single event transients in a 180 nm fully depleted SOI process

    E-print Network

    Gouker, Pascale M.

    Heavy-ion-induced single events transients (SETs) in advanced digital circuits are a significant reliability issue for space-based systems. SET pulse widths in silicon-on-insulator (SOI) technologies are often significantly ...

  12. Dopamine D1 Receptor Signaling in the Medial Preoptic Area Facilitates Experience-induced Enhancement of Mating Behavior in Male Rats

    PubMed Central

    McHenry, Jenna A.; Bell, Genevieve A.; Parrish, Bradley P.; Hull, Elaine M.

    2012-01-01

    The medial preoptic area (MPOA) is an integral site for male sexual behavior. Dopamine is released in the MPOA before and during copulation and facilitates male rat sexual behavior. Repeated sexual experience and noncopulatory exposures to an estrous female facilitate subsequent copulation. However, the neurobiological mechanisms that mediate such enhancement remain unclear. Here, we examined the role of dopamine D1 receptors in the MPOA in experience-induced enhancement of male sexual behavior in rats. In Experiment 1, microinjections of the D1 antagonist SCH-23390 into the MPOA before each of 7 daily 30-min noncopulatory exposures to a receptive female impaired copulation on a drug-free test on day 8, compared to vehicle-treated female-exposed animals. Copulatory performance in drug-treated animals was similar to vehicle-treated males that had not been pre-exposed to females. This effect was site specific. There were no group differences in locomotor activity in an open field on the copulation test day. In Experiment 2, a separate cohort of animals was used to examine phosphorylation of dopamine-and cAMP-regulated phosphoprotein (DARPP-32) in the MPOA of animals with acute and/or chronic sexual experience. DARPP-32 is a downstream marker of D1 receptor signaling and substrate of cAMP-dependent protein kinase (PKA). Western immunoblot analysis revealed that p-DARPP-32 expression was greatest in the MPOA of males that received both acute and chronic sexual experience, compared to all other mated conditions and naďve controls. These data suggest that D1 receptors in the MPOA contribute to experience-induced enhancement of male sexual behavior, perhaps through a PKA regulated mechanism. PMID:22708956

  13. Extended-access, but not limited-access, methamphetamine self-administration induces behavioral and nucleus accumbens dopamine response changes in rats

    PubMed Central

    Cozannet, Romain Le; Markou, Athina; Kuczenski, Ronald

    2013-01-01

    To better understand the neurobiology of methamphetamine (METH) dependence and the cognitive impairments induced by METH use, we compared the effects of extended (12 h) and limited (1 h) access to METH self-administration on locomotor activity and object place recognition, and on extracellular dopamine levels in the nucleus accumbens and caudate-putamen. Rats were trained to self-administer intravenous METH (0.05 mg/kg). One group had progressively extended access up to 12-h sessions. The other group had limited-access 1-h sessions. Microdialysis experiments were conducted during a 12-h and 1-h session, in which the effects of a single METH injection (self-administered, 0.05 mg/kg, i.v.) on extracellular dopamine levels were assessed in the nucleus accumbens and caudate-putamen compared with a drug-naive group. The day after the last 12-h session and the following day experimental groups were assessed for their locomotor activities and in a place recognition procedure, respectively. The microdialysis results revealed tolerance to the METH-induced increases in extracellular dopamine only in the nucleus accumbens, but not in the caudate-putamen in the extended-access group compared with the control and limited-access groups. These effects may be associated with the increased lever-pressing and drug-seeking observed during the first hour of drug exposure in the extended-access group. This increase in drug-seeking leads to higher METH intake and may result in more severe consequences in other structures responsible for the behavioral deficits (memory and locomotor activity) observed in the extended-access group, but not in the limited-access group. PMID:24112125

  14. Synergistic activation of the Nrf2-signaling pathway by glyceollins under oxidative stress induced by glutathione depletion.

    PubMed

    Jung, Chae Lim; Kim, Hyo Jung; Park, Jung Han Yoon; Kong, Ah-Ng Tony; Lee, Choong Hwan; Kim, Jong-Sang

    2013-05-01

    Oxidative stress state such as depletion of the intracellular glutathione (GSH) is associated with the development of cancer. Some dietary phytochemicals have been shown to possess a cancer preventive effect, although the understanding of the involved mechanisms is still limited. Recent study has shown that glyceollins, phytoalexins derived from soybean by biotic elicitor, might have a cancer preventive effect through induction of detoxifying/antioxidant enzymes. The objective of this study was to investigate the effects of glyceollins on the Nrf2 signaling pathway under excessive oxidative stress induced by GSH depletion. In mouse hepatoma cells (Hepa1c1c7) subjected to the buthionine sulfoximine (BSO), an inhibitor of ?-glutamylcysteine synthetase (?GCS), the intracellular GSH content was significantly lowered. On the other hand, incubation with glyceollins in the presence of BSO increased the level of GSH, expression of ?GCS, and nuclear translocation of NF-E2-related factor-2 (Nrf2), compared to the cells treated with BSO only. Nrf2-antioxidant responsive element (ARE)-reporter activity assay in HepG2-C8 showed that BSO increased the ARE-reporter activity in a dose-dependent manner, compared to vehicle-treated cells, whereas cotreatment with glyceollins caused further increase in reporter luciferase activity relative to BSO alone. Taken together, glyceollins synergistically activated the Nrf2 signaling pathway and subsequently the expression of phase 2/antioxidant enzymes in the presence of BSO, suggesting that BSO-induced oxidative stress and that glyceollins regulate the expression of phase 2/antioxidant enzymes through different mechanisms from each other. PMID:23573869

  15. Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

    E-print Network

    Burke, Robert E

    Neurons of the Substantia Nigra Maria J. Marti, Christopher J. James, Tinmarlar F. Oo, William J. Kelly. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development; programmed cell death; 6-hydroxydo- pamine; substantia nigra; dopamine; Parkinson's disease In many

  16. Novelty-induced increase in dopamine release in the rat prefrontal cortex in vivo: inhibition by diazepam

    Microsoft Academic Search

    M. G. P. Feenstra; M. H. A. Botterblom; J. F. M. van Uum

    1995-01-01

    The effects of graded stressful conditions on extracellular concentrations of dopamine (DA) in the medial prefrontal cortex of rats were measured in vivo using microdialysis. Picking up the rat twice with a 20-min interval increased extracellular DA to 120%, exposure to a novel environment by placement in a clean cage for 20 min to 150% and holding the rat in

  17. Local 5HT 3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex

    Microsoft Academic Search

    G. Tanda; R. Frau; G. Chiara

    1995-01-01

    Fluoxetine and desipramine, two antidepressants that block selectively the serotonin and the noradrenaline carrier, increase extracellular dopamine concentrations in the prefrontal cortex of freely-moving rats. This effect is calcium dependent and is prevented, in the case of fluoxetine but not desipramine, by systemic pretreatment with low doses or by low concentrations in the dialyzing Ringer of the potent 5-HT3 antagonist

  18. Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats

    Microsoft Academic Search

    I. M. Maisonneuve; K. L. Rossman; R. W. Keller Jr; S. D. Glick

    1992-01-01

    lbogaine, an indolalkylamine. proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic iystem acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopa- nine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at

  19. A Dopamine D1 Receptor-Dependent ?-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice

    PubMed Central

    Urs, Nikhil M; Daigle, Tanya L; Caron, Marc G

    2011-01-01

    Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These effects likely involve functionally selective mechanisms. Indeed, G protein-coupled receptor desensitization and adaptor protein ?-arrestin 2 (?arr2) through its interaction with the ?-opioid receptor regulates the analgesic but not the rewarding properties of morphine. However, ?arr2 is also required for morphine-induced locomotor activity in mice, but the exact cellular and molecular mechanisms that mediate this arrestin-dependent behavior are not understood. In this study, we show that ?arr2 is required for morphine-induced locomotor activity in a dopamine D1 receptor (D1R)-dependent manner and that a ?arr2/phospho-ERK (?arr2/pERK) signaling complex may mediate this behavior. Systemic administration of SL327, an MEK inhibitor, inhibits morphine-induced locomotion in wild-type mice in a dose-dependent manner. Acute morphine administration to mice promotes the formation of a ?arr2/pERK signaling complex. Morphine-induced locomotor activity and formation of the ?arr2/pERK signaling complex is blunted in D1R knockout (D1-KO) mice and is presumably independent of D2 dopamine receptors. However, D1Rs are not required for morphine-induced reward as D1-KO mice show the same conditioned place preference for morphine as do control mice. Taken together, these results suggest a potential role for a D1R-dependent ?arr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine. PMID:20980993

  20. A dopamine D1 receptor-dependent ?-arrestin signaling complex potentially regulates morphine-induced psychomotor activation but not reward in mice.

    PubMed

    Urs, Nikhil M; Daigle, Tanya L; Caron, Marc G

    2011-02-01

    Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These effects likely involve functionally selective mechanisms. Indeed, G protein-coupled receptor desensitization and adaptor protein ?-arrestin 2 (?arr2) through its interaction with the ?-opioid receptor regulates the analgesic but not the rewarding properties of morphine. However, ?arr2 is also required for morphine-induced locomotor activity in mice, but the exact cellular and molecular mechanisms that mediate this arrestin-dependent behavior are not understood. In this study, we show that ?arr2 is required for morphine-induced locomotor activity in a dopamine D1 receptor (D1R)-dependent manner and that a ?arr2/phospho-ERK (?arr2/pERK) signaling complex may mediate this behavior. Systemic administration of SL327, an MEK inhibitor, inhibits morphine-induced locomotion in wild-type mice in a dose-dependent manner. Acute morphine administration to mice promotes the formation of a ?arr2/pERK signaling complex. Morphine-induced locomotor activity and formation of the ?arr2/pERK signaling complex is blunted in D1R knockout (D1-KO) mice and is presumably independent of D2 dopamine receptors. However, D1Rs are not required for morphine-induced reward as D1-KO mice show the same conditioned place preference for morphine as do control mice. Taken together, these results suggest a potential role for a D1R-dependent ?arr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine. PMID:20980993

  1. Anti-aging effects of deuterium depletion on Mn-induced toxicity in a C. elegans model.

    PubMed

    Avila, Daiana Silva; Somlyai, Gábor; Somlyai, Ildikó; Aschner, Michael

    2012-06-20

    Work with sub-natural levels of deuterium (D) in animals has demonstrated an anti-cancer effect of low D-concentration in water. Our objective was to investigate whether deuterium-depleted water (DDW) can overturn reverse manganese (Mn)-induced reduction in life span, using the Caenorhabditis elegans (C. elegans) as a model system. DDW per se had no effect on worm's life span 48 h after treatment; however, it reversed the Mn-induced decrease in C. elegans life span. Mn reduced DAF-16 levels, a transcription factor strongly associated with life-span regulation. Low D-concentration (90 ppm) restored the Mn-induced changes in DAF-16 to levels indistinguishable from controls, suggesting DDW can regulate the DAF-16 pathway. We further show that insulin-like receptor DAF-2 levels were unaltered by Mn exposure, tAKT levels increased, whilst superoxide dismutase (SOD-3) levels were decreased by Mn. DDW (90 ppm) restored the levels of tAKT and superoxide dismutase (SOD) to control values without changing DAF-2 levels. Treatment of Mn exposed worms with DDW (90 ppm) restored life-span, DAF-16 and SOD-3 levels to control levels, strongly suggesting that low D concentrations can protect against Mn toxic effects. PMID:22561170

  2. Depletion-induced surface alignment of asymmetric diblock copolymer in selective solvents.

    PubMed

    Wang, Rong; Chen, Yeng-Long; Hu, Jinglei; Xue, Gi

    2008-07-28

    Phase separation of asymmetric diblock copolymer near surfaces in selective solvents is theoretically investigated by using the real-space version of self-consistent field theory (SCFT). Several morphologies are predicted and the phase diagram is constructed by varying the distance between two parallel hard surfaces (or the film thickness) W and the block copolymer concentration f(P). Morphologies of the diblock copolymer in dilute solution are found to change significantly with different film thicknesses. In confined systems, stable morphologies found in the bulk solution become unstable due to the loss of polymer conformation entropy. The vesicle phase region contracts when the repulsive interaction between the blocks is strong (strong segregation regime). The mixture of vesicles, rodlike and spherelike micelles and the mixture of vesicles and sphere-like micelles disappear in contrast to the weakly segregating regime. The walls strongly affect the phase separation of block copolymer in selective solvent, and the depletion layer near the surface contributes much to the micelle formation of the block copolymer. Interestingly, the self-assembled morphologies stay near the walls with the distance on the order of the radius of gyration of the block copolymer. The oscillation of the polymer distribution near the walls allows the surface phase separation to be observed due to the strong repulsion between the blocks A and B. PMID:18681678

  3. Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses.

    PubMed

    Fornai, F; Giorgi, F S; Alessandrě, M G; Giusiani, M; Corsini, G U

    1999-02-01

    We recently demonstrated that pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs. PMID:9930753

  4. Comparative effects of scopolamine and quinpirole on the striatal fos expression induced by stimulation of D(1) dopamine receptors in the rat.

    PubMed

    Wirtshafter, D; Asin, K E

    2001-03-01

    Treatment of intact rats with the full D(1) dopamine agonist A-77636 induced Fos-like immunoreactivity in the medial and, to a lesser extent, the lateral portions of the striatum. Pretreatment with the muscarinic antagonist scopolamine hydrobromide (1.5-6 mg/kg) potentiated the response to A-77636 and eliminated the mediolateral staining gradient seen after A-77636 alone. Similar effects were not produced by scopolamine methylbromide, which fails to cross the blood-brain barrier, demonstrating that the actions of scopolamine were centrally mediated. The effects of scopolamine were further compared to those of the D(2)-like dopamine agonist quinpirole using a factorial design in which subjects were pretreated with either scopolamine, quinpirole, or a combination of the two drugs before receiving A-77636. Pretreatment with either scopolamine or quinpirole increased staining in the lateral striatum, but the combination of the two drugs was no more effective than was quinpirole alone. Pretreatment with quinpirole, but not scopolamine, resulted in a markedly "patchy" pattern of staining and actually suppressed staining in the region between patches in the medial striatum. These findings demonstrate that there are both differences and similarities between the effects of scopolamine and quinpirole on D(1) agonist-induced Fos expression and suggest that although inhibition of cholinergic neurons may be one of the mechanisms through which the effects of quinpirole are produced, other factors must also contribute. PMID:11223008

  5. Glutathione depletion due to copper-induced phytochelatin synthesis causes oxidative stress in Silene cucubalus

    Microsoft Academic Search

    C. H. Ric De Vos; M. J. Vonk; R. Vooijs; H. Schat

    1992-01-01

    The relation between loss of glutathione due to metal-induced phytochelatin synthesis and oxidative stress was studied in the roots of copper-sensitive and tolerant Silene cucubalus (L.) Wib., resistant to 1 and 40 micromolar Cu, respectively. The amount of nonprotein sulfhydryl compounds other then glutathione was taken as a measure of phytochelatins. At a supply of 20 micromolar Cu, which is

  6. Depletion of trace elements and acute ocular toxicity induced by desferrioxamine in patients with thalassaemia

    Microsoft Academic Search

    S De Virgiliis; M Congia; M P Turco; F Frau; C Dessi; F Argiolu; R Sorcinelli; A Sitzia; A Cao

    1988-01-01

    High doses of intravenous desferrioxamine infused over a short period of time induce a large faecal and urinary iron excretion but also produce retinal abnormalities that are characterised by decreased amplitude on electroretinography and defective dark adaptation. This regimen also results in high faecal iron, zinc, and copper excretion, and reduced granulocyte zinc concentrations and alkaline phosphatase activity. The retinal

  7. Acetic acid induces pH-independent cellular energy depletion in Salmonella enterica.

    PubMed

    Tan, Sin Mei; Lee, Sui Mae; Dykes, Gary A

    2015-03-01

    Weak organic acids are widely used as preservatives and disinfectants in the food industry. Despite their widespread use, the antimicrobial mode of action of organic acids is still not fully understood. This study investigated the effect of acetic acid on the cell membranes and cellular energy generation of four Salmonella strains. Using a nucleic acid/protein assay, it was established that acetic acid did not cause leakage of intracellular components from the strains. A scanning electron microscopy study further confirmed that membrane disruption was not the antimicrobial mode of action of acetic acid. Some elongated Salmonella cells observed in the micrographs indicated a possibility that acetic acid may inhibit DNA synthesis in the bacterial cells. Using an ATP assay, it was found that at a neutral pH, acetic acid caused cellular energy depletion with an ADP/ATP ratio in the range between 0.48 and 2.63 (p<0.05) that was apparent for the four Salmonella strains. We suggest that this effect was probably due solely to the action of undissociated acid molecules. The antimicrobial effect of acetic acid was better under acidic conditions (ADP/ATP ratio of 5.56 ± 1.27; p<0.05), where the role of both pH and undissociated acid molecules can act together. We concluded that the inhibitory effect of acetic acid is not solely attributable to acidic pH but also to undissociated acid molecules. This finding has implication for the use of acetic acid as an antimicrobial against Salmonella on food products, such as chicken meat, which can buffer its pH. PMID:25562466

  8. Mulberry Leaf Extract Attenuates Oxidative Stress-Mediated Testosterone Depletion in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Hajizadeh, Mohammad Reza; Eftekhar, Ebrahim; Zal, Fatemeh; Jafarian, Aida; Mostafavi-Pour, Zohreh

    2014-01-01

    Background: It has been proposed that oxidative stress may contribute to the development of testicular abnormalities in diabetes. Morus alba leaf extract (MAE) has hypoglycemic and antioxidant properties. We, therefore, explored the impact of the administration of MAE on steroidogenesis in diabetic rats. Methods: To address this hypothesis, we measured the serum level of glucose, insulin, and free testosterone (Ts) as well as oxidative stress parameters (including glutathione peroxidase, glutathione reductase, total antioxidant capacity, and malondialdehyde) in the testis of control, untreated and MAE-treated (1 g/day/kg) diabetic rats. In order to determine the likely mechanism of MAE action on Ts levels, we analyzed the quantitative mRNA expression level of the two key steroidogenic proteins, namely steroid acute regulatory protein (StAR) and P450 cholesterol side-chain cleavage enzyme (P450scc), by real-time PCR. Results: The MAE-treated diabetic rats had significantly decreased glucose levels and on the other hand increased insulin and free Ts levels than the untreated diabetic rats. In addition, the administration of MAE to the diabetic rats restored the oxidative stress parameters toward control. Induction of diabetes decreased testicular StAR mRNA expression by 66% and MAE treatment enhanced mRNA expression to the same level of the control group. However, the expression of P540scc was not significantly decreased in the diabetic group as compared to the control group. Conclusion: Our findings indicated that MAE significantly increased Ts production in the diabetic rats, probably through the induction of StAR mRNA expression levels. Administration of MAE to experimental models of diabetes can effectively attenuate oxidative stress-mediated testosterone depletion. PMID:24644381

  9. Depletion of JARID1B induces cellular senescence in human colorectal cancer.

    PubMed

    Ohta, Katsuya; Haraguchi, Naotsugu; Kano, Yoshihiro; Kagawa, Yoshinori; Konno, Masamitsu; Nishikawa, Shimpei; Hamabe, Atsushi; Hasegawa, Shinichiro; Ogawa, Hisataka; Fukusumi, Takahito; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Noguchi, Yuko; Ozaki, Miyuki; Kudo, Toshihiro; Sakai, Daisuke; Satoh, Taroh; Fukami, Miwa; Ishii, Masaru; Yamamoto, Hirofumi; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

    2013-04-01

    The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44(+)/aldehyde dehydrogenase (ALDH)(+) slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16/INK4A. Of note, lentiviral?mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c?Jun N?terminal kinase (Jnk/Sapk) and senescence?associated ??galactosidase activity. Moreover, green fluorescent?labeled cell tracking indicated that JARID1B?positive CRC cells had greater tumorigenicity than JARID1B?negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B?negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy?resistant cancer cells by the induction of cellular senescence. PMID:23354547

  10. Bicarbonate stimulated phospholipid scrambling induces cholesterol redistribution and enables cholesterol depletion in the sperm plasma membrane.

    PubMed

    Flesch, F M; Brouwers, J F; Nievelstein, P F; Verkleij, A J; van Golde, L M; Colenbrander, B; Gadella, B M

    2001-10-01

    Mammalian sperm cells are activated prior to fertilization by high bicarbonate levels, which facilitate lipoprotein-mediated cholesterol efflux. The role of bicarbonate and cholesterol acceptors on the cholesterol organization in the sperm plasma membrane was tested. Bicarbonate induced an albumin-independent change in lipid architecture that was detectable by an increase in merocyanine staining (due to protein kinase A-mediated phospholipid scrambling). The response was limited to a subpopulation of viable sperm cells that were sorted from the non-responding subpopulation by flow cytometry. The responding cells had reduced cholesterol levels (30% reduction) compared with non-responding cells. The subpopulation differences were caused by variable efficiencies in epididymal maturation as judged by cell morphology. Membrane cholesterol organization was observed with filipin, which labeled the entire sperm surface of non-stimulated and non-responding cells, but labeled only the apical surface area of bicarbonate-responding cells. Addition of albumin caused cholesterol efflux, but only in bicarbonate-responding cells that exhibited virtually no filipin labeling in the sperm head area. Albumin had no effect on other lipid components, and no affinity for cholesterol in the absence of bicarbonate. Therefore, bicarbonate induces first a lateral redistribution in the low cholesterol containing spermatozoa, which in turn facilitates cholesterol extraction by albumin. A model is proposed in which phospholipid scrambling induces the formation of an apical membrane raft in the sperm head surface that enables albumin mediated efflux of cholesterol. PMID:11682613

  11. What's shaking?: Understanding creep and induced seismicity in depleting sandstone reservoirs

    NASA Astrophysics Data System (ADS)

    Hangx, Suzanne; Spiers, Christopher

    2015-04-01

    Subsurface exploitation of the Earth's natural resources, such as oil, gas and groundwater, removes the natural system from its chemical and physical equilibrium. With global energy and water demand increasing rapidly, while availability diminishes, densely populated areas are becoming increasingly targeted for exploitation. Indeed, the impact of our geo-resources needs on the environment has already become noticeable. Deep groundwater pumping has led to significant surface subsidence in urban areas such as Venice and Bangkok. Hydrocarbons production has also led to subsidence and seismicity in offshore (e.g. Ekofisk, Norway) and onshore hydrocarbon fields (e.g. Groningen, the Netherlands). Fluid extraction inevitably leads to (poro)elastic compaction of reservoirs, hence subsidence and occasional fault reactivation. However, such effects often exceed what is expected from purely elastic reservoir behaviour and may continue long after exploitation has ceased or show other time-lag effects in relation to changes in production rates. One of the main hypotheses advanced to explain this is time-dependent compaction, or 'creep deformation', of such reservoirs, driven by the reduction in pore fluid pressure compared with the vertical rock overburden pressure. The operative deformation mechanisms may include grain-scale brittle fracturing and thermally-activated mass transfer processes (e.g. pressure solution). Unfortunately, these mechanisms are poorly known and poorly quantified. As a first step to better describe creep in sedimentary granular aggregates, we have derived a universal, simple model for intergranular pressure solution (IPS) within an ordered pack of spherical grains. This universal model is able to predict the conditions under which each of the respective pressure solution serial processes, i.e. diffusion, precipitation or dissolution, is dominant. In essence, this creates a generic deformation mechanism map for IPS in any granular material. We have used our model to predict the amount and rate of compaction for depleting reservoirs, and compared our predictions to known subsidence rates for reservoirs around the world. This gives a first order-comparison to verify whether or not IPS is an important mechanism in controlling reservoir creep.

  12. Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells.

    PubMed

    Götze, Silke; Coersmeyer, Monique; Müller, Oliver; Sievers, Sonja

    2014-10-01

    Histone deacetylase inhibitors (HDIs) specifically affect cancer cells by inducing cell cycle arrest, activate apoptotic pathways and re-activate epigenetically silenced tumor suppressor genes, but their pleiotropic mode of action is not fully understood. Despite the clinical effects of HDIs in the treatment of hematological malignancies, their potency against solid tumors is still unclear. We investigated the effects and mechanisms of HDI action in colorectal carcinoma cell lines with an activated Wnt signaling pathway, which is implicated in different aspects of tumorigenesis, including cell proliferation, apoptosis, angiogenesis and metastasis. We assessed the effects of HDI treatment in colorectal carcinoma cell lines by measuring histone hyperacetylation, cell viability and expression of Wnt target genes. Upon treatment with HDIs of the hydroxamate class, we found attenuation of Wnt signaling with concomitant induction of apoptosis and colorectal cancer cell death. Strikingly, the effects of HDIs on Wnt signaling were independent of histone hyperacetylation, thus we investigated the role of non-histone target proteins of histone deacetylases (HDACs). The compounds TSA and SAHA induced a rapid proteasome-dependent depletion of the Wnt transcription factor TCF7L2, which may be mediated by inhibition of HDAC 6 and 10. Our findings provide a molecular rationale for the use of HDIs against colorectal carcinomas with activated Wnt signaling. PMID:25050608

  13. Effect of certain toxicants on gonadotropin-induced ovarian non-esterified cholesterol depletion and steroidogenic enzyme stimulation of the common carp Cyprinus carpio in vitro

    SciTech Connect

    Mukherjee, D.; Guha, D.; Kumar, V. (Department of Zoology, University of Kalyani (India))

    1992-06-01

    Isolated ovarian tissues from the common carp, Cyprinus carpio were incubated in vitro to obtain a discrete effect of four common toxicants of industrial origin, namely phenol, sulfide, mercuric chloride and cadmium chloride, on gonadotropin-induced alteration of nonesterified and esterified cholesterol and steroidogenic enzymes, delta 5-3 beta-HSD and 17 beta-HSD activity. Stage II ovarian tissue containing 30-40% mature oocytes were shown to be most responsive to gonadotropins in depleting only nonesterified cholesterol moiety and stimulating the activity of both. Safe doses of above mentioned toxicants when added separately to stage II ovarian tissue with oLH (1 microgram/incubation) gonadotropin-induced depletion of nonesterified cholesterol and gonadotropin-induced stimulation of the activity of both enzymes was significantly inhibited. Esterified cholesterol remained almost unaltered. Findings clearly indicate the impairment of gonadotropin induced fish ovarian steroidogenesis by the four toxicants separately.

  14. The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat.

    PubMed

    Goutier, W; O'Connor, J J; Lowry, J P; McCreary, A C

    2015-06-01

    Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a range of psychostimulants, and other compounds, and may model neuroplastic changes seen in addictive processes and neuropsychiatric disease. The aim of the present study was to investigate the effect of dopamine D1 receptor (D1R) ligands on nicotine-induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically treated (5 days) with vehicle or nicotine (0.4mg/kg; s.c.) and locomotor activity was measured. Following a 5 day withdrawal period, rats were pretreated with vehicle or the D1R antagonist SCH-23390 (0.03mg/kg; i.p.) and challenged with nicotine. Either 45min or 24h post-challenge, the striatum was isolated and ex vivo receptor binding and cAMP accumulation (using LC-MS/MS) were assessed. It was shown that chronic nicotine administration induced the development and expression of locomotor sensitization, of which the latter was blocked by SCH-23390. Nicotine-induced sensitization had no effect on forskolin stimulated cAMP accumulation but increased the efficacy of dopamine for the D1R and decreased the potency of D1R agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. No effect on D1 receptor binding was observed. Moreover, time dependent effects were observed between tissue taken 45min and 24h post-challenge. The present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the D1R. Together these data suggest that changes in D1R signaling in the dorsal striatum may play an important role in the underlying mechanisms of nicotine-induced behavioral sensitization. PMID:25795518

  15. A haplotype at the DBH locus, associated with low plasma dopamine ?-hydroxylase activity, also associates with cocaine-induced paranoia

    Microsoft Academic Search

    J F Cubells; H R Kranzler; E McCance-Katz; G M Anderson; R T Malison; L H Price; J Gelernter

    2000-01-01

    Low levels of dopamine ?-hydroxylase (D?H) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. D?H level is a stable, genetically controlled trait. DBH, the locus encoding D?H protein, is the major quantitative trait locus controlling plasma and CSF D?H levels. We therefore hypothesized that DBH variants or

  16. Chemical Hypoxia-Induced Cell Death in Human Glioma Cells: Role of Reactive Oxygen Species, ATP Depletion, Mitochondrial Damage and Ca 2+

    Microsoft Academic Search

    Jae Ick Jeong; Young Woo Lee; Yong Keun Kim

    2003-01-01

    This study was undertaken to evaluate whether chemical hypoxia-induced cell injury is a result of reactive oxygen species (ROS) generation, ATP depletion, mitochondrial permeability transition, and an increase in intracellular Ca2+, in A172 cells, a human glioma cell line. Chemical hypoxia was induced by incubating cells with antimycin A, an inhibitor of mitochondrial electron transport, in a glucose-free medium. Exposure

  17. The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis.

    PubMed

    Gjoksi, Bebeka; Ghayor, Chafik; Siegenthaler, Barbara; Ruangsawasdi, Nisarat; Zenobi-Wong, Marcy; Weber, Franz E

    2015-09-01

    Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption. In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague-Dawley rats were ovariectomized and weekly NMP treatment was administrated 1week after surgery for 15weeks. Bone parameters and related serum biomarkers were analyzed. 15weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group. Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis. PMID:25959414

  18. Dopamine receptor 3 might be an essential molecule in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

    PubMed Central

    2013-01-01

    Background 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson’s disease (PD)-like neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) via its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), which is transported by the dopamine (DA) transporter into DA nerve terminals. DA receptor subtype 3 (D3 receptor) participates in neurotransmitter transport, gene regulation in the DA system, physiological accommodation via G protein-coupled superfamily receptors and other physiological processes in the nervous system. This study investigated the possible correlation between D3 receptors and MPTP-induced neurotoxicity. A series of behavioral experiments and histological analyses were conducted in D3 receptor-deficient mice, using an MPTP-induced model of PD. Results After the fourth MPTP injection, wild-type animals that received 15 mg/kg per day displayed significant neurotoxin-related bradykinesia. D3 receptor-deficient mice displayed attenuated MPTP-induced locomotor activity changes. Consistent with the behavioral observations, further neurohistological assessment showed that MPTP-induced neuronal damage in the SNpc was reduced in D3 receptor-deficient mice. Conclusions Our study indicates that the D3 receptor might be an essential molecule in MPTP-induced PD and provides a new molecular mechanism for MPTP neurotoxicity. PMID:23902361

  19. Raman and loss induced quantum noise in depleted fiber optical parametric amplifiers.

    PubMed

    Friis, S M M; Rottwitt, K; McKinstrie, C J

    2013-12-01

    We present a semi-classical approach for predicting the quantum noise properties of fiber optical parametric amplifiers. The unavoidable contributors of noise, vacuum fluctuations, loss-induced noise, and spontaneous Raman scattering, are included in the analysis of both phase-insensitive and phase-sensitive amplifiers. We show that the model agrees with earlier fully quantum approaches in the linear gain regime, whereas in the saturated gain regime, in which the classical equations are valid, we predict that the amplifier increases the signal-to-noise ratio by generating an amplitude-squeezed state of light. Also, in the same process, we analyze the quantum noise properties of the pump, which is difficult using standard quantum approaches, and we discover that the pump displays complicated dynamics in both the linear and the nonlinear gain regimes. PMID:24514485

  20. Exogenous dopamine induces dehydroepiandrosterone sulfotransferase (rSULT2A1) in rat liver and changes the pharmacokinetic profile of moxifloxacin in rats.

    PubMed

    Shao, Xueyan; Li, Jian; Wang, Siyuan; Chen, Guangping; Xu, Jiaojiao; Ji, Xiwei; Li, Liang; Lu, Wei; Zhou, Tianyan

    2015-02-01

    Dehydroepiandrosterone sulfotransferase (SULT2A1) plays an important role in the detoxification of hydroxyl-containing xenobitotics and in the regulation of the biological activities of hydroxysteroids. Although dopamine (DA) is a vital neurotransmitter, DA also has some special functions in outer peripheral system and takes effect by binding with dopamine receptors including five subtypes (D1-D5). The objective of this study was to investigate the effect of exogenous DA on both the regulation of rSULT2A1 (rat SULT2A1) and the pharmacokinetics of moxifloxacin which is a specific substrate of rSULT2A1. After different doses of DA (0, 2, 10 and 100 mg/kg/d) were administrated to both male and female rats for 7 days, the activity, protein level and mRNA expression of rSULT2A1 increased significantly. Moreover, both Cmax and AUC of moxifloxacin decreased and AUC of moxifloxacin sulfate conjugate metabolite increased significantly when moxifloxacin was administered to rats with DA pretreatment. Additionally, D1 expression in liver and cAMP concentration also increased after the treatment with DA. Overall these results suggest that exogenous DA may induce rSULT2A1 in rat liver and may further change the pharmacokinetic characteristics of some substrates of SULT2A1, and the activation of D1-like receptor is probably involved in rSULT2A1 induction by DA. PMID:25760536

  1. Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): Implications to manganese-induced parkinsonism

    PubMed Central

    Guilarte, Tomás R.; Burton, Neal C.; McGlothan, Jennifer L.; Verina, Tatyana; Zhou, Yun; Alexander, Mohab; Pham, Luu; Griswold, Michael; Wong, Dean F.; Syversen, Tore; Schneider, Jay S.

    2010-01-01

    The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using Positron Emission Tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n=4), 5.0-6.7 mg Mn/kg (n=5), or 8.3-10.0 mg Mn/kg (n=3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals. PMID:18808452

  2. Serotonin depletion-induced maladaptive aggression requires the presence of androgens.

    PubMed

    Studer, Erik; Näslund, Jakob; Andersson, Erik; Nilsson, Staffan; Westberg, Lars; Eriksson, Elias

    2015-01-01

    The sex hormone testosterone and the neurotransmitter serotonin exert opposite effects on several aspects of behavior including territorial aggression. It is however not settled if testosterone exerts its pro-aggressive effects by reducing serotonin transmission and/or if the anti-aggressive effect of serotonin requires the presence of the androgen. Using the resident intruder test, we now show that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (300 mg/kg x 3 days) increases the total time of attack as well as the percentage amount of social behavior spent on attack but not that spent on threat - i.e. that it induces a pattern of unrestricted, maladaptive aggression - in gonadectomized C57Bl/6 male mice receiving testosterone replacement; in contrast, it failed to reinstate aggression in those not given testosterone. Whereas these results suggest the pro-aggressive effect of testosterone to be independent of serotonin, and not caused by an inhibition of serotonergic activity, the pCPA-induced induction of maladaptive aggression appears to require the presence of the hormone. In line with these findings, pCPA enhanced the total time of attack as well the relative time spent on attacks but not threats also in wild-type gonadally intact male C57Bl/6 mice, but failed to reinstate aggression in mice rendered hypo-aggressive by early knock-out of androgen receptors in the brain (ARNesDel mice). We conclude that androgenic deficiency does not dampen aggression by unleashing an anti-aggressive serotonergic influence; instead serotonin seems to modulate aggressive behavior by exerting a parallel-coupled inhibitory role on androgen-driven aggression, which is irrelevant in the absence of the hormone, and the arresting of which leads to enhanced maladaptive aggression. PMID:25978464

  3. 600 ns pulse electric field-induced phosphatidylinositol4,5-bisphosphate depletion.

    PubMed

    Tolstykh, Gleb P; Beier, Hope T; Roth, Caleb C; Thompson, Gary L; Ibey, Bennett L

    2014-12-01

    The interaction between nsPEF-induced Ca(2+) release and nsPEF-induced phosphatidylinositol4,5-bisphosphate (PIP2) hydrolysis is not well understood. To better understand this interrelation we monitored intracellular calcium changes, in cells loaded with Calcium Green-1 AM, and generation of PIP2 hydrolysis byproducts (inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)) in cells transfected with one of two fluorescent reporter genes: PLC?-PH-EGFP or GFP-C1-PKC?-C1a. The percentage fluorescence differences (?F %) after exposures were determined. Upon nsPEF impact, we found that in the absence of extracellular Ca(2+) the population of IP3 liberated during nsPEF exposure (?F 6%±3, n=22), is diminished compared to the response in the presence of calcium (?F 84%±15, n=20). The production of DAG in the absence of extracellular Ca(2+) (?F 29%±5, n=25), as well as in cells exposed to thapsigargin (?F 40%±12, n=15), was not statistically different from cells exposed in the presence of extracellular calcium (?F 22±6%, n=18). This finding suggests that the change in intracellular calcium concentration is not solely driving the observed response. Interestingly, the DAG produced in the absence of Ca(2+) is the strongest near the membrane regions facing the electrodes, whereas the presence of extracellular Ca(2+) leads to a whole cell response. The reported observations of Ca(2+) dynamics combined with IP3 and DAG production suggest that nsPEF may cause a direct effect on the phospholipids within the plasma membrane. PMID:24530104

  4. Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts

    PubMed Central

    Wang, Shusen; Tasch, James; Kheradmand, Taba; Ulaszek, Jodie; Ely, Sora; Zhang, Xiaomin; Hering, Bernhard J.; Miller, Stephen D.; Luo, Xunrong

    2013-01-01

    Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation. PMID:23852699

  5. Involvement of dopamine D1/D2 receptors on harmane-induced amnesia in the step-down passive avoidance test.

    PubMed

    Nasehi, Mohammad; Piri, Morteza; Nouri, Maryam; Farzin, Davood; Nayer-Nouri, Touraj; Zarrindast, Mohammad Reza

    2010-05-25

    Ingestion of harmane and other alkaloids derived from plant Peganum harmala has been shown to elicit profound behavioural and toxic effects in humans, including hallucinations, excitation, feelings of elation, and euphoria. These alkaloids in the high doses can cause a toxic syndrome characterized by tremors and convulsions. Harmane has also been shown to act on a variety of receptor systems in the mammalian brain, including those for serotonin, dopamine and benzodiazepines. In animals, it has been reported to affect short and long term memory. In the present study, effects of dopamine D1 and D2 receptor antagonists on the harmane (HA)-induced amnesia and exploratory behaviors were examined in mice. One-trial step-down and hole-board paradigms were used for the assessment of memory retention and exploratory behaviors in adult male NMRI mice respectively. Intraperitoneal (i.p.) administration of HA (5 and 10 mg/kg) immediately after training decreased memory consolidation, while had no effect on anxiety-like behavior. Memory retrieval was not altered by 15- or 30 min pre-testing administration of the D1 (SCH23390, 0.025, 0.05 and 0.1 mg/kg) or D2 (sulpiride 12.5, 25 and 50 mg/kg) receptor antagonists, respectively. In contrast, SCH23390 (0.05 and 0.1 mg/kg) or sulpiride (25 and 50 mg/kg) pre-test administration fully reversed HA-induced impairment of memory consolidation. Finally, neither D1 nor D2 receptor blockade affected exploratory behaviors in the hole-board paradigm. Altogether, these findings strongly suggest an involvement of D1 and D2 receptors modulation in the HA-induced impairment of memory consolidation. PMID:20188725

  6. Temporally Dependent Changes in Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens Shell are Reversed by D1-Like Dopamine Receptor Stimulation

    PubMed Central

    Ortinski, Pavel I; Vassoler, Fair M; Carlson, Gregory C; Pierce, R Christopher

    2012-01-01

    Dopaminergic and glutamatergic inputs to the nucleus accumbens shell have a central role in reward processing. Non-contingent cocaine administration generates a number of long-term AMPA receptor-dependent changes in synaptic efficacy. However, the synaptic consequences of cocaine self-administration and the potential role of dopamine in these processes remain unclear. Here, we examined the influence of D1 dopamine receptor (D1DR) activation on excitatory synaptic plasticity in the accumbens shell of adult rats following cocaine self-administration. Our results indicated that during the first 2 days following cocaine exposure both pre- and post-synaptic mechanisms contribute to a net decrease in AMPA receptor-mediated signaling. This is reflected by decreased frequency of miniature EPSCs (mEPSCs) attributable to enhanced cannabinoid receptor activity, decreased mEPSC amplitude, and increased paired-pulse ratio of evoked EPSCs. In contrast, the only changes observed in the shell 3–4 weeks following cocaine self-administration were increased mEPSCs amplitudes and AMPA/NMDA ratios. We further found that although these cocaine-induced neuroadaptations during early and late abstinence have different synaptic expression mechanisms, they were normalized by stimulation of D1DRs. Thus, pre-exposure to the D1DR agonist, SKF38393, during the initial period of abstinence increased excitatory synaptic strength, but reduced excitatory signaling after weeks of abstinence. Taken together, these results indicate that the direction of changes in excitatory transmission induced by cocaine self-administration switches over the first few weeks of abstinence. Moreover, D1DRs gate the stability of these cocaine-induced changes at glutamatergic synapses in the accumbens shell by utilizing multiple temporally distinct mechanisms, which has implications for the treatment of cocaine craving and addiction. PMID:22414814

  7. FAS-Based Cell Depletion Facilitates the Selective Isolation of Mouse Induced Pluripotent Stem Cells

    PubMed Central

    Warlich, Eva; Schambach, Axel; Lock, Dominik; Wedekind, Dirk; Glage, Silke; Eckardt, Dominik; Bosio, Andreas; Knöbel, Sebastian

    2014-01-01

    Cellular reprogramming of somatic cells into induced pluripotent stem cells (iPSC) opens up new avenues for basic research and regenerative medicine. However, the low efficiency of the procedure remains a major limitation. To identify iPSC, many studies to date relied on the activation of pluripotency-associated transcription factors. Such strategies are either retrospective or depend on genetically modified reporter cells. We aimed at identifying naturally occurring surface proteins in a systematic approach, focusing on antibody-targeted markers to enable live-cell identification and selective isolation. We tested 170 antibodies for differential expression between mouse embryonic fibroblasts (MEF) and mouse pluripotent stem cells (PSC). Differentially expressed markers were evaluated for their ability to identify and isolate iPSC in reprogramming cultures. Epithelial cell adhesion molecule (EPCAM) and stage-specific embryonic antigen 1 (SSEA1) were upregulated early during reprogramming and enabled enrichment of OCT4 expressing cells by magnetic cell sorting. Downregulation of somatic marker FAS was equally suitable to enrich OCT4 expressing cells, which has not been described so far. Furthermore, FAS downregulation correlated with viral transgene silencing. Finally, using the marker SSEA-1 we exemplified that magnetic separation enables the establishment of bona fide iPSC and propose strategies to enrich iPSC from a variety of human source tissues. PMID:25029550

  8. Experimentally-induced immune activation in natural hosts of SIV induces significant increases in viral replication and CD4+ T cell depletion

    SciTech Connect

    Ribeiro, Ruy M [Los Alamos National Laboratory

    2008-01-01

    Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable non-pathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and stable viral loads (VLs) for long periods of time. In vivo administration of lipopolysaccharide (LPS) or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4{sup +} T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell prolifeation are key factors in AIDS pathogenesis.

  9. Prevention of immunodeficiency virus induced CD4+ T-cell depletion by prior infection with a non-pathogenic virus

    SciTech Connect

    TerWee, Julie A.; Carlson, Jennifer K.; Sprague, Wendy S.; Sondgeroth, Kerry S.; Shropshire, Sarah B.; Troyer, Jennifer L. [Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado (United States); VandeWoude, Sue [Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado (United States)], E-mail: suev@lamar.colostate.edu

    2008-07-20

    Immune dysregulation initiated by a profound loss of CD4+ T-cells is fundamental to HIV-induced pathogenesis. Infection of domestic cats with a non-pathogenic lentivirus prevalent in the puma (puma lentivirus, PLV or FIV{sub PCO}) prevented peripheral blood CD4+ T-cell depletion caused by subsequent virulent FIV infection. Maintenance of this critical population was not associated with a significant decrease in FIV viremia, lending support to the hypothesis that direct viral cytopathic effect is not the primary cause of immunodeficiency. Although this approach was analogous to immunization with a modified live vaccine, correlates of immunity such as a serum-neutralizing antibody or virus-specific T-cell proliferative response were not found in protected animals. Differences in cytokine transcription profile, most notably in interferon gamma, were observed between the protected and unprotected groups. These data provide support for the importance of non-adaptive enhancement of the immune response in the prevention of CD4+ T-cell loss.

  10. Na+ appetite induced by depleting extracellular fluid volume activates the enkephalin/mu-opioid receptor system in the rat forebrain.

    PubMed

    Grondin, M-E; Gobeil-Simard, A; Drolet, G; Mouginot, D

    2011-09-29

    In Na(+) appetite neurobiology, it is essential to investigate whether endogenous opioids modulate the output of the neural substrates that are involved in both the detection and integration of Na(+) deficiency and the motivational aspect of Na(+) intake. Thus, evaluating the recruitment dynamics of enkephalin (ENK)-containing and/or mu-opioid receptor (?-OR)-expressing neurons in close correlation with the hydromineral state of the rat might provide useful information regarding the role of the opioid system in regulating the central network that controls water and Na(+) intake. Furosemide was used to deplete both fluid volume and the Na(+) content of the extracellular fluid (ECF) compartment when combined with water repletion and a short-term Na(+)-free diet. Na(+) restoration in the ECF compartment was achieved by providing unrestricted access to both saline (0.3 M NaCl) and water. Combining in situ hybridization (against ENK and ?-OR mRNA) and immunohistochemistry (against Fos) revealed a specific pattern of hypovolemia-induced Fos expression in the enkephalinergic subpopulations of the central amygdala, in the oval nucleus of the bed nucleus of the stria terminalis and in the nucleus accumbens shell. Hypovolemia also induced transient Fos expression in ?-OR-expressing neurons in the same nuclei and in the median preoptic nucleus and subfornical organ. However, this specific hydromineral state did not activate the ENK and/or ?-OR-expressing neurons in the lateral parabrachial nucleus or in the medial nucleus of the solitary tract. These results implicate the ENK/?-OR system as a putative facilitator of Na(+) intake in discrete regions of the forebrain, possibly by modulating the hedonic and reward value of Na(+) by increasing ENK release in these regions. PMID:21745545

  11. Spirafolide from bay leaf (Laurus nobilis) prevents dopamine-induced apoptosis by decreasing reactive oxygen species production in human neuroblastoma SH-SY5Y cells.

    PubMed

    Ham, Ahrom; Kim, Bora; Koo, Uk; Nam, Kung-Woo; Lee, Sung-Jin; Kim, Kyeong Ho; Shin, Jongheon; Mar, Woongchon

    2010-12-01

    Reactive oxygen species (ROS) are important mediators in many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. This study tested the neuroprotective effects of spirafolide, a compound purified from the leaves of Laurus nobilis L. (Lauraceae), against dopamine (DA)-induced apoptosis in human neuroblastoma SH-SY5Y cells. Following a 24-h exposure of cells to DA (final conc., 0.6 mM), we observed a marked increase in apoptosis, increased generation of ROS and decreased cell viability. Pretreatment of the cells for 24 h with spirafolide (0.4, 2, and 10 ?M) before exposure to DA notably increased cell survival (p < 0.01) and lowered intracellular ROS levels (p < 0.01). These results indicate that spirafolide has neuroprotective effects against DA toxicity. These effects may contribute to the treatment of neurodegenerative diseases. PMID:21191760

  12. Salviae Miltiorrhizae BGE Radix increases rat striatal K(+)-stimulated dopamine release and activates the dopamine release with protection against hydrogen peroxide-induced injury in rat pheochromocytoma PC12 cells.

    PubMed

    Chung, Tae-Wook; Koo, Byung-Soo; Kim, Kyeong-Oh; Jeong, Hee-Sang; Kim, Min-Gon; Chung, Kang-Hung; Lee, In-Seon; Kim, Cheorl-Ho

    2006-01-01

    The present study investigated the effect of the medicinal plant Salviae miltiorrhizae radix (SMR) on dopaminergic neurotransmission in comparison with amphetamine. The effect of SM (0.1 g/ml) on K(+) (20 mM)-stimulated dopamine (DA) release from rat striatal slices was compared with amphetamine (10(-4) M). Amphetamine and SMR significantly increased K(+)-stimulated DA release (P<0.001) from rat striatal slices when compared with K(+)-stimulated alone. On the other hand, to examine whether in vitro SMR treatment induces DA release in PC12 cells, the role of protein kinases has been investigated in the induction of the SMR-mediated events by using inhibitors of protein kinase C (PKC), mitogen activated protein kinase (MAP kinase) or protein kinase A (PKA). PKC inhibitors chelerythrine (50 and 100 nM), Ro31-8220 (100 nM) and the MAP kinase inhibitor, PD98059 (20 microM) inhibited the ability of SMR to elicit the SMR-stimulated DA release. The direct-acting PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA, 100 nM) mimicked the ability of SMR to elicit DA release. On the contrary, a selective PKA inhibitor, 50 microM Rp-8-Br-cAMP, blocked the development of SMR-stimulated DA release. The results demonstrated that SMR may stimulate DA release and that SMR-induced increases in MAP kinase and PKC are important for induction of the enhancement in transporter-mediated DA release and PKA was also required for the enhancement in SMR-stimulated DA release. SMR treatment (0.1-10 microg/ml) to the hydrogen peroxide (H(2)O(2))-treated PC12 cells activated the enzyme activities such as catalase, superoxide dismutase and glutathione peroxidase, and decreased the malondialdehyde level, indicating that SMR has also protective effects against free radical-induced cell toxicity. Therefore, the mechanism by which SMR induces the enhancement in SMR-stimulated DA release is apparent. It remains to be determined whether the effect of SMR on DA function is important in its therapeutic use in the treatment of drug addiction. PMID:16475004

  13. Nutrient Depletion

    NSDL National Science Digital Library

    In this activity, students observe nutrient depletion as they germinate and grow nutrient-demanding seedlings. They will discover that all plants require nutrients to grow and thrive and that these nutrients are found in the soil and absorbed through the plants' root systems. They will also learn that nutrients are dissolved in water and are distributed throughout the plant via its circulatory system; when the plants are harvested, they take the nutrients with them, depleting the soil of these essential components.

  14. Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice.

    PubMed

    Wen, Jie; Xiao, Yongtao; Wang, Jun; Pan, Weihua; Zhou, Ying; Zhang, Xiaoling; Guan, Wenbin; Chen, Yingwei; Zhou, Kejun; Wang, Yang; Shi, Bisheng; Zhou, Xiaohui; Yuan, Zhenghong; Cai, Wei

    2015-02-01

    Recent studies have indicated that perinatal infection with cytomegalovirus (CMV) may promote bile duct damage in biliary atresia (BA) and that the decreased regulatory T cell (Treg) percentage associated with BA may further amplify the bile duct damage. Although a majority of BA patients have had previous CMV infections and lower percentages of Tregs, it is unknown whether an initial exposure to a low dose of CMV could induce exaggerated and progressive biliary injury. A Treg-depleted neonatal mouse was infected with low-dose CMV (LD-CMV) as a model to study BA patients. LD-CMV infection in Treg-depleted mice induced extensive inflammation in both the intrahepatic and extrahepatic bile ducts, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts. Serum total and direct bilirubin amounts were also elevated. Evidence for the involvement of cellular and humoral autoimmune responses in LD-CMV-infection of Treg-depleted mice was also obtained through detection of increased percentages of CD3 and CD8 mononuclear cells and serum autoantibodies reactive to bile duct epithelial proteins, one of which was identified as ?-enolase. Depletion of Tregs that can lead to the decreased inhibition of aberrantly activated hepatic T-lymphocytes and generation of autoantibodies may lead to further injury. Increased hepatic expression of Th1-related genes (TNF-?), IFN-?-activated genes (STAT-1) and Th1 cytokines (TNF-?, lymphotactin, IL-12p40 and MIP -1?) were also identified. In conclusion, autoimmune-mediated and inflammatory responses induced by LD-CMV infection in Treg-depleted mice results in increased intrahepatic and extrahepatic bile duct injury and contributed to disease progression. PMID:25531565

  15. Use of Fluorescent Probes to Assess the Early Sulfhydryl Depletion and Oxidative Stress Induced by Mechlorethamine in Human Bronchial Epithelial Cells

    Microsoft Academic Search

    S Rappeneau; A Baeza-Squiban; F Braut-Boucher; M Aubery; M.-C Gendron; F Marano

    1999-01-01

    In this study, we report in vitro methods using fluorescent probes to assess thiol depletion and the oxidative stress induced by mechlorethamine (HN2), a nitrogen mustard, on a human bronchial epithelial cell line (16HBE14o-). Monobromobimane (mBBr) and 2?,7?-dichlorofluorescin-diacetate (H2DCF-DA) were respectively used to monitor the intracellular thiol and peroxide levels. Fluorescent measurements were realized on gated live cells with a

  16. Inducible dopaminergic glutathione depletion in an alpha-synuclein transgenic mouse model results in age-related olfactory dysfunction

    PubMed Central

    Kim, Yong-Hwan; Lussier, Stephanie; Rane, Anand; Choi, Sung W.; Andersen, Julie K.

    2010-01-01

    Parkinson's disease (PD) involves both motor and non-motor disturbances. Non-motor features include alterations in sensory olfactory function which may constitute a viable biomarker for the disorder. It is not clear what causes olfactory dysfunction but it appears to coincide with the development of synucleopathy within the olfactory bulb (OB). Elevation in alpha-synuclein is indeed a risk factor for development of the sporadic disorder. The multifactorial nature of the idiopathic disease combined with variability in its presentation suggests that it is likely to be influenced by several factors and that in vivo models that explore the synergistic effect of alpha-synuclein elevation with other potential contributing factors are likely to be of importance in understanding the disease etiology. Using a dual transgenic mouse model of dopaminergic alpha-synuclein overexpression coupled with doxycycline (Dox)-inducible glutathione depletion in these same cells, we demonstrate an age-related loss in behavioral olfactory function coupled with a significant neurodegeneration of glomerular dopaminergic neurons. This is accompanied by increases in alpha-synuclein levels in non-dopaminergic cells in the granule cell layer. In addition, isolated olfactory bulb synaptosomes from dual transgenic lines with Dox consistently showed a slight but significant reduction in maximum mitochondrial respiration compared to controls. These results suggest that in the presence of increased oxidative stress, increased alpha-synuclein expression within dopaminergic OB neurons results in neurodegeneration in the glomerular layer and increased alpha-synuclein levels in the granular cell layer which coincide with olfactory dysfunction. PMID:21055449

  17. ATP Depletion Via Mitochondrial F1F0 Complex by Lethal Factor is an Early Event in B. Anthracis-Induced Sudden Cell Death

    PubMed Central

    Woodberry, Mitchell W.; Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Chopra, Ashok K.; Kurosky, Alexander; Peterson, Johnny W.; Boldogh, Istvan

    2009-01-01

    Bacillus anthracis’ primary virulence factor is a tripartite anthrax toxin consisting of edema factor (EF), lethal factor (LF) and protective antigen (PA). In complex with PA, EF and LF are internalized via receptor-mediated endocytosis. EF is a calmodulin-dependent adenylate cyclase that induces tissue edema. LF is a zinc-metalloprotease that cleaves members of mitogen-activated protein kinase kinases. Lethal toxin (LT: PA plus LF)-induced death of macrophages is primarily attributed to expression of the sensitive Nalp1b allele, inflammasome formation and activation of caspase-1, but early events that initiate these processes are unknown. Here we provide evidence that an early essential event in pyroptosis of alveolar macrophages is LF-mediated depletion of cellular ATP. The underlying mechanism involves interaction of LF with F1F0-complex gamma and beta subunits leading to increased ATPase activity in mitochondria. In support, mitochondrial DNA-depleted MH-S cells have decreased F1F0 ATPase activity due to the lack of F06 and F08 polypeptides and show increased resistance to LT. We conclude that ATP depletion is an important early event in LT-induced sudden cell death and its prevention increases survival of toxin-sensitive cells.

  18. Dopamine D1 and ?-opioid receptor antagonism blocks anticipatory 50 kHz ultrasonic vocalizations induced by palatable food cues in Wistar rats

    PubMed Central

    Buck, Cara L.; Vendruscolo, Leandro F.; Koob, George F.; George, Olivier

    2014-01-01

    Rationale Fifty kilohertz ultrasonic vocalizations (USVs) have been sometimes shown to reflect positive affective-like states in rats. Rewarding events, such as access to palatable food or drugs of abuse, increase the number of anticipatory 50 kHz USVs. However, little is known about the predictability of USVs, subtypes of USVs involved, and underlying neurobiological mechanisms. Objectives We examined whether cue-induced anticipatory 50 kHz USVs predict palatable food intake and tested the effects of dopamine D1 and ?-opioid receptor antagonism on anticipatory USVs. Materials Food-restricted rats received repeated sessions of a 2 min cue light immediately followed by 5 min access to palatable food. Ultrasonic vocalizations were recorded during cue presentation. After 24 pairing sessions, the rats were pretreated with the D1 receptor antagonist SCH 23390 (5, 10, and 20 ?g/kg) and ?-opioid receptor antagonist naltrexone (0.03, 0.06, 0.13, 0.25, 0.5, and 1 mg/kg) in a Latin-square design, and USVs were recorded during cue presentation. Results Rats emitted 50 kHz USVs during cue presentation, and the number of USVs increased across sessions with robust and stable interindividual differences. Escalation in USVs was subtype-dependent, with non-trill calls significantly increasing over time. Palatable food intake was positively correlated with anticipatory 50 kHz USVs. Moreover, anticipatory USVs were dose-dependently prevented by antagonism of D1 and ?-opioid receptors. Conclusions These findings demonstrate that anticipatory 50 kHz USVs represent a stable phenotype of increased motivation for food, and dopamine and opioid systems appear to mediate anticipatory 50 kHz USVs. PMID:24221826

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

    PubMed Central

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

    1989-01-01

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

  20. Dopamine D2 receptor gene expression in human adenohypophysial adenomas

    Microsoft Academic Search

    Lucia Stefaneanu; Kalman Kovacs; Eva Horvath; Michael Buchfelder; Rudolf Fahlbusch; Ioana Lancranjan

    2001-01-01

    The inhibitory effects of dopamine on adenohypophysial cells are mediated via dopamine subtype 2 receptor (D2R). Dopamine\\u000a agonists inhibit hormone release and induce tumor shrinkage in most prolactin-secreting adenomas, whereas in other adenoma\\u000a types such effects are sporadic. We investigated D2R gene expression by in situ hybridization (ISH) and immunocytochemistry in different types of pituitary adenomas. By ISH, a variable

  1. The Dopamine Metabolite 3-Methoxytyramine Is a Neuromodulator

    Microsoft Academic Search

    Tatyana D. Sotnikova; Jean-Martin Beaulieu; Stefano Espinoza; Bernard Masri; Xiaodong Zhang; Ali Salahpour; Larry S. Barak; Marc G. Caron; Raul R. Gainetdinov; Alessandro Bartolomucci

    2010-01-01

    Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for

  2. Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats.

    PubMed

    Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang; Zhong, Wei; Zhang, Jiayuan; Zhang, Xiang; Wang, Yuhua; McClain, Craig J

    2015-06-01

    High-fructose feeding impairs copper status and leads to low copper availability, which is a novel mechanism in obesity-related fatty liver. Copper deficiency-associated hepatic iron overload likely plays an important role in fructose-induced liver injury. Excess iron in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver disease induced by a marginal-copper high-fructose diet (CuMF). Male weanling Sprague-Dawley rats were fed either a copper-adequate or a marginally copper-deficient diet for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was also given ad libitum. KCs were depleted by intravenous administration of gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. Hepatic triglyceride accumulation was completely eliminated with KC depletion in CuMF consumption rats, which was associated with the normalization of elevated plasma monocyte chemoattractant protein-1 (MCP-1) and increased hepatic sterol regulatory element binding protein-1 expression. However, hepatic copper and iron content were not significantly affected by KC depletion. In addition, KC depletion reduced body weight and epididymal fat weight as well as adipocyte size. Plasma endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP-1 was robustly increased in the culture medium when isolated KCs from CuMF rats were treated with LPS. Our data suggest that KCs play a critical role in the development of hepatic steatosis induced by marginal-copper high-fructose diet. PMID:25813056

  3. Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

    PubMed

    Devroye, Céline; Cathala, Adeline; Maitre, Marlčne; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto

    2015-02-01

    The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum. PMID:25446572

  4. Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium.

    PubMed Central

    Spivey, J R; Bronk, S F; Gores, G J

    1993-01-01

    Chenodeoxycholate is toxic to hepatocytes, and accumulation of chenodeoxycholate in the liver during cholestasis may potentiate hepatocellular injury. However, the mechanism of hepatocellular injury by chenodeoxycholate remains obscure. Our aim was to determine the mechanism of cytotoxicity by chenodeoxycholate in rat hepatocytes. At a concentration of 250 microM, glycochenodeoxycholate was more toxic than either chenodeoxycholate or taurochenodeoxycholate. Cellular ATP was 86% depleted within 30 min after addition of glycochenodeoxycholate. Fructose, a glycolytic substrate, maintained ATP concentrations at 50% of the initial value and protected against glycochenodeoxycholate cytotoxicity. ATP depletion in the absence of a glycolytic substrate suggested impairment of mitochondrial function. Indeed, glycochenodeoxycholate inhibited state 3 respiration in digitonin-permeabilized cells in a dose-dependent manner. After ATP depletion, a sustained rise in cytosolic free calcium (Cai2+) was observed. Removal of extracellular Ca2+ abolished the rise in Cai2+, decreased cellular proteolysis, and protected against cell killing by glycochenodeoxycholate. The results suggest that glycochenodeoxycholate cytotoxicity results from ATP depletion followed by a subsequent rise in Cai2+. The rise in Cai2+ leads to an increase in calcium-dependent degradative proteolysis and, ultimately, cell death. We conclude that glycochenodeoxycholate causes a bioenergetic form of lethal cell injury dependent on ATP depletion analogous to the lethal cell injury of anoxia. PMID:8325981

  5. Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation

    SciTech Connect

    Yun, Hong Shik; Hong, Eun-Hee [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of) [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of); Lee, Su-Jae [Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of)] [Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of); Baek, Jeong-Hwa [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of) [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of); Lee, Chang-Woo [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746 (Korea, Republic of); Yim, Ji-Hye; Um, Hong-Duck [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Hwang, Sang-Gu, E-mail: sgh63@kcch.re.kr [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

    2013-09-27

    Highlights: •HRP-3 is a radiation- and anticancer drug-responsive protein in A549 cells. •Depletion of HRP-3 induces apoptosis of radio- and chemoresistant A549 cells. •Depletion of HRP-3 promotes ROS generation via inhibition of the Nrf2/HO-1 pathway. •Depletion of HRP-3 enhances ROS-dependent p53 activation and PUMA expression. -- Abstract: Biomarkers based on functional signaling have the potential to provide greater insight into the pathogenesis of cancer and may offer additional targets for anticancer therapeutics. Here, we identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistance-related gene and characterized the molecular mechanism by which its encoded protein regulates the radio- and chemoresistant phenotype of lung cancer-derived A549 cells. Knockdown of HRP-3 promoted apoptosis of A549 cells and potentiated the apoptosis-inducing action of radio- and chemotherapy. This increase in apoptosis was associated with a substantial generation of reactive oxygen species (ROS) that was attributable to inhibition of the Nrf2/HO-1 antioxidant pathway and resulted in enhanced ROS-dependent p53 activation and p53-dependent expression of PUMA (p53 upregulated modulator of apoptosis). Therefore, the HRP-3/Nrf2/HO-1/ROS/p53/PUMA cascade is an essential feature of the A549 cell phenotype and a potential radiotherapy target, extending the range of targets in multimodal therapies against lung cancer.

  6. 5HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

    Microsoft Academic Search

    Franz X Vollenweider; Peter Vontobel; Daniel Hell; Klaus L Leenders

    1999-01-01

    The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine

  7. The protein l-isoaspartyl (d-aspartyl) methyltransferase protects against dopamine-induced apoptosis in neuroblastoma SH-SY5Y cells.

    PubMed

    Ouazia, D; Levros, L-C; Rassart, É; Desrosiers, R R

    2015-06-01

    Parkinson's disease (PD) is the most common neurodegenerative motor disorder in the world. The main causes of neurodegeneration in PD are mitochondrial impairment and oxidative stress promoted by dopamine (DA) metabolism in the cytosol. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a protein repair enzyme with anti-apoptotic properties. We previously reported that PIMT was downregulated at both gene and protein levels by DA-induced oxidative stresses in SH-SY5Y neuroblastoma cells. The purpose of the current study was to investigate the anti-apoptotic function of PIMT toward DA-induced cell death to better understand its specific neuroprotective role. Overexpression of wild-type PIMT, in contrast to its inactive mutant, protected SH-SY5Y cells from cell death and caspase 3 activation upon DA treatments. The intrinsic pathway of apoptosis as measured by caspase 9 activity was triggered by reactive oxygen species produced from DA metabolism, and overexpression of wild-type PIMT completely prevented caspase 9 activity stimulated by DA. In addition, cells overexpressing wild-type PIMT produced significantly less reactive oxygen species despite DA treatment compared to cells that do not overexpress PIMT. Together, these data indicate that DA-associated PIMT downregulation is an important event contributing to neuronal cell death. More importantly, the PIMT anti-apoptotic capacity seems to be dependent on its involvement in the cellular antioxidant machinery. PMID:25800307

  8. Prolonged copper depletion induces expression of antioxidants and triggers apoptosis in SH-SY5Y neuroblastoma cells.

    PubMed

    Lombardo, M F; Ciriolo, M R; Rotilio, G; Rossi, L

    2003-08-01

    SH-SY5Y neuroblastoma cells were cultured for up to three serial passages in the presence of the copper chelator triethylene tetramine (Trien). The copper-depleted neuroblastoma cell line obtained showed decreased activities of the copper enzymes Cu, Zn super-oxide dismutase and cytochrome c oxidase with concomitant increases in reactive oxygen species. Mitochondrial antioxidants (Mn superoxide dismutase and Bcl-2)were up-regulated. Overexpression and activation of p53 were early responses, leading to an increase in p21. Eventually, copper-depleted cells detached from the monolayer and underwent apoptosis. Activation of upstream caspase-9, but not caspase-8, suggested that apoptosis proceeds via a mitochondrial pathway, followed by caspase-3 activation. The addition of copper sulfate to the copper-depleted cells restored copper enzymes, normalized antioxidant levels and improved cell viability. We conclude that prolonged copper starvation in these replicating cells leads to mitochondrial damage and oxidative stress and ultimately, apoptosis. PMID:14513838

  9. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.

    PubMed

    Özdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L; Zheng, Xiaofeng; Wu, Chia-Chin; Simpson, Tyler R; Laklai, Hanane; Sugimoto, Hikaru; Kahlert, Christoph; Novitskiy, Sergey V; De Jesus-Acosta, Ana; Sharma, Padmanee; Heidari, Pedram; Mahmood, Umar; Chin, Lynda; Moses, Harold L; Weaver, Valerie M; Maitra, Anirban; Allison, James P; LeBleu, Valerie S; Kalluri, Raghu

    2014-06-16

    Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete ?SMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC. PMID:24856586

  10. Effects of Thy-1+ cell depletion on the capacity of donor lymphoid cells to induce tolerance across an entire MHC disparity in sublethally irradiated adult hosts

    SciTech Connect

    Pierce, G.E.; Watts, L.M. (Univ. of Kansas College of Health Sciences, Kansas City (USA))

    1989-08-01

    Thy-1+ cell depletion with anti-Thy-1.2 mAb and complement markedly reduced the capacity of C57BL/6J, H-2b bone marrow to establish mixed lymphoid chimerism and induce tolerance to C57BL/6J skin grafts across an entire MHC disparity in BALB/c, H-2d hosts conditioned with sublethal, fractionated 7.5 Gy total-body irradiation. In this model tolerance can be transferred to secondary irradiated BALB/c hosts only by cells of C57BL/6J donor, not host, genotype isolated from the spleens of tolerant hosts. Thy-1+ cell depletion abolished the capacity of C57BL/6J donor cells from tolerant BALB/c host spleens to transfer tolerance. The capacity of semiallogeneic BALB/c x C57BL/6J F1, H-2d/b donor BM and spleen cells to induce chimerism and tolerance to C57BL/6J skin grafts in BALB/c parental hosts was also reduced by Thy-1+ cell depletion. Thus the requirement for donor Thy-1+ cells cannot be explained simply on the basis of alloaggression. It is unlikely that the requisite Thy-1+ cells are nonspecific suppressor cells: Thy-1+ cell depletion had no effect on the slight but significant prolongation of third-party C3H/HeJ, H-2k skin grafts in irradiated BALB/c hosts injected with allogeneic C57BL/6J or semiallogeneic BALB/c x C57BL/6J F1 BM compared to irradiated controls injected with medium only. Furthermore, injections of semiallogeneic F1 spleen cells had no significant effect on the survival of the third-party grafts, although these cells were fully capable of inducing tolerance, and their capacity to induce tolerance was significantly reduced by Thy-1+ cell depletion. The requirement for a specific population of lymphoid cells, i.e. Thy-1+, remains unexplained but suggests that donor cells might play a role in the induction or maintenance of tolerance in this model other than merely providing a circulating source of donor antigens.

  11. Optical suppression of drug-evoked phasic dopamine release

    PubMed Central

    McCutcheon, James E.; Cone, Jackson J.; Sinon, Christopher G.; Fortin, Samantha M.; Kantak, Pranish A.; Witten, Ilana B.; Deisseroth, Karl; Stuber, Garret D.; Roitman, Mitchell F.

    2014-01-01

    Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior. PMID:25278845

  12. Dopamine: the rewarding years

    PubMed Central

    Marsden, Charles A

    2006-01-01

    Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine. PMID:16402097

  13. A tobacco extract containing alkaloids induces distinct effects compared to pure nicotine on dopamine release in the rat.

    PubMed

    Khalki, Hanane; Navailles, Sylvia; Piron, Camille L; De Deurwaerdčre, Philippe

    2013-06-01

    It has been suggested that minor alkaloids in plants play a role in the biological and neuronal actions of nicotine. We hypothesized that these molecules modulate the effect of nicotine on the activity of central dopamine (DA) neurons, one of the main cellular targets in addiction to drugs. In this study the effect of a single intraperitoneal injection of either nicotine or an alkaloid extract of the tobacco plant (0.5 mg/kg) on the efflux of DA were investigated. DA was measured in vivo by intracerebral microdialysis in the nucleus accumbens and the striatum of freely-moving rats. Results show that nicotine enhanced accumbal and striatal DA extracellular levels (+47 and 20% above baseline, respectively). The extract also evoked a significant increase in DA extracellular levels in both regions (+33 and +38% above baseline). However, this effect was significantly higher compared to nicotine in the striatum only. In conclusion, the tobacco extract enhanced the neurochemical effect of nicotine alone in the striatum, a response that could underlie the higher propensity of developing addictive-like behavior using nicotine with tobacco alkaloids. PMID:23583588

  14. A53T human ?-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration.

    PubMed

    Chen, Linan; Xie, Zhiguo; Turkson, Susie; Zhuang, Xiaoxi

    2015-01-21

    In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated a transgenic mouse line with human ?-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of ?-synuclein and their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration in an in vivo model based on known PD genetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have set the stage and direction of emphasis for future studies. PMID:25609609

  15. Altered profile and D2-dopamine receptor modulation of high voltage-activated calcium current in striatal medium spiny neurons from animal models of Parkinson's disease.

    PubMed

    Martella, G; Madeo, G; Schirinzi, T; Tassone, A; Sciamanna, G; Spadoni, F; Stefani, A; Shen, J; Pisani, A; Bonsi, P

    2011-03-17

    In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) currents in freshly isolated striatal medium spiny neurons (MSNs) from rodent models of both idiopathic and familial forms of Parkinson's disease (PD). MSNs were recorded from reserpine-treated and 6-hydroxydopamine (6-OHDA)-lesioned rats, and from DJ-1 and PINK1 (PTEN induced kinase 1) knockout (-/-) mice. Our analysis showed no significant changes in total HVA Ca2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1-/- mice, whereas no significant change in Ca2+ current profile was observed in PINK1-/- mice. Dopamine modulates HVA Ca2+ channels in MSNs, thus we also analyzed the effect of D1 and D2 receptor activation. The effect of the D1 receptor agonist SKF 83822 on Ca2+ current was not significantly different among MSNs from control animals or PD models. However, in both dopamine-depleted rats and DJ-1-/- mice the D2 receptor agonist quinpirole inhibited a greater fraction of HVA Ca2+ current than in the respective controls. Conversely, in MSNs from PINK1-/- mice we did not observe alterations in the effect of D2 receptor activation. Additionally, in both reserpine-treated and 6-OHDA-lesioned rats, the effect of quinpirole was occluded by the selective L-type Ca2+ channel blocker nifedipine, while in DJ-1-/- mice it was mostly occluded by ?-conotoxin GVIA, blocker of N-type channels. These results demonstrate that both dopamine depletion and DJ-1 deletion induce a rearrangement in the HVA Ca2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors. PMID:21195752

  16. Dopamine uptake inhibitor-induced rotation in 6-hydroxydopamine-lesioned rats involves both D1 and D2 receptors but is modulated through 5-hydroxytryptamine and noradrenaline receptors.

    PubMed

    Lane, E L; Cheetham, S; Jenner, P

    2005-03-01

    Dopamine uptake inhibitors may provide a means of sustaining endogenous and exogenous striatal dopamine levels in Parkinson's disease, but most are not selective and also inhibit the noradrenaline and 5-hydroxytryptamine (5-HT) transporters. To determine the involvement of the individual monoamine transporters in the production of motor activity, the effect of the nonselective monoamine uptake inhibitor BTS 74 398 1-([1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio) ethanone monocitrate) and the selective dopamine, GBR 12909 [1-(2-(bis-(4-fluorphenyl)-methyl)ethyl)-4-(3-phenylpropyl)piperazine) dihydrochloride], noradrenaline (nisoxetine), and 5-HT (fluvoxamine) reuptake inhibitors on circling in the unilateral 6-hydroxydopamine-lesioned rat was investigated. GBR 12909 induced ipsilateral circling, but fluvoxamine and nisoxetine were without effect. However, when administered with GBR 12909, fluvoxamine enhanced rotation, whereas nisoxetine had no effect. The results suggest that 5-HT, but not noradrenaline, reuptake inhibition facilitates dopamine-mediated motor activity. To test this hypothesis, BTS 74 398 was administered in combination with selective dopamine, 5-HT, and noradrenaline receptor antagonists. Both D(1) and D(2) receptor antagonists, SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] and raclopride, inhibited BTS 74 398-induced circling. In contrast, the 5-HT(1A) 5-HT(1A/B) antagonists, WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexane-carboxamide maleate) and pindolol, and the 5-HT(2A) antagonist, ketanserin, had no effect. The nonspecific 5-HT((1/2)) antagonists, methysergide and metergoline, and the specific 5-HT(2C) antagonist, N-desmethylclozapine, enhanced BTS 74 398-induced circling, as did the alpha(2)-adrenoceptor antagonist idazoxan. Overall, the data suggest that inhibition of the 5-HT and noradrenaline transporters modulate dopamine uptake inhibitor-mediated motor activity. However, the mechanism of this interaction is complex, involving opposing effects of noradrenaline and 5-HT agonism and antagonism. PMID:15542624

  17. Excitatory nature of dopamine in the nigro-caudate pathway

    Microsoft Academic Search

    S. T. Kitai; M. Sugimori; J. D. Kocsis

    1976-01-01

    Inputs from the substantia nigra (SN) to the caudate nucleus (Cd) and the effects of electrophoretic dopamine on Cd neurones were studied in cats anaesthetized with pentobarbitone with intracellular techniques. Single shock electrical stimulation of the SN or the medial forebrain bundle (MFB) induced monosynaptic EPSPs in Cd neurones. Dopamine depolarized Cd neurones and chlorpromazine suppressed the SN or MFB

  18. Dopamine, behavioral economics, and effort.

    PubMed

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

    2009-01-01

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

  19. Acute 3-nitropropionic acid intoxication induces striatal astrocytic cell death and dysfunction of the blood-brain barrier: involvement of dopamine toxicity.

    PubMed

    Nishino, H; Kumazaki, M; Fukuda, A; Fujimoto, I; Shimano, Y; Hida, H; Sakurai, T; Deshpande, S B; Shimizu, H; Morikawa, S; Inubushi, T

    1997-04-01

    Mechanisms underlying the selective vulnerability of the lateral striatal area to the toxic effects of 3-nitropropionic acid (3-NPA) were investigated in rats. A single exposure to 3-NPA (20 mg/kg, s.c.) induced no deficits in behavior and histology, but subsequent injection produced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 30% of the animals within a few hours. Diffusion-weighted magnetic resonance imaging of the brains revealed an area of high signal intensity in the bilateral striata. By this stage (within a few hours), striatal astrocytes had become swollen and disintegrated. Extravasation of immunoglobulin G was detected, indicating blood-brain barrier (BBB) dysfunction. Electron microscopy revealed edema and disorganization of structures inside the astrocytic end-feet around the branches of the lateral striatal artery. Neurons were less vulnerable than astrocytes to the 3-NPA injury. Treatment of the rats with D2 receptor agonist prior to exposure to 3-NPA attenuated the behavioral abnormalities and histological damage whereas pretreatment with D2 antagonist exacerbated these changes. The concentrations of extracellular dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) were both increased in rats exposed to 3-NPA. In vitro imaging of astrocytes revealed a progressive increase in [Ca2+]i after superfusion with 3-NPA, and the 'ceiling' level was maintained even after extensive washing. DA superfusion also increased the astrocytic [Ca2+]i and this increase was reversible. Data indicate that 3-NPA-induced striatal damage was associated with astrocytic cell death and dysfunction of the BBB. Intracellular edema and extreme Ca2+ overload induced by the toxin were further aggravated by an increase in the level of DA activity. These factors acting either singly or in combination may trigger astrocyte destruction. PMID:9152047

  20. Cocaine Cue-Induced Dopamine Release in Amygdala and Hippocampus: A High-Resolution PET [18F]Fallypride Study in Cocaine Dependent Participants

    PubMed Central

    Fotros, Aryandokht; Casey, Kevin F; Larcher, Kevin; Verhaeghe, Jeroen AJ; Cox, Sylvia ML; Gravel, Paul; Reader, Andrew J; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco

    2013-01-01

    Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [18F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6±8.0 years; years of cocaine use: 15.9±7.4) underwent two [18F]fallypride high-resolution research tomography–PET scans, one with exposure to neutral cues and one with cocaine cues. [18F]Fallypride non-displaceable-binding potential (BPND) values were derived for five regions of interest (ROI; amygdala, hippocampus, ventral limbic striatum, associative striatum, and sensorimotor striatum). Subjective responses to the cues were measured with visual analog scales and grouped using principal component analysis. Drug cue exposure significantly decreased BPND values in all five ROI in subjects who had a high-, but not low-, craving response (limbic striatum: p=0.019, associative striatum: p=0.008, sensorimotor striatum: p=0.004, amygdala: p=0.040, and right hippocampus: p=0.025). Individual differences in the cue-induced craving response predicted the magnitude of [18F]fallypride responses within the striatum (ventral limbic: r=0.581, p=0.048; associative: r=0.589, p=0.044; sensorimotor: r=0.675, p=0.016). To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior. PMID:23546387

  1. Ultrasonic Vocalizations Induced by Sex and Amphetamine in M2, M4, M5 Muscarinic and D2 Dopamine Receptor Knockout Mice

    PubMed Central

    Wang, Haoran; Liang, Shuyin; Burgdorf, Jeffrey; Wess, Jurgen; Yeomans, John

    2008-01-01

    Adult mice communicate by emitting ultrasonic vocalizations (USVs) during the appetitive phases of sexual behavior. However, little is known about the genes important in controlling call production. Here, we study the induction and regulation of USVs in muscarinic and dopaminergic receptor knockout (KO) mice as well as wild-type controls during sexual behavior. Female mouse urine, but not female rat or human urine, induced USVs in male mice, whereas male urine did not induce USVs in females. Direct contact of males with females is required for eliciting high level of USVs in males. USVs (25 to120 kHz) were emitted only by males, suggesting positive state; however human-audible squeaks were produced only by females, implying negative state during male-female pairing. USVs were divided into flat and frequency-modulated calls. Male USVs often changed from continuous to broken frequency-modulated calls after initiation of mounting. In M2 KO mice, USVs were lost in about 70–80% of the mice, correlating with a loss of sexual interaction. In M5 KO mice, mean USVs were reduced by almost 80% even though sexual interaction was vigorous. In D2 KOs, the duration of USVs was extended by 20%. In M4 KOs, no significant differences were observed. Amphetamine dose-dependently induced USVs in wild-type males (most at 0.5 mg/kg i.p.), but did not elicit USVs in M5 KO or female mice. These studies suggest that M2 and M5 muscarinic receptors are needed for male USV production during male-female interactions, likely via their roles in dopamine activation. These findings are important for the understanding of the neural substrates for positive affect. PMID:18382674

  2. Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

    PubMed Central

    Le Foll, Bernard; Guranda, Mihail; Wilson, Alan A; Houle, Sylvain; Rusjan, Pablo M; Wing, Victoria C; Zawertailo, Laurie; Busto, Usoa; Selby, Peter; Brody, Arthur L; George, Tony P; Boileau, Isabelle

    2014-01-01

    Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [11C]-(+)-PHNO ([11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [11C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [11C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [11C]-(+)-PHNO binding in D2 and D3-rich areas (?12.0 and ?15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [11C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission. PMID:23954846

  3. Troxerutin protects against 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD?-depletion.

    PubMed

    Zhang, Zi-Feng; Zhang, Yan-Qiu; Fan, Shao-Hua; Zhuang, Juan; Zheng, Yuan-Lin; Lu, Jun; Wu, Dong-Mei; Shan, Qun; Hu, Bin

    2015-02-11

    Emerging evidence indicates that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD(+)-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD(+)-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-?B p65 and the acetylation of NF-?B p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity. PMID:25262482

  4. Inhibition of Phosphatidylinositol 3-kinase/Akt Signaling Attenuates Hypoxia-induced Pulmonary Artery Remodeling and Suppresses CREB Depletion in Arterial Smooth Muscle Cells

    PubMed Central

    Garat, Chrystelle V.; Crossno, Joseph T.; Sullivan, Timothy M.; Reusch, Jane E. B.; Klemm, Dwight J.

    2014-01-01

    Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase–mediated vasoconstriction. PMID:24084215

  5. Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3–Dependent Manner in Caenorhabditis elegans

    PubMed Central

    Benedetto, Alexandre; Au, Catherine; Avila, Daiana Silva; Milatovic, Dejan; Aschner, Michael

    2010-01-01

    Parkinson's disease (PD)-mimicking drugs and pesticides, and more recently PD-associated gene mutations, have been studied in cell cultures and mammalian models to decipher the molecular basis of PD. Thus far, a dozen of genes have been identified that are responsible for inherited PD. However they only account for about 8% of PD cases, most of the cases likely involving environmental contributions. Environmental manganese (Mn) exposure represents an established risk factor for PD occurrence, and both PD and Mn-intoxicated patients display a characteristic extrapyramidal syndrome primarily involving dopaminergic (DAergic) neurodegeneration with shared common molecular mechanisms. To better understand the specificity of DAergic neurodegeneration, we studied Mn toxicity in vivo in Caenorhabditis elegans. Combining genetics and biochemical assays, we established that extracellular, and not intracellular, dopamine (DA) is responsible for Mn-induced DAergic neurodegeneration and that this process (1) requires functional DA-reuptake transporter (DAT-1) and (2) is associated with oxidative stress and lifespan reduction. Overexpression of the anti-oxidant transcription factor, SKN-1, affords protection against Mn toxicity, while the DA-dependency of Mn toxicity requires the NADPH dual-oxidase BLI-3. These results suggest that in vivo BLI-3 activity promotes the conversion of extracellular DA into toxic reactive species, which, in turn, can be taken up by DAT-1 in DAergic neurons, thus leading to oxidative stress and cell degeneration. PMID:20865164

  6. Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism.

    PubMed

    Sagi, Yotam; Mandel, Silvia; Amit, Tamar; Youdim, Moussa B H

    2007-01-01

    The anti-Parkinson monoamine oxidase (MAO)-B inhibitor rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway including ShcC, SOS, AF6, Rin1 and Ras and the increase in the Trk-downstream effector phosphatidylinositol 3 kinase (PI3K) protein. Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3beta and Raf1. Thus, the activation of Ras-PI3K-Akt survival pathway may contribute to rasagiline-mediated neurorescue effect. It is interesting to determine whether a similar effect is seen in parkinsonian patients after long-term treatment with rasagiline. PMID:17055733

  7. Levodopa or D2 agonist induced dyskinesia in MPTP monkeys: correlation with changes in dopamine and GABAA receptors in the striatopallidal complex.

    PubMed

    Calon, F; Goulet, M; Blanchet, P J; Martel, J C; Piercey, M F; Bédard, P J; Di Paolo, T

    1995-05-22

    Dopamine D1 and D2 receptors as well as the GABA/benzodiazepine receptor complex in the striatum and the globus pallidus (internal: GPi and external: GPe) were studied by autoradiography using [3H]SCH 23390, [3H]spiperone, and [3H]flunitrazepam ([3H]FNZ) respectively, in five groups of cynomolgus monkeys. These included (i) untreated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-monkeys; (ii) MPTP monkeys treated chronically with levodopa injections; (iii) MPTP monkeys treated chronically with injections of the novel D2 agonist U91356A; (iv) MPTP monkeys treated chronically with U91356A delivered through an osmotic mini-pump; and (5) naive controls. Animals treated in a pulsatile mode with U91356A or levodopa injections showed progressive sensitization to their respective drug and developed choreic dyskinesia. In contrast, animals treated in a continuous mode with U91356A showed behavioral tolerance but did not develop dyskinesia. A trend for a down-regulation of putaminal D2 receptors was observed following D2 agonist stimulation with U913356A. Striatal [3H]FNZ binding was significantly decreased only in animals treated in a continuous mode with U91356A. The dopamine receptor decrease in the striatum could be implicated with the development of tolerance but cannot explain the appearance of dyskinesia. Denervation by MPTP was associated with a decrease of the GPe/GPi [3H]FNZ binding ratio which reflects an imbalance of striatal output pathways; this ratio was not reversed by any of the treatments although changes were observed in the GPe and GPi. Indeed, pulsatile U91356A treatment restored the decreased [3H]FNZ binding in the GPe near control values and levodopa showed a similar tendency. A significant increase of [3H]FNZ binding in the GPi only of dyskinetic monkeys, namely those treated with pulsatile U91356A or levodopa was seen compared to untreated MPTP or naive controls. This GABAA receptor up-regulation might lead to a supersensitive state of the GPi to gabaergic input which may be involved in the mechanism underlying the development of dopaminomimetic-induced dyskinesia. PMID:7663983

  8. Membrane Cholesterol Depletion with ?-Cyclodextrin Impairs Pressure-Induced Contraction and Calcium Signalling in Isolated Skeletal Muscle Arterioles

    Microsoft Academic Search

    Simon J. Potocnik; Nicole Jenkins; Timothy V. Murphy; Michael A. Hill

    2007-01-01

    Objective: Given evidence for clustering of signalling molecules and ion channels in cholesterol-rich membrane domains, the involvement of such structures in arteriolar smooth muscle mechanotransduction was examined. Method: To determine the contribution of smooth muscle cholesterol-rich membrane domains to the myogenic response, isolated arterioles were exposed to the cholesterol-depleting agent ?-cyclodextrin (1–10 mM) in the absence and presence of excess

  9. Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells.

    PubMed

    Liu, J; Shen, H M; Ong, C N

    2001-09-01

    Recent studies have demonstrated that induction of apoptosis is related to the cell growth inhibition potential of Salvia Miltiorrhiza (SM), a traditional herbal medicine. In the present study, we further explore the mechanistic pathway involved in SM-induced apoptosis in human hepatoma HepG2 cells. A rapid decline of intracellular glutathione (GSH) and protein thiol content was found in SM-treated cells. Moreover. SM exposure resulted in mitochondrial dysfunction as demonstrated by: (i) the onset of mitochondrial permeability transition (MPT); (ii) the disruption of mitochondrial membrane potential (MMP); and (iii) the release of cytochrome c from mitochondria into the cytosol. Subsequently, elevated level of intracellular reactive oxygen species (ROS) was observed prior to the onset of DNA fragmentation. However, no caspase-3 cleavage was observed throughout the whole period of SM treatment, while a caspase-3-independent poly(ADP-ribose) polymerase (PARP) cleavage was noted at the late stage in SM-induced apoptosis. Pretreatment of cells with N-acetylcysteine (NAC), the GSH synthesis precursor, conferred complete protection against MMP loss, ROS generation and apoptosis induced by SM. MPT inhibitors, cyclosporin A plus trifluoperazine, partially restored intracellular GSH content, and reduced SM-induced ROS formation and subsequently inhibited cell death. Moreover, antioxidants NAC, deferoxamine and catalase had little effect on GSH depletion and mitochondrial dysfunction, yet still were able to completely protect cells from SM-induced apoptosis. Taken together, our results suggest that SM deplete intracellular thiols, which, in turn, causes MPT and subsequent increase in ROS generation, and eventually apoptotic cell death. PMID:11693264

  10. Differential effects of M1 and 5-hydroxytryptamine1A receptors on atypical antipsychotic drug-induced dopamine efflux in the medial prefrontal cortex.

    PubMed

    Li, Zhu; Prus, Adam J; Dai, Jin; Meltzer, Herbert Y

    2009-09-01

    Systemic administration of the M(1) receptor agonists N-desmethylclozapine (NDMC) and 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) increase dopamine (DA) efflux in rat medial prefrontal cortex (mPFC). This increase is blocked by systemic administration of both telenzepine, a preferential M(1) receptor antagonist, and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), a 5-hydroxytryptamine(1A) receptor antagonist. The present study sought to determine whether DA efflux in the mPFC induced by the atypical antipsychotic drugs clozapine, risperidone, and olanzapine is also mediated by M(1) receptor stimulation and, specifically, to determine whether these effects are mediated M(1) receptors in the mPFC through use of in vivo microdialysis in awake, freely moving Sprague-Dawley rats. Telenzepine (3 mg/kg) significantly attenuated clozapine- (20 mg/kg), olanzapine- (10 mg/kg), and risperidone- (1.0 mg/kg) induced increases in mPFC DA efflux. Local mPFC perfusion of NDMC, AC260584, clozapine, risperidone, or olanzapine (10-500 microM), significantly increased DA efflux in the mPFC. Local mPFC perfusion of telenzepine (0.1 microM) prevented increases in mPFC DA efflux induced by systemic administration of AC260584 (10 mg/kg), NDMC (20 mg/kg), and clozapine (10 mg/kg), but not by risperidone (1.0 mg/kg) or olanzapine (10 mg/kg). However, local mPFC perfusion of WAY-100635 (0.1 microM) prevented mPFC DA efflux induced by clozapine, risperidone, and olanzapine, but not by AC260584 or NDMC. These results suggest that the AC260584-, NDMC-, and clozapine-induced DA efflux in the mPFC is mediated directly by mPFC M(1) receptors. PMID:19491322

  11. Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus.

    PubMed

    Yamawaki, N; Magill, P J; Woodhall, G L; Hall, S D; Stanford, I M

    2012-02-17

    In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex. PMID:22209920

  12. Biphasic Mechanisms of Amphetamine Action at the Dopamine Terminal

    PubMed Central

    Siciliano, Cody A.; Calipari, Erin S.; Ferris, Mark J.

    2014-01-01

    In light of recent studies suggesting that amphetamine (AMPH) increases electrically evoked dopamine release ([DA]o), we examined discrepancies between these findings and literature that has demonstrated AMPH-induced decreases in [DA]o. The current study has expanded the inventory of AMPH actions by defining two separate mechanisms of AMPH effects on [DA]o at high and low doses, one dopamine transporter (DAT) independent and one DAT dependent, respectively. AMPH concentrations were measured via microdialysis in rat nucleus accumbens after intraperitoneal injections of 1 and 10 mg/kg and yielded values of ?10 and 200 nm, respectively. Subsequently, voltammetry in brain slices was used to examine the effects of low (10 nm), moderate (100 nm), and high (10 ?m) concentrations of AMPH across a range of frequency stimulations (one pulse; five pulses, 20 Hz; 24 pulses, 60 Hz). We discovered biphasic, concentration-dependent effects in WT mice, in which AMPH increased [DA]o at low concentrations and decreased [DA]o at high concentrations across all stimulation types. However, in slices from DAT-KO mice, [DA]o was decreased by all concentrations of AMPH, demonstrating that AMPH-induced increases in [DA]o are DAT dependent, whereas the decreases at high concentrations are DAT independent. We propose that low AMPH concentrations are insufficient to disrupt vesicular sequestration, and therefore AMPH acts solely as a DAT inhibitor to increase [DA]o. When AMPH concentrations are high, the added mechanism of vesicular depletion leads to reduced [DA]o. The biphasic mechanisms observed here confirm and extend the traditional actions of AMPH, but do not support mechanisms involving increased exocytotic release. PMID:24741047

  13. Edaravone Mitigates Hexavalent Chromium-Induced Oxidative Stress and Depletion of Antioxidant Enzymes while Estrogen Restores Antioxidant Enzymes in the Rat Ovary in F1 Offspring1

    PubMed Central

    Stanley, Jone A.; Sivakumar, Kirthiram K.; Arosh, Joe A.; Burghardt, Robert C.; Banu, Sakhila K.

    2014-01-01

    ABSTRACT Environmental contamination of drinking water with chromium (Cr) has been increasing in more than 30 cities in the United States. Previous studies from our group have shown that Cr affects reproductive functions in female Sprague Dawley rats. Although it is impossible to completely remove Cr from the drinking water, it is imperative to develop effective intervention strategies to inhibit Cr-induced deleterious health effects. Edaravone (EDA), a potential inhibitor of free radicals, has been clinically used to treat cancer and cardiac ischemia. This study evaluated the efficacy of EDA against Cr-induced ovarian toxicity. Results showed that maternal exposure to CrVI in rats increased follicular atresia, decreased steroidogenesis, and delayed puberty in F1 offspring. CrVI increased oxidative stress and decreased antioxidant (AOX) enzyme levels in the ovary. CrVI increased follicle atresia by increased expression of cleaved caspase 3, and decreased expression of Bcl2 and Bcl2l1 in the ovary. EDA mitigated or inhibited the effects of CrVI on follicle atresia, pubertal onset, steroid hormone levels, and AOX enzyme activity, as well as the expression of Bcl2 and Bcl2l1 in the ovary. In a second study, CrVI treatment was withdrawn, and F1 rats were injected with estradiol (E2) (10 ?g in PBS/ethanol per 100 g body weight) for a period of 2 wk to evaluate whether E2 treatment will restore Cr-induced depletion of AOX enzymes. E2 restored CrVI-induced depletion of glutathione peroxidase 1, catalase, thioredoxin 2, and peroxiredoxin 3 in the ovary. This is the first study to demonstrate the protective effects of EDA against any toxicant in the ovary. PMID:24804965

  14. 1Benzyl1,2,3,4-Tetrahydroisoquinoline, an Endogenous Parkinsonism-Inducing Toxin, Strongly Potentiates MAO-Dependent Dopamine Oxidation and Impairs Dopamine Release: Ex vivo and In vivo Neurochemical Studies

    Microsoft Academic Search

    Agnieszka W?sik; Irena Roma?ska; Lucyna Antkiewicz-Michaluk

    2009-01-01

    1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause a parkinsonism-like syndrome\\u000a in rodents and primates. In this study we evaluated the effects of single and multiple 1BnTIQ (50 mg\\/kg i.p.) administration\\u000a on the concentrations of dopamine, serotonin, and respective metabolites (homovanillic acid, HVA; 3,4-dihydroxyphenylacetic\\u000a acid, DOPAC; 3-methoxytyramine, 3-MT; and 5-hydroxyindolacetic acid, 5-HIAA), in substantia nigra, striatum (STR), and nucleus\\u000a accumbens

  15. RPA70 depletion induces hSSB1/2-INTS3 complex to initiate ATR signaling.

    PubMed

    Kar, Ananya; Kaur, Manpreet; Ghosh, Tanushree; Khan, Md Muntaz; Sharma, Aparna; Shekhar, Ritu; Varshney, Akhil; Saxena, Sandeep

    2015-05-26

    The primary eukaryotic single-stranded DNA-binding protein, Replication protein A (RPA), binds to single-stranded DNA at the sites of DNA damage and recruits the apical checkpoint kinase, ATR via its partner protein, ATRIP. It has been demonstrated that absence of RPA incapacitates the ATR-mediated checkpoint response. We report that in the absence of RPA, human single-stranded DNA-binding protein 1 (hSSB1) and its partner protein INTS3 form sub-nuclear foci, associate with the ATR-ATRIP complex and recruit it to the sites of genomic stress. The ATRIP foci formed after RPA depletion are abrogated in the absence of INTS3, establishing that hSSB-INTS3 complex recruits the ATR-ATRIP checkpoint complex to the sites of genomic stress. Depletion of homologs hSSB1/2 and INTS3 in RPA-deficient cells attenuates Chk1 phosphorylation, indicating that the cells are debilitated in responding to stress. We have identified that TopBP1 and the Rad9-Rad1-Hus1 complex are essential for the alternate mode of ATR activation. In summation, we report that the single-stranded DNA-binding protein complex, hSSB1/2-INTS3 can recruit the checkpoint complex to initiate ATR signaling. PMID:25916848

  16. RPA70 depletion induces hSSB1/2-INTS3 complex to initiate ATR signaling

    PubMed Central

    Kar, Ananya; Kaur, Manpreet; Ghosh, Tanushree; Khan, Md. Muntaz; Sharma, Aparna; Shekhar, Ritu; Varshney, Akhil; Saxena, Sandeep

    2015-01-01

    The primary eukaryotic single-stranded DNA-binding protein, Replication protein A (RPA), binds to single-stranded DNA at the sites of DNA damage and recruits the apical checkpoint kinase, ATR via its partner protein, ATRIP. It has been demonstrated that absence of RPA incapacitates the ATR-mediated checkpoint response. We report that in the absence of RPA, human single-stranded DNA-binding protein 1 (hSSB1) and its partner protein INTS3 form sub-nuclear foci, associate with the ATR-ATRIP complex and recruit it to the sites of genomic stress. The ATRIP foci formed after RPA depletion are abrogated in the absence of INTS3, establishing that hSSB-INTS3 complex recruits the ATR-ATRIP checkpoint complex to the sites of genomic stress. Depletion of homologs hSSB1/2 and INTS3 in RPA-deficient cells attenuates Chk1 phosphorylation, indicating that the cells are debilitated in responding to stress. We have identified that TopBP1 and the Rad9-Rad1-Hus1 complex are essential for the alternate mode of ATR activation. In summation, we report that the single-stranded DNA-binding protein complex, hSSB1/2-INTS3 can recruit the checkpoint complex to initiate ATR signaling. PMID:25916848

  17. Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism

    PubMed Central

    Kitao, Yasuko; Ageta-Ishihara, Natsumi; Takahashi, Ryosuke; Kinoshita, Makoto; Hori, Osamu

    2015-01-01

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

  18. The effects of additional treatment with terguride, a partial dopamine agonist, on hyperprolactinemia induced by antipsychotics in schizophrenia patients: a preliminary study

    PubMed Central

    Hashimoto, Kojiro; Sugawara, Norio; Ishioka, Masamichi; Nakamura, Kazuhiko; Yasui-Furukori, Norio

    2014-01-01

    Hyperprolactinemia is a frequent consequence of treatment with antipsychotics. Earlier studies have indicated that terguride, which is a partial dopamine agonist, reduces the prolactin levels that are induced by prolactinemia. Thus, we examined the dose effects of adjunctive treatment with terguride on the plasma concentrations of prolactin in patients with elevated prolactin levels resulting from antipsychotic treatment. Terguride was concomitantly administered to 20 schizophrenic patients (10 males and 10 females) receiving paliperidone and risperidone. The dose of terguride was 1.0 mg/day. Sample collections for prolactin were conducted before terguride (baseline) and 2–4 weeks after administration. The samples were obtained after the morning dose of terguride. The average (± standard deviation) plasma prolactin concentration during terguride coadministration was significantly lower than the baseline concentration in females (82.3±37.1 ng/mL versus 56.5±28.5 ng/mL, P<0.01) but not in males (28.8±18.0 ng/mL versus 26.2±13.1 ng/mL, not significant). Additionally, a significant correlation between the ratio of prolactin reduction and the baseline prolactin concentration was identified in males (rs=?0.638, P<0.05) but not in females (rs=?0.152, not significant). Many patients complained of various adverse events following terguride administration, such as insomnia, agitation, and/or the aggravation of hallucinations. This study suggests that additional treatment with terguride decreases the prolactin concentrations in females experiencing high prolactin levels as a result of antipsychotic treatment. However, its utility for schizophrenia may be diminished because of its low tolerability. PMID:25187719

  19. Cytokine Effects on the Basal Ganglia and Dopamine Function: the Subcortical Source of Inflammatory Malaise

    PubMed Central

    Felger, Jennifer C.; Miller, Andrew H.

    2012-01-01

    Data suggest that cytokines released during the inflammatory response target subcortical structures including the basal ganglia as well as dopamine function to acutely induce behavioral changes that support fighting infection and wound healing. However, chronic inflammation and exposure to inflammatory cytokines appears to lead to persisting alterations in the basal ganglia and dopamine function reflected by anhedonia, fatigue, and psychomotor slowing. Moreover, reduced neural responses to hedonic reward, decreased dopamine metabolites in the cerebrospinal fluid and increased presynaptic dopamine uptake and decreased turnover have been described. This multiplicity of changes in the basal ganglia and dopamine function suggest fundamental effects of inflammatory cytokines on dopamine synthesis, packaging, release and/or reuptake, which may sabotage and circumvent the efficacy of current treatment approaches. Thus, examination of the mechanisms by which cytokines alter the basal ganglia and dopamine function will yield novel insights into the treatment of cytokine-induced behavioral changes and inflammatory malaise. PMID:23000204

  20. Basal ganglia circuit loops, dopamine and motivation: A review and enquiry.

    PubMed

    Ikemoto, Satoshi; Yang, Chen; Tan, Aaron

    2015-09-01

    Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine's role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders. PMID:25907747

  1. Depletion of intermediate filament protein Nestin, a target of microRNA-940, suppresses tumorigenesis by inducing spontaneous DNA damage accumulation in human nasopharyngeal carcinoma

    PubMed Central

    Ma, J; Sun, F; Li, C; Zhang, Y; Xiao, W; Li, Z; Pan, Q; Zeng, H; Xiao, G; Yao, K; Hong, A; An, J

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is a major malignant tumor of the head and neck region in southern China. The understanding of its underlying etiology is essential for the development of novel effective therapies. We report for the first time that microRNA-940 (miR-940) significantly suppresses the proliferation of a variety of cancer cell lines, arrests cells cycle, induces caspase-3/7-dependent apoptosis and inhibits the formation of NPC xenograft tumors in mice. We further show that miR-940 directly binds to the 3?-untranslated regions of Nestin mRNA and promotes its degradation. Likewise, depletion of Nestin inhibits tumor cell proliferation, arrest cells at G2/M, induces apoptosis and suppresses xenograft tumor formation in vivo. These functions of miR-940 can be reversed by ectopic expression of Nestin, suggesting that miR-940 regulates cell proliferation and survival through Nestin. Notably, we observed reduced miR-940 and increased Nestin levels in NPC patient samples. Protein microarray revealed that knockdown of Nestin in 5-8F NPC cells alters the phosphorylation of proteins involved in the DNA damage response, suggesting a mechanism for the miR-940/Nestin axis. Consistently, depletion of Nestin induced spontaneous DNA damage accumulation, delayed the DNA damage repair process and increased the sensitivity to irradiation and the chemotherapeutic agent doxorubicin. Collectively, our findings indicate that Nestin, which is downregulated by miR-940, can promote tumorigenesis in NPC cells through involvement in the DNA damage response. The levels of microRNA-940 and Nestin may serve as indicators of cancer status and prognosis. PMID:25118937

  2. Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression.

    PubMed

    Bell, Charlotte R; MacHugh, Niall D; Connelley, Timothy K; Degnan, Kathryn; Morrison, W Ivan

    2015-07-01

    Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP-alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I-defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells used in vaccine production, coupled with a powerful adjuvant, are responsible for the generation of pathogenic alloantibodies. PMID:26055292

  3. The chlorophyllin-induced cell cycle arrest and apoptosis in human breast cancer MCF-7 cells is associated with ERK deactivation and Cyclin D1 depletion.

    PubMed

    Chiu, Lawrence C-M; Kong, Carrie K-L; Ooi, Vincent E-C

    2005-10-01

    Targeting the mitogen-activated protein kinases (MAPKs) has been suggested as a novel strategy to treat cancer. Chlorophyllin (CHL) is the sodium-copper salt of chlorophyll derivative and is a commonly used food dye for green coloration; CHL was found previously to retard growth of the human breast carcinoma MCF-7 cells. Extracellular signal-regulated kinases (ERKs) constitute a subfamily of MAPKs, participating in cell survival, proliferation and differentiation. We report here the first evidence that CHL deactivates ERKs to inhibit the breast cancer cell proliferation. The results from flow cytometry showed that 200 microg/ml CHL reduced the phosphorylated and activated ERK-positive cells in different cell cycle phases from the control of >96 to <38% at 24 h of incubation; the ERK deactivations occurred in both dose- and time-dependent manner, so that nearly all ERKs were de-activated by 400 microg/ml CHL at 72 h of treatment. Immunoblot studies, however, illustrated that the levels of total ERKs were not significantly affected by the CHL treatments, suggesting that the phytochemical retards the enzyme activation rather than its expression. Cyclin D1, but not its enzyme Cdk6, was also depleted after the CHL treatments; the depletions were associated with elevations of G0/G1 cells. Apoptosis occurred time-dependently with the ERK deactivations by 400 microg/ml CHL; the apoptotic cells elevated from 2.7-fold of the control level at 24 h, to 4.7-fold at 48 h and to 16.6-fold at 72 h of treatment. Bcl-2 was also depleted at 72 h when there was the most prominent elevation of the apoptotic cells, suggesting that it participates during the exacerbation rather than the initiation phases of the CHL-induced apoptosis. Results from this study support further research on CHL for preventing and treating those tumors with deregulated ERK activations. PMID:16142413

  4. Dopamine transporters govern diurnal variation in extracellular dopamine tone

    PubMed Central

    Ferris, Mark J.; Espańa, Rodrigo A.; Locke, Jason L.; Konstantopoulos, Joanne K.; Rose, Jamie H.; Chen, Rong; Jones, Sara R.

    2014-01-01

    The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system. PMID:24979798

  5. The effect of experimentally induced bronchopneumonia on the pharmacokinetics and tissue depletion of gentamicin in healthy and pneumonic calves 

    E-print Network

    Hunter, Robert Paul

    1989-01-01

    and pharmacokinetic parameters may be altered by P. haemolytica-induced pneumonia. Gentamicin Gentamicin is an aminoglycoside antibiotic. It is water-soluble, excreted by glomerular filtration, and actively accumulates in renal tissue by binding to, specifically...

  6. Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice.

    PubMed

    Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M; Piganelli, Jon D; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H Henry

    2015-06-19

    Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. PMID:25944898

  7. Depletion of the cellular antioxidant system contributes to tenofovir disoproxil fumarate - induced mitochondrial damage and increased oxido-nitrosative stress in the kidney

    PubMed Central

    2013-01-01

    Background Nephrotoxicity is a dose limiting side effect of tenofovir, a reverse transcriptase inhibitor that is used for the treatment of HIV infection. The mechanism of tenofovir nephrotoxicity is not clear. Tenofovir is specifically toxic to the proximal convoluted tubules and proximal tubular mitochondria are the targets of tenofovir cytotoxicity. Damaged mitochondria are major sources of reactive oxygen species and cellular damage is reported to occur after the antioxidants are depleted. The purpose of the study is to investigate the alterations in cellular antioxidant system in tenofovir induced renal damage using a rat model. Results Chronic tenofovir administration to adult Wistar rats resulted in proximal tubular damage (as evidenced by light microscopy), proximal tubular dysfunction (as shown by Fanconi syndrome and tubular proteinuria), and extensive proximal tubular mitochondrial injury (as revealed by electron microscopy). A 50% increase in protein carbonyl content was observed in the kidneys of TDF treated rats as compared with the control. Reduced glutathione was decreased by 50%. The activity of superoxide dismutase was decreased by 57%, glutathione peroxidase by 45%, and glutathione reductase by 150% as compared with control. Carbonic Anhydrase activity was decreased by 45% in the TDF treated rat kidneys as compared with control. Succinate dehydrogenase activity, an indicator of mitochondrial activity was decreased by 29% in the TDF treated rat kidneys as compared with controls, suggesting mitochondrial dysfunction. Conclusion Tenofovir- induced mitochondrial damage and increased oxidative stress in the rat kidneys may be due to depletion of the antioxidant system particularly, the glutathione dependent system and MnSOD. PMID:23957306

  8. Antioxidative responses related to H(2)O(2) depletion in Hypnum plumaeforme under the combined stress induced by Pb and Ni.

    PubMed

    Sun, Shou-Qin; He, Ming; Cao, Tong; Yusuyin, Yusufujiang; Han, Wei; Li, Jin-Ling

    2010-04-01

    The short-term responses of H(2)O(2)-depletion-related parameters in moss Hypnum plumaeforme to the combined stress induced by Pb and Ni were investigated. The results showed that the Pb and Ni stress induced dose-dependent accumulation of hydrogen peroxide (H(2)O(2)). The increase of peroxidase (POD) activity and decrease of ascorbate peroxidase (APX) activity were observed under the combined heavy metal application. The antioxidants, ascorbate (AsA) and proline content, increased significantly when the metals were applied together. The study indicated that the cell damage caused by Pb stress was higher than that caused by Ni stress, Pb and Ni had synergistic effect in inducing the oxidative stress in moss H. plumaeforme, especially under the combination of high concentration of Ni (0.1 and 1.0 mM) and Pb. Content of proline, H(2)O(2) and the activity of POD, all showed a dose-dependent increase under Pb and Ni stress, suggesting their practical value as biomarkers in moss biomonitoring, especially in the case of light pollution caused by heavy metals without the changes in the appearance of mosses. PMID:19283499

  9. Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells.

    PubMed

    Liu, Youhong; Chen, Lin; Gong, Zhicheng; Shen, Liangfang; Kao, Chinghai; Hock, Janet M; Sun, Lunquan; Li, Xiong

    2015-02-20

    Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future. PMID:25605010

  10. Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells

    PubMed Central

    Gong, Zhicheng; Shen, Liangfang; Kao, Chinghai; Hock, Janet M.; Sun, Lunquan; Li, Xiong

    2015-01-01

    Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future. PMID:25605010

  11. Neuroprotective Effects of ?-Asarone Against 6-Hydroxy Dopamine-Induced Parkinsonism via JNK/Bcl-2/Beclin-1 Pathway.

    PubMed

    Zhang, Sheng; Gui, Xue-Hong; Huang, Li-Ping; Deng, Min-Zhen; Fang, Ruo-Ming; Ke, Xue-Hong; He, Yu-Ping; Li, Ling; Fang, Yong-Qi

    2014-11-18

    ?-asarone, a major component of Acorus tatarinowii Schott, has positive effects in neurodegeneration disease, however, its effect on the Parkinson's disease (PD) remains unclear. In this study, the effects of ?-asarone on behavioral tests, neurotransmitters, tyrosine hydroxylase (TH), and ?-synuclein (?-syn) were investigated in 6-hydroxydopamine (6-OHDA) induced rats. Furthermore, the JNK/Bcl-2/Beclin-1 autophagy pathway was also studied. The results showed that ?-asarone improved the behavioral symptoms of rats in the open field, rotarod test, initiation time, and stepping time. And it increased the HVA, Dopacl, and 5-HIAA levels in striatum but not the DA and 5-HT levels. After administration of ?-asarone, the TH level was elevated but the ?-syn was declined in rats. It inhibited the expressions of LC3-II, but increased the p62 expression in SN4741 cells. Moreover, it affected the expressions of Beclin-1, Bcl-2, JNK, and p-JNK in vivo. We deduced that ?-asarone may firstly downregulate expressions of JNK and p-JNK, and then indirectly increase the expression of Bcl-2. And the function of Beclin-1 could be inhibited, which could inhibit autophagy activation. Collectively, all data indicated that ?-asarone may be explored as a potential therapeutic agent in PD therapy. PMID:25404088

  12. Lack of involvement of dopamine and serotonin during the orphanin FQ/Nociceptin (OFQ/N)-induced prolactin secretory response.

    PubMed

    Kraska, Amy; Bryant, Winnifred; Murphree, Emily; Callahan, Phyllis; Janik, James

    2005-08-12

    The purpose of these studies was to examine possible mechanisms of Orphanin FQ/Nociceptin (OFQ/N)-induced prolactin release. We investigated the involvement of the dopaminergic neurons by quantifying DOPAC:DA levels in the median eminence and neurointermediate lobe following central administration of OFQ/N to female Sprague-Dawley rats. To specifically determine the involvement of the tuberoinfundibular dopaminergic neurons, immunocytochemical studies were conducted to visualize c-fos protein expression in the arcuate nucleus following central administration of OFQ/N. In addition, the role of serotonergic activation was examined in dose response studies using the selective serotonin antagonist ritansarin and the nonselective antagonist metergoline. Finally, the pharmacological specificity of the prolactin response was examined by pretreating animals with [Nphe1] NC (1-13)NH2, a drug reported to antagonize OFQ/N effects. The results of these studies indicate that the increase in prolactin release following central administration of OFQ/N does not inhibit tuberoinfundibular, tuberohypophyseal or periventricular hypophysial dopaminergic neuronal activity at 10 min after drug administration, a time when prolactin levels were significantly elevated. Furthermore, serotonergic activation is not involved since pharmacological blockade of serotonergic receptors did not alter the prolactin secretory response to OFQ/N. NC (1-13)NH2 did not antagonize the stimulatory effects of OFQ/N on prolactin secretion. The neural effects of OFQ/N on dopaminergic neuronal activity may occur following a different time course than that of the prolactin increase. PMID:15996688

  13. Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography

    Microsoft Academic Search

    P. Hartvig; R. Torstenson; J. Tedroff; Y. Watanabe; K. J. Fasth; P. Bjurling; B. Lĺngström

    1997-01-01

    Summary Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys.l-[ß-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed

  14. Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats

    Microsoft Academic Search

    David J. Mokler; Olga I. Torres; Janina R. Galler; Peter J. Morgane

    2007-01-01

    Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment, we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal

  15. Effect of ibogaine on cocaine-induced efflux of [ 3H]dopamine and [ 3H]serotonin from mouse striatum

    Microsoft Academic Search

    Sershen Henry; Hashim Audrey; Lajtha Abel

    1996-01-01

    Ibogaine, an indole alkaloid with proposed antiaddictive properties, has structural similarity to serotonin and has been shown to have affinity to the k-opioid binding site. In addition to the dopamine system, the serotonin system is a major target for cocaine action and the opioid system can affect the serotonin system. Therefore, the present study examined the effect of ibogaine on

  16. Glutamine deprivation facilitates tumour necrosis factor induced bacterial translocation in Caco-2 cells by depletion of enterocyte fuel substrate

    Microsoft Academic Search

    E C Clark; S D Patel; P R Chadwick; G Warhurst; A Curry; G L Carlson

    2003-01-01

    Background and aims: Factors that induce luminal bacteria to cross the intestinal epithelium following injury remain poorly defined. The aim of this study was to investigate the interaction between glutamine metabolism, energy supply, and inflammatory mediators in determining the translocation of non-pathogenic bacteria across cultured enterocytes.Methods: The effect of tumour necrosis factor ? (TNF-?) on translocation of Escherichia coli C25

  17. Depletion of cortical target induced by prenatal ionizing irradiation: effects on the lateral geniculate nucleus and on the retinofugal pathways.

    PubMed

    Schmidt, S L; Vitral, R W; Linden, R

    2001-07-01

    Studies using neonatal surgical lesions to reduce the target area of the retina have supported the idea that developing axons show only a limited specificity in their targeting. This investigation tested whether retinogeniculate axons adjust for partial target depletion by repositioning of axons. We used adult Swiss mice exposed to gamma rays at the time when layer IV cells are generated in the ventricular zone (16 days of gestation). Nissl-stained brain sections were used for histological analyses in thalamus and cortex. Retinal ganglion cells were backfilled from the optic tract with horseradish peroxidase. Intraocular injections of horseradish peroxidase were used to study the retinal projections. In the posterior cortex there was a nearly complete absence of layer IV. The irradiated animals showed a 75% reduction of the dorsal lateral geniculate nucleus. The ventral division, superior colliculus, and other visually related nuclei were not affected. The loss in the ganglion cells (15.7%) was significant but clearly smaller than that observed in the dorsal lateral geniculate nucleus (75%). Therefore, the shrinkage of the dorsal lateral geniculate nucleus led to a reduction in the area available for retinal projections. Despite partial target loss, pattern of retinal projections did not differ from that of the controls. The effect on the dorsal lateral geniculate nucleus is discussed in the light of differences between prenatal and neonatal damage of the presumptive visual cortex. The absence of aberrant retinal projections suggests that repositioning of axons is not the first mechanism employed by retinal axons to match connections in numerically disparate populations. PMID:11378307

  18. The fight and flight responses of crickets depleted of biogenic amines

    Microsoft Academic Search

    Paul A. Stevenson; Hans A. Hofmann; Korinna Schoch; Klaus Schildberger

    2000-01-01

    Aggressive and escape behaviors were analysed in crickets (Orthoptera) treated with ei- ther reserpine, a nonspecific depleter of biogenic amines, or the synthesis inhibitors a-methyltryptophan (AMTP) and a-methyl-p-tyrosine (AMT) to specifically deplete serotonin, respectively dopamine and octopamine. Stan- dard immunocytochemical techniques were used to ver- ify depletion from central nervous tissue, and determine the effective dosages. Reserpinized crickets became ex-

  19. N,N?-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-induced Dopamine Release and Hyperactivity

    PubMed Central

    Dwoskin, Linda P.; Wooters, Thomas E.; Sumithran, Sangeetha P.; Siripurapu, Kiran B.; Joyce, B. Matthew; Lockman, Paul R.; Manda, Vamshi K.; Ayers, Joshua T.; Zhang, Zhenfa; Deaciuc, Agripina G.; McIntosh, J. Michael; Crooks, Peter A.; Bardo, Michael T.

    2009-01-01

    The current study evaluated a new series of N,N?-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6–C12 methylene linkers as nicotinic receptor (nAChR) antagonists, for nicotine-evoked [3H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for?4?2* and?7* high affinity ligand binding sites, nor for nAChRs modulating DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50=2 nM–6?M; Imax=54–64%), with N,N?-dodecane-1,12-diyl-bis-3-picolinium dibromide (C12, bPiDDB) being most potent. bPiDDB did not inhibit electrically-evoked [3H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [3H]DA overflow. To determine if bPiDDB interacts with ?-conotoxin MII-sensitive ?6?2-containing nAChRs, slices were exposed concomitantly to maximally-effective concentrations of bPiDDB (10 nM) and ?-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with ?6?2-containing nAChRs. C7, C8, C10 and C12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although, none of the analogs altered the discriminative stimulus effect of nicotine, C8, C9, C10 and C12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted. PMID:18460644

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

    PubMed

    Bass, Caroline E; Grinevich, Valentina P; Gioia, Dominic; Day-Brown, Jonathan D; Bonin, Keith D; Stuber, Garret D; Weiner, Jeff L; Budygin, Evgeny A

    2013-01-01

    There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2) on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors. PMID:24324415

  1. Polyamine depletion enhances the roscovitine-induced apoptosis through the activation of mitochondria in HCT116 colon carcinoma cells

    Microsoft Academic Search

    Elif Damla Ar?san; Ajda Çoker; Narçin Palavan-Ünsal

    Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential in various cancer types which\\u000a are characterized by the accumulation of transformed cells due to impaired apoptotic machinery. Roscovitine, a CDK inhibitor\\u000a showed to be a potent apoptotic inducer in several cancer cells. Polyamines, putrescine, spermidine and spermine, are biogenic\\u000a amines involved in many cellular processes, including apoptosis. In

  2. A superoxide anion generator, pyrogallol induces apoptosis in As4.1 cells through the depletion of intracellular GSH content

    Microsoft Academic Search

    Woo Hyun Park; Yong Whan Han; Suhn Hee Kim; Sung Zoo Kim

    2007-01-01

    We investigated the involvement of ROS such as H2O2 and O2?, and GSH in As4.1 cell death induced by pyrogallol. The intracellular H2O2 levels were decreased or increased depending on the concentration and incubation time of pyrogallol. The levels of O2? were significantly increased. Pyrogallol reduced the intracellular GSH content. And ROS scavengers, Tempol, Tiron, Trimetazidine and NAC could not

  3. The influence of cerebral 5-hydroxytryptamine on catalepsy induced by brain-amine depleting neuroleptics or by cholinomimetics.

    PubMed

    Fuenmayor, L D; Vogt, M

    1979-10-01

    1 Catalepsy was produced in rats and mice by the subcutaneous injection of either tetrabenazine or the butyrophenone U-32,802A (4'-fluoro-4-{[4-(p-fluorophenyl)-3-cyclohexen-1-yl]amino} butyrophenone hydrochloride). Catalepsy was evaluated by the duration of total immobility on a vertical grid.2 Pretreatment with p-chlorophenylalanine (PCPA) reduced the intensity of catalepsy by 50% or more, whereas its time course remained the same.3 5-Hydroxytryptophan (5-HTP), 10 mg/kg, enhanced the catalepsy induced by U-32,802A or tetrabenazine, provided it was administered soon (45 min) after the neuroleptic; injections at 90 min had no effect. Otherwise untreated rats given this dose of 5-HTP behaved normally on the grid.4 The anticataleptic effect of PCPA was reversed by 5-HTP.5 Measurable changes in 5-hydroxytryptamine (5-HT) metabolism in the rat forebrain accompanied the modification of catalepsy by 5-HTP and PCPA.6 Methysergide (5 mg/kg) given 30 min before the neuroleptics to either mice or rats reduced the catalepsy, assessed 2.5 h after the methysergide. It also prevented the increase in neuroleptic-induced catalepsy following 5-HTP, 10 mg/kg.7 Tryptophan, like 5-HTP, increased the catalepsy seen in mice after U-32,802A and tetrabenazine, and increased the production of 5-hydroxyindol-3-ylacetic acid in the forebrain.8 In the rat, intracerebroventricular injection of physostigmine produced catalepsy which was not modified by methysergide or PCPA but was abolished by atropine. Similarly, in the mouse, catalepsy induced by the subcutaneous injection of pilocarpine was abolished by atropine but not affected by either methysergide or 5-HTP.9 Atropine greatly reduced the catalepsy induced by U-32,802A and tetrabenazine but lowered striatal homovanillic acid (HVA) only after U-32,802A. D,L-DOPA, 20 mg/kg, diminished the cataleptogenic effect of both neuroleptics and raised striatal HVA.10 The results support the view that there is a facilitating or permissive action of 5-HT-containing neurones on neuroleptic-induced catalepsy. PMID:40649

  4. Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway

    PubMed Central

    Deng, Q; Yu, X; Xiao, L; Hu, Z; Luo, X; Tao, Y; Yang, L; Liu, X; Chen, H; Ding, Z; Feng, T; Tang, Y; Weng, X; Gao, J; Yi, W; Bode, A M; Dong, Z; Liu, J; Cao, Y

    2013-01-01

    Many natural compounds derived from plants or microbes show promising potential for anticancer treatment, but few have been found to target energy-relevant regulators. In this study, we report that neoalbaconol (NA), a novel small-molecular compound isolated from the fungus, Albatrellus confluens, could target 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibit its downstream phosphoinositide-3 kinase (PI3-K)/Akt-hexokinase 2 (HK2) pathway, which eventually resulted in energy depletion. By targeting PDK1, NA reduced the consumption of glucose and ATP generation, activated autophagy and caused apoptotic and necroptotic death of cancer cells through independent pathway. Necroptosis was remarkably induced, which was confirmed by several necroptosis-specific markers: the activation of autophagy, presence of necrotic morphology, increase of receptor-interacting protein 1 (RIP1)/RIP3 colocalization and interaction and rescued by necroptosis inhibitor necrostatin-1. The possibility that Akt overexpression reversed the NA-induced energy crisis confirmed the importance of the PDK1-Akt-energy pathway in NA-mediated cell death. Moreover, NA shows the capability to inhibit PI3-K/Akt signaling and suppress tumor growth in the nasopharyngeal carcinoma (NPC) nude mouse model. These results supported the feasibility of NA in anticancer treatments. PMID:24052072

  5. Dopamine Signaling in C. elegans Is Mediated in Part by HLH-17-Dependent Regulation of Extracellular Dopamine Levels

    PubMed Central

    Felton, Chaquettea M.; Johnson, Casonya M.

    2014-01-01

    In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites, where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming-induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent on and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1. PMID:24709946

  6. Role of T lymphocytes in rat 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis: increased mortality after ?? T cell depletion and no effect of ?? T cell depletion

    Microsoft Academic Search

    J C Hoffmann; K Peters; S Henschke; B Herrmann; K Pfister; J Westermann; M Zeitz

    2001-01-01

    BACKGROUND AND AIMIndirect evidence suggests that CD4+ T cells have a pathogenic while ?? T cells have a protective role in the initiation and perpetuation of inflammatory bowel disease. To define the role of T cell subsets in a rat colitis model (2,4,6-trinitrobenzene sulphonic acid (TNBS)) we analysed colitis severity after effective depletion of T helper cells, ?? ? cells,

  7. Multiple dopamine D4 receptor variants in the human population

    Microsoft Academic Search

    Hubert H. M. Van Tol; Caren M. Wu; Hong-Chang Guan; Koichi Ohara; James R. Bunzow; Olivier Civelli; James Kennedy; Philip Seeman; Hyman B. Niznik; Vera Jovanovic

    1992-01-01

    THE dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors1-5. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia6,7, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors1. This may explain clozapine's atypical properties. Here we report the

  8. Dopamine receptors in the learning, memory and drug reward circuitry

    Microsoft Academic Search

    Jeffrey W. Dalley; Barry J. Everitt

    2009-01-01

    As primary targets of a variety of abused drugs G-protein-coupled dopamine receptors in the brain play an important role in mediating the various drug-induced alterations in neural and psychological processes thought to underlie the transition from voluntary drug use to habitual and progressively compulsive drug-taking. This review considers the functional involvement of the five major dopamine receptor subtypes in drug

  9. Kupffer cell proliferation and glucan-induced granuloma formation in mice depleted of blood monocytes by strontium-89

    SciTech Connect

    Yamada, M.; Naito, M.; Takahashi, K. (Kumamoto Univ. Medical School (Japan))

    1990-03-01

    In mice with prolonged severe monocytopenia induced by selective irradiation of the bone marrow with the bone-seeking isotope 89Sr, the proliferative capacity of Kupffer cells was studied by immunohistochemistry with an anti-mouse macrophage monoclonal antibody, F4/80, ultrastructural peroxidase (PO) cytochemistry, and tritiated thymidine (3HTdR) autoradiography. The number and 3HTdR uptake of Kupffer cells were significantly increased in the splenectomized mice after severe monocytopenia had continued for more than 4 wk, and almost all the Kupffer cells showed a localization pattern of PO activity similar to that of resident macrophages in the liver of normal mice. In the glucan-induced granuloma formation in similar monocytopenic mice, Kupffer cells proliferated, conglomerated, and transformed into epithelioid cells, which fused together to become multinuclear giant cells. These results suggest that Kupffer cells are a self-renewing population by their own cell division and can participate actively in granulomatous inflammations in severely monocytopenic and intact mice.

  10. Paradoxical Effect of Dopamine Medication on Cognition in Parkinson's Disease: Relationship to Side of Motor Onset

    PubMed Central

    Hanna-Pladdy, Brenda; Pahwa, Rajesh; Lyons, Kelly E.

    2015-01-01

    Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n = 36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n = 42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing. PMID:25923830

  11. The Dopamine Uptake Inhibitor 3?-[bis(4?-fluorophenyl)metoxy]-tropane Reduces Cocaine-Induced Early-Gene Expression, Locomotor Activity, and Conditioned Reward

    Microsoft Academic Search

    Clara Velázquez-Sánchez; Antonio Ferragud; Vicente Hernández-Rabaza; Amparo Nácher; Virginia Merino; Miguel Cardá; Juan Murga; Juan J Canales

    2009-01-01

    Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3?-[bis(4?-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low

  12. ONTD induces apoptosis of human hepatoma Bel-7402 cells via a MAPK-dependent mitochondrial pathway and the depletion of intracellular glutathione.

    PubMed

    Tan, Jiani; Lai, Zhonghui; Liu, Ling; Long, Wenyan; Chen, Tong; Zha, Jun; Wang, Linna; Chen, Meiyu; Ji, Hui; Lai, Yisheng

    2013-11-01

    3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile (ONTD) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has the ability to inhibit the proliferation of human hepatocellular carcinoma (HCC) cells. However, the mechanisms by which ONTD exerts its inhibitory effects remain elusive. The present study was conducted to investigate the cytotoxicity of ONTD in Bel-7402 cells and its molecular mechanisms. We found that ONTD depleted intracellular GSH, increased the level of ROS, and consequently induced mitochondrial permeability transition (MPT) leading to the release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) to the cytosol. Mitochondrial alteration and subsequent apoptotic cell death in ONTD-treated Bel-7402 cells could be blocked by addition of exogenous antioxidants N-acetylcystein (NAC), GSH and the MTP inhibitor cyclosporin A (CsA). In addition, ONTD activated the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) but not extracellular signal-regulated protein kinases (ERK 1/2). When the cells were exposed to SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), the deregulation of the expression of apoptotic proteins was attenuated. Furthermore, 40 mg/kg ONTD significantly reduced tumor weight (-70.62%, p<0.01) in the H22 tumor-bearing mouse model in vivo. Taken together, these findings provide the first experimental evidence supporting that ONTD could induce apoptosis of Bel-7402 cells via MAPK-mediated mitochondrial pathway and ONTD has the potential to be developed as a therapeutic agent for the treatment of HCC. PMID:24036456

  13. Diabetes-induced increases in sup 131 I-albumin permeation are unaffected by essential fatty acid depletion

    SciTech Connect

    Williamson, J.R.; Lefkowith, J.B.; Chang, K.; Tilton, R.G. (Washington Univ., St. Louis, MO (United States))

    1990-02-26

    The authors assessed effects of essential fatty acid deficiency (EFAD) on regional {sup 131}I-albumin permeation in diabetic and age-matched control rats. Male, Sprague-Dawley rats (50-75 g) were randomized into EFAD diet or normal diet groups. Three months later, diabetes was induced in one half of the rats in each group by injecting i.v. 35-45 mg/kg b.w. streptozotocin. One month later, {sup 131}I-albumin clearance ({mu} g plasma/g tissue/minute) was assessed as described previously (Circ Res 64;890, 1989). Within controls, EFAD decreased body weight gain 28% but did not affect control values for plasma glucose (118{plus minus}8 (SD) mg/dl) or glycosylated hemoglobin (1.33{plus minus}0.22 % of total hemoglobin). In normal diet and EFAD diabetics, plasma glucose (535{plus minus}64 and 419{plus minus}161, respectively) and glycosylated hemoglobin (4.38{plus minus}0.97 and 2.97{plus minus}1.69) were increased significantly versus controls. Diabetes increased {sup 131}I-albumin clearance in retinal (5.1x controls), choroid (3.4x), anterior uvea (2.7x), aorta (3.5x), and sciatic nerve (2.2x). No differences were evident in tissue {sup 131}I-albumin clearances between both control groups or both diabetic groups. These results suggest that essential fatty acids do not modulate diabetes-induced changes in endothelial cell barrier function.

  14. Determination of the hydrogen-bonding induced local viscosity enhancement in room temperature ionic liquids via femtosecond time-resolved depleted spontaneous emission.

    PubMed

    Ma, Xiaonan; Yan, Linyin; Wang, Xuefei; Guo, Qianjin; Xia, And Andong

    2011-07-14

    The fluorescence depletion dynamics of Rhodamine 700 (R-700) molecules in room temperature ionic liquids (RTILs) 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim][BF(4)]) and 1-hydroxyethyl-3-methylimidazolium tetrafluoroborate ([HOemim][BF(4)]) were investigated to determine the local viscosity of the microenvironment surrounding the fluorescent molecules, which is induced by strong hydrogen bonding interaction between cationic and anionic components in RTILs. The solvation and rotation dynamics of R-700 molecules in RTILs show slower time constants relative to that in conventional protic solvents with the same bulk viscosity, indicating that the probe molecule is facing a more viscous microenvironment in RTILs than in conventional solvents because of the strong hydrogen bonding interaction between cationic and anionic components. In addition, this effect is more pronounced in hydroxyl-functionalized ionic liquid than in the regular RTIL due to the presence of a hydroxyl group as a strong hydrogen bonding donor. The hydrogen-bonding-induced local viscosity enhancement effect related to the heterogeneity character of RTILs is confirmed by the nonexponential rotational relaxation of R-700 determined by time-correlated single photon counting (TCSPC). The geometry of hydrogen bonding complexes with different components and sizes are further optimized by density functional theory methods to show the possible hydrogen-bond networks. A model of the hydrogen-bonding network in RTILs is further proposed to interpret the observed specific solvation and local viscosity enhancement effect in RTILs, where most of the fluoroprobes exist as the free nonbonding species in the RTIL solutions and are surrounded by the hydrogen-bonding network formed by the strong hydrogen-bonding between the cationic and anionic components in RTIL. The optimized geometry of hydrogen bonding complexes with different components and sizes by density functional theory methods confirms the local viscosity enhancement effect deduced from fluorescence depletion and TCSPC experiments. The calculated interaction energies reveal the existence of the stronger hydrogen bonding network in RTILs (especially in hydroxyl-functionalized ionic liquid) than that in conventional protic solvent, which leads to the enhancement effect of local microviscosity, and therefore leads to the slow solvation and rotation dynamics of probe molecules observed in RTILs. PMID:21648476

  15. The role of dopamine receptors in the neurotoxicity of methamphetamine.

    PubMed

    Ares-Santos, S; Granado, N; Moratalla, R

    2013-05-01

    Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice. PMID:23600399

  16. Exploratory Simulation Studies of Caprock Alteration Induced byStorage of CO2 in Depleted Gas Reservoirs

    SciTech Connect

    Gherardi, Fabrizio; Xu, Tianfu; Pruess, Karsten

    2005-11-23

    This report presents numerical simulations of isothermalreactive flows which might be induced in the caprock of an Italiandepleted gas reservoir by the geological sequestration of carbon dioxide.Our objective is to verify that CO2 geological disposal activitiesalready planned for the study area are safe and do not induce anyundesired environmental impact.Gas-water-rock interactions have beenmodelled under two different intial conditions, i.e., assuming that i)caprock is perfectly sealed, or ii) partially fractured. Field conditionsare better approximated in terms of the "sealed caprock model". Thefractured caprock model has been implemented because it permits toexplore the geochemical beahvior of the system under particularly severeconditions which are not currently encountered in the field, and then todelineate a sort of hypothetical maximum risk scenario.Major evidencessupporting the assumption of a sealed caprock stem from the fact that nogas leakages have been detected during the exploitation phase, subsequentreservoir repressurization due to the ingression of a lateral aquifer,and during several cycles of gas storage in the latest life of reservoirmanagement.An extensive program of multidisciplinary laboratory tests onrock properties, geochemical and microseismic monitoring, and reservoirsimulation studies is underway to better characterize the reservoir andcap-rock behavior before the performance of a planned CO2 sequestrationpilot test.In our models, fluid flow and mineral alteration are inducedin the caprock by penetration of high CO2 concentrations from theunderlying reservoir, i.e., it was assumed that large amounts of CO2 havebeen already injected at depth. The main focus is on the potential effectof these geochemical transformations on the sealing efficiency of caprockformations. Batch and multi-dimensional 1D and 2D modeling has been usedto investigate multicomponent geochemical processes. Our simulationsaccount for fracture-matrix interactions, gas phase participation inmultiphase fluid flow and geochemical reactions, and kinetics offluid-rock interactions.The main objectives of the modeling are torecognize the geochemical processes or parameters to which theadvancement of high CO2 concentrations in the caprock is most sensitive,and to describe the most relevant mineralogical transformations occurringin the caprock as a consequence of such CO2 storage in the underlyingreservoir. We also examine the feedback of these geochemical processes onphysical properties such as porosity, and evaluate how the sealingcapacity of the caprock evolves in time.

  17. Triphenyltin acetate-induced cytotoxicity and CD4(+) and CD8(+) depletion in mouse thymocyte primary cultures.

    PubMed

    Dacasto, M; Cornaglia, E; Nebbia, C; Bollo, E

    2001-12-28

    Organotin compounds (OTs) find application worldwide as catalysts, stabilizers and biocides. Triphenyltin derivatives (TPs), including the fungicide triphenyltin acetate (TPTA), are OTs mostly used in our country. Some OTs were proved to be immunotoxic and in this paper the cytotoxicity, the possible selective activity upon definite lymphocyte subsets as well as the antiproliferative effect of TPTA was investigated in vitro by using primary cultures of mouse thymocytes. TPTA (5, 10 and 25 microM) was cytotoxic to these cells, as demonstrated by the significant (P<0.05) reduction of the cell viability percentage (trypan blue dye exclusion test), the neutral red uptake and the reduction of tetrazolium salts to formazan products (MTT assay). These overt effects were already noticed after 4 h of exposure to TPTA. The fungicide otherwise significantly reduced, after 24 h of incubation, the percentage of mature single positive thymocytes, particularly the CD4(+)/CD8(-) one. Finally, a significative dose-dependent inhibition of the T-cell mitogen-induced cell proliferation was observed in thymocytes exposed to 1 and 8 microM TPTA. These results are indicative of the TPTA immunotoxic properties, according to previous published reports concerning the in vitro and in vivo toxicity of some di- and triorganotin compounds. PMID:11718962

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

    PubMed

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

    2015-07-01

    Dopaminergic system dysfunction is proved to be a possible mechanism in acrylamide (ACR) -induced neurotoxicity. The neurotransmitter dopamine (DA) has an increasingly important role in the dopaminergic system. Thus, the goal of this study is to evaluate effects of ACR on dopamine and its metabolite levels, dopamine transport and metabolic gene expression in dopaminergic neurons. Male Sprague-Dawley (SD) rats were dosed orally with ACR at 0 (saline), 20, 30, and 40mg/kg/day for 20 days. Splayed hind limbs, reduced tail flick time and abnormal gait which preceded other neurologic parameters were observed in the above rats. ACR significantly increased dopamine levels, decreased 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) contents in an area dependent manner in rat striatum. Immunohistochemical staining of the striatum revealed that the number of tyrosine hydroxylase (TH) positive cells significantly increased, while monoamine oxidase (MAO) positive cells were drastically reduced, which was consistent with changes in their mRNA and protein expressions. In addition, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression levels were both down-regulated in the striatum. These results suggest that dopamine levels increase significantly in response to ACR, presumably due to changes in the dopamine transport and metabolism related genes expression in the striatal dopaminergic neurons. PMID:25943760

  19. Telomerase Cajal body protein 1 depletion inhibits telomerase trafficking to telomeres and induces G1 cell cycle arrest in A549 cells

    PubMed Central

    YUAN, PING; WANG, ZHITIAN; LV, WANG; PAN, HUI; YANG, YUNHAI; YUAN, XIAOSHUAI; HU, JIAN

    2014-01-01

    Telomerase Cajal body protein 1 (TCAB1) is a telomerase holoenzyme, which is markedly enriched in Cajal bodies (CBs) and facilitates the recruitment of telomerase to CBs in the S phase of the cell cycle. This recruitment is dependent on TCAB1 binding to a telomerase RNA component. The majority of cancer cells are able to grow indefinitely due to telomerase and its mechanism of trafficking to telomeres. In the present study, a certain level of TCAB1 expression in A549 human lung cells was identified and TCAB1 knockdown exhibited a potent antiproliferative effect on these cells, which was coupled with a decrease in the cell density and activity of the cellular enzymes. In addition, TCAB1-depletion was demonstrated to inhibit telomerase trafficking to telomeres in the A549 cells, leading to subsequent G1 cell cycle arrest without inducing apoptotic cell death. Overall, these observations indicated that TCAB1 may be essential for A549 cell proliferation and cell cycle regulation, and may be a potential candidate for the development of a therapeutic target for lung adenocarcinomas. PMID:25120649

  20. A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes

    SciTech Connect

    Xi Zhu; Eichberg, J. (Univ. of Houston, TX (United States))

    1990-12-01

    Peripheral nerve from experimentally diabetic rats exhibits lowered levels of myo-inositol (MI) and decreased incorporation of ({sup 3}H)MI into phosphatidylinositol (PI). There are indications that diminished PI turnover may be causally related to reduced Na{sup +}, K{sup +} -ATPase activity in diabetic nerve. The authors have investigated whether a metabolic compartment of MI that is essential for PI synthesis is decreased in this tissue. Sciatic nerve segments form streptozotocin-induced diabetic and age-matched normal rats were incubated in vitro with either {sup 32}P{sub i} or ({sup 3}H)cytidine in the presence of propranolol. This cationic amphiphilic agent redirected nerve phospholipid metabolism to produce enhanced {sup 32}P incorporation into PI and decreased labeling of phosphatidylcholine and phosphatidyl-ethanolamine. The incorporation of ({sup 3}H)cytidine into CMP-PA in normal nerve increased up to 15-fold when 0.6 mM propranolol was present. These results strongly suggest the presence in nerve of a pool of MI that is not in equilibrium with the bulk of nerve MI and that is preferentially used for PI synthesis. This metabolic compartment is depleted in diabetic nerve but can be readily replenished by exogenous MI and may correspond to the MI pool that has been proposed to be required for the turnover of a portion of tissue PI involved in maintenance of normal Na{sup +}, K{sup +} -ATPase activity.

  1. Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity.

    PubMed

    Thrash-Williams, Bessy; Ahuja, Manuj; Karuppagounder, Senthilkumar S; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2013-10-01

    Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity. PMID:23918203

  2. Homeostasis and effector function of lymphopenia-induced ‘memory-like’ T cells in constitutively T cell-depleted mice.1

    PubMed Central

    Voehringer, David; Liang, Hong-Erh; Locksley, Richard M.

    2009-01-01

    Summary Naive T lymphocytes acquire a phenotype similar to antigen-experienced memory T cells as a result of proliferation under lymphopenic conditions. Such ‘memory-like’ T cells (TML) constitute a large fraction of the peripheral T cell pool in patients recovering from T cell ablative therapies, HIV patients under highly active antiretroviral therapy and in the elderly population. To generate a model which allows characterization of TML cells without adoptive transfer, irradiation or thymectomy, we developed genetically modified mice which express diphtheria toxin A under control of a loxP flanked stop cassette (R-DTA mice). Crossing these mice to CD4Cre mice resulted in efficient ablation of CD4 single positive thymocytes whereas double positive and CD8 single positive thymocytes were only partially affected. In the periphery the pool of naďve (CD44lo CD62Lhi) T cells was depleted. However, some T cells were resistant to Cre-activity, escaped deletion in the thymus and underwent lymphopenia-induced proliferation resulting in a pool of TML cells that was similar in size and turnover to the pool of CD44hiCD62Llo memory-phenotype T cells in control mice. CD4Cre/R-DTA mice remained lymphopenic despite the large available immunological ‘space’ and normal antigen-induced T cell proliferation. CD4Cre/R-DTA mice showed a biased T cell receptor repertoire indicating oligoclonal T cell expansion. Infection with the helminth Nippostrongylus brasiliensis resulted in diminished effector cell recruitment and impaired worm expulsion demonstrating that TML cells are not sufficient to mediate an effective immune response. PMID:18354198

  3. The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors.

    PubMed

    Wicke, K; Garcia-Ladona, J

    2001-07-20

    Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist. PMID:11476753

  4. DEPLETED URANIUM TECHNICAL WORK

    EPA Science Inventory

    The Depleted Uranium Technical Work is designed to convey available information and knowledge about depleted uranium to EPA Remedial Project Managers, On-Scene Coordinators, contractors, and other Agency managers involved with the remediation of sites contaminated with this mater...

  5. Cellular prion protein (PrP(C)) modulates ethanol-induced behavioral adaptive changes in mice.

    PubMed

    Rial, Daniel; Pandolfo, Pablo; Bitencourt, Rafael M; Pamplona, Fabrício A; Moreira, Karin M; Hipolide, Débora; Dombrowski, Patrícia A; Da Cunha, Claudio; Walz, Roger; Cunha, Rodrigo A; Takahashi, Reinaldo N; Prediger, Rui D

    2014-09-01

    Chronic consumption of drugs with addictive potential induces profound synaptic changes in the dopaminergic mesocorticolimbic pathway that underlie the long-term behavioral alterations seen in addicted subjects. Thus, exploring modulation systems of dopaminergic function may reveal novel targets to interfere with drug addiction. We recently showed that cellular prion protein (PrP(C)) affects the homeostasis of the dopaminergic system by interfering with dopamine synthesis, content, receptor density and signaling pathways in different brain areas. Here we report that the genetic deletion of PrP(C) modulates ethanol (EtOH)-induced behavioral alterations including the maintenance of drug seeking, voluntary consumption and the development of EtOH tolerance, all pivotal steps in drug addiction. Notably, these behavioral changes were accompanied by a significant depletion of dopamine levels in the prefrontal cortex and reduced dopamine D1 receptors in PrP(C) knockout mice. Furthermore, the pharmacological blockade of dopamine D1 receptors, but not D2 receptors, attenuated the abnormal EtOH consumption in PrP(C) knockout mice. Altogether, these findings provide new evidence that the PrP(C)/dopamine interaction plays a pivotal role in EtOH addictive properties in mice. PMID:24975422

  6. The Michelin red guide of the brain: role of dopamine in goal-oriented navigation

    PubMed Central

    Retailleau, Aude; Boraud, Thomas

    2014-01-01

    Spatial learning has been recognized over the years to be under the control of the hippocampus and related temporal lobe structures. Hippocampal damage often causes severe impairments in the ability to learn and remember a location in space defined by distal visual cues. Such cognitive disabilities are found in Parkinsonian patients. We recently investigated the role of dopamine in navigation in the 6-Hydroxy-dopamine (6-OHDA) rat, a model of Parkinson’s disease (PD) commonly used to investigate the pathophysiology of dopamine depletion (Retailleau et al., 2013). We demonstrated that dopamine (DA) is essential to spatial learning as its depletion results in spatial impairments. Our results showed that the behavioral effect of DA depletion is correlated with modification of the neural encoding of spatial features and decision making processes in hippocampus. However, the origin of these alterations in the neural processing of the spatial information needs to be clarified. It could result from a local effect: dopamine depletion disturbs directly the processing of relevant spatial information at hippocampal level. Alternatively, it could result from a more distributed network effect: dopamine depletion elsewhere in the brain (entorhinal cortex, striatum, etc.) modifies the way hippocampus processes spatial information. Recent experimental evidence in rodents, demonstrated indeed, that other brain areas are involved in the acquisition of spatial information. Amongst these, the cortex—basal ganglia (BG) loop is known to be involved in reinforcement learning and has been identified as an important contributor to spatial learning. In particular, it has been shown that altered activity of the BG striatal complex can impair the ability to perform spatial learning tasks. The present review provides a glimpse of the findings obtained over the past decade that support a dialog between these two structures during spatial learning under DA control. PMID:24672436

  7. Depleted Uranium Technical Brief

    E-print Network

    Depleted Uranium Technical Brief United States Environmental Protection Agency Office of Air and Radiation Washington, DC 20460 EPA-402-R-06-011 December 2006 #12;#12;Depleted Uranium Technical Brief EPA of Radiation and Indoor Air Radiation Protection Division ii #12;iii #12;FOREWARD The Depleted Uranium

  8. Numerical modeling of self-limiting and self-enhancing caprock alteration induced by CO2 storage in a depleted gas reservoir

    SciTech Connect

    Xu, Tianfu; Gherardi, Fabrizio; Xu, Tianfu; Pruess, Karsten

    2007-09-07

    This paper presents numerical simulations of reactive transport which may be induced in the caprock of an on-shore depleted gas reservoir by the geological sequestration of carbon dioxide. The objective is to verify that CO{sub 2} geological disposal activities currently being planned for the study area are safe and do not induce any undesired environmental impact. In our model, fluid flow and mineral alteration are induced in the caprock by penetration of high CO{sub 2} concentrations from the underlying reservoir, where it was assumed that large amounts of CO{sub 2} have already been injected at depth. The main focus is on the potential effect of precipitation and dissolution processes on the sealing efficiency of caprock formations. Concerns that some leakage may occur in the investigated system arise because the seal is made up of potentially highly-reactive rocks, consisting of carbonate-rich shales (calcite+dolomite averaging up to more than 30% of solid volume fraction). Batch simulations and multi-dimensional 1D and 2D modeling have been used to investigate multicomponent geochemical processes. Numerical simulations account for fracture-matrix interactions, gas phase participation in multiphase fluid flow and geochemical reactions, and kinetics of fluid-rock interactions. The geochemical processes and parameters to which the occurrence of high CO{sub 2} concentrations are most sensitive are investigated by conceptualizing different mass transport mechanisms (i.e. diffusion and mixed advection+diffusion). The most relevant mineralogical transformations occurring in the caprock are described, and the feedback of these geochemical processes on physical properties such as porosity is examined to evaluate how the sealing capacity of the caprock could evolve in time. The simulations demonstrate that the occurrence of some gas leakage from the reservoir may have a strong influence on the geochemical evolution of the caprock. In fact, when a free CO{sub 2}-dominated phase migrates into the caprock through fractures, or through zones with high initial porosity possibly acting as preferential flow paths for reservoir fluids, low pH values are predicted, accompanied by significant calcite dissolution and porosity enhancement. In contrast, when fluid-rock interactions occur under fully liquid-saturated conditions and a diffusion-controlled regime, pH will be buffered at higher values, and some calcite precipitation is predicted which leads to further sealing of the storage reservoir.

  9. Discrimination between induced, triggered, and natural earthquakes close to hydrocarbon reservoirs: A probabilistic approach based on the modeling of depletion-induced stress changes and seismological source parameters

    NASA Astrophysics Data System (ADS)

    Dahm, Torsten; Cesca, Simone; Hainzl, Sebastian; Braun, Thomas; Krüger, Frank

    2015-04-01

    Earthquakes occurring close to hydrocarbon fields under production are often under critical view of being induced or triggered. However, clear and testable rules to discriminate the different events have rarely been developed and tested. The unresolved scientific problem may lead to lengthy public disputes with unpredictable impact on the local acceptance of the exploitation and field operations. We propose a quantitative approach to discriminate induced, triggered, and natural earthquakes, which is based on testable input parameters. Maxima of occurrence probabilities are compared for the cases under question, and a single probability of being triggered or induced is reported. The uncertainties of earthquake location and other input parameters are considered in terms of the integration over probability density functions. The probability that events have been human triggered/induced is derived from the modeling of Coulomb stress changes and a rate and state-dependent seismicity model. In our case a 3-D boundary element method has been adapted for the nuclei of strain approach to estimate the stress changes outside the reservoir, which are related to pore pressure changes in the field formation. The predicted rate of natural earthquakes is either derived from the background seismicity or, in case of rare events, from an estimate of the tectonic stress rate. Instrumentally derived seismological information on the event location, source mechanism, and the size of the rupture plane is of advantage for the method. If the rupture plane has been estimated, the discrimination between induced or only triggered events is theoretically possible if probability functions are convolved with a rupture fault filter. We apply the approach to three recent main shock events: (1) the Mw 4.3 Ekofisk 2001, North Sea, earthquake close to the Ekofisk oil field; (2) the Mw 4.4 Rotenburg 2004, Northern Germany, earthquake in the vicinity of the Söhlingen gas field; and (3) the Mw 6.1 Emilia 2012, Northern Italy, earthquake in the vicinity of a hydrocarbon reservoir. The three test cases cover the complete range of possible causes: clearly "human induced," "not even human triggered," and a third case in between both extremes.

  10. Selective Decreases in Amphetamine Self-Administration and Regulation of Dopamine Transporter Function in Diabetic Rats

    Microsoft Academic Search

    Ruggero Galici; Aurelio Galli; David J. Jones; Teresa A. Sanchez; Christine Saunders; Alan Frazer; Georgianna G. Gould; Richard Z. Lin; Charles P. France

    2003-01-01

    The dopamine transporter (DAT) regulates extracellular dopamine DA levels and is an important site of action for amphetamine and cocaine. Amphetamine and cocaine increase extracellular levels of DA by acting on the DAT; thus, variations in DAT binding sites or activity might influence the action of some drugs of abuse. It was hypothesized that streptozotocin-induced diabetes decreases amphetamine self-administration and

  11. Dopamine D 4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation

    Microsoft Academic Search

    Robert S. Bitner; Arthur L. Nikkel; Stephani Otte; Brenda Martino; Eve H. Barlow; Pramila Bhatia; Andrew O. Stewart; Jorge D. Brioni; Michael W. Decker; Robert B. Moreland

    2006-01-01

    The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces

  12. Long-term exposure to depleted uranium in Gulf-War veterans does not induce chromosome aberrations in peripheral blood lymphocytes.

    PubMed

    Bakhmutsky, Marina V; Squibb, Katherine; McDiarmid, Melissa; Oliver, Marc; Tucker, James D

    2013-10-01

    Depleted uranium (DU) is a high-density heavy metal that has been used in munitions since the 1991 Gulf War. DU is weakly radioactive and chemically toxic, and long-term exposure may cause adverse health effects. This study evaluates genotoxic effects of exposure to DU by measuring chromosome damage in peripheral blood lymphocytes with fluorescence in situ hybridization whole-chromosome painting. Study participants are Gulf War-I Veterans with embedded DU fragments and/or inhalation exposure due to involvement in friendly-fire incidents; they are enrolled in a long-term health surveillance program at the Baltimore Veterans Administration Medical Center. Blood was drawn from 35 exposed male veterans aged 39 to 62 years. Chromosomes 1, 2, and 4 were painted red and chromosomes 3, 5, and 6 were simultaneously labeled green. At least 1800 metaphase cells per subject were scored. Univariate regression analyses were performed to evaluate the effects of log(urine uranium), age at time of blood draw, log(lifetime X-rays), pack-years smoked and alcohol use, against frequencies of cells with translocated chromosomes, dicentrics, acentric fragments, color junctions and abnormal cells. No significant relationships were observed between any cytogenetic endpoint and log(urine uranium) levels, smoking, or log(lifetime X-rays). Age at the time of blood draw showed significant relationships with all endpoints except for cells with acentric fragments. Translocation frequencies in these Veterans were all well within the normal range of published values for healthy control subjects from around the world. These results indicate that chronic exposure to DU does not induce significant levels of chromosome damage in these Veterans. PMID:23933231

  13. Mitochondrial genome depletion dysregulates bile acid- and paracetamol-induced expression of the transporters Mdr1, Mrp1 and Mrp4 in liver cells

    PubMed Central

    Perez, MJ; Gonzalez-Sanchez, E; Gonzalez-Loyola, A; Gonzalez-Buitrago, JM; Marin, JJG

    2011-01-01

    BACKGROUND AND PURPOSE Mitochondria are involved in the toxicity of several compounds, retro-control of gene expression and apoptosis activation. The effect of mitochondrial genome (mtDNA) depletion on changes in ABC transporter protein expression in response to bile acids and paracetamol was investigated. EXPERIMENTAL APPROACH Hepa 1-6 mouse hepatoma cells with 70% decrease in 16S/18S rRNA ratio (Rho cells) were obtained by long-term treatment with ethidium bromide. KEY RESULTS Spontaneous apoptosis and reactive oxygen species (ROS) generation were decreased in Rho cells. Following glycochenodeoxycholic acid (GCDCA) or paracetamol, Rho cells generated less ROS and were more resistant to cell death. Apoptosis induced by GCDCA and Fas was also reduced. The basal expression of Mdr1 was significantly enhanced, but this was not further stimulated by GCDCA or paracetamol, as observed in wild-type (WT) cells. Basal expression of Mrp1 and Mrp4 was similar in WT and Rho cells, whereas they were up-regulated only in WT cells after GCDCA or paracetamol, along with the transcription factors Shp and Nrf2, but not Fxr or Pxr. Increased expression of Nrf2 was accompanied by its enhanced nuclear translocation. Glycoursodeoxycholic acid failed to cause any of the effects observed for GCDCA or paracetamol. CONCLUSIONS AND IMPLICATIONS The Nrf2-mediated pathway is partly independent of ROS production. Nuclear translocation of Nrf2 is insufficient to up-regulate Mdr1, Mrp1 and Mrp4, which requires the participation of other regulatory element(s) whose activation in response to GCDCA and paracetamol is impaired in Rho cells and hence probably sensitive to ROS. PMID:21175587

  14. Serum Oxidative Stress-Induced Repression of Nrf2 and GSH Depletion: A Mechanism Potentially Involved in Endothelial Dysfunction of Young Smokers

    PubMed Central

    Fratta Pasini, Anna; Albiero, Anna; Stranieri, Chiara; Cominacini, Mattia; Pasini, Andrea; Mozzini, Chiara; Vallerio, Paola; Cominacini, Luciano; Garbin, Ulisse

    2012-01-01

    Background Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs). Methods and Results 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers' serum but not to non-smokers' serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamate-cysteine ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers' serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs. Conclusions In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ARE pathway leading to GSH depletion. PMID:22272327

  15. Dopamine receptors - IUPHAR Review 13.

    PubMed

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

    2015-01-01

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

  16. Memory, Mood, Dopamine, and Serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Mouse Model of Basal Ganglia Injury

    PubMed Central

    Vu?kovi?, Marta G.; Wood, Ruth I.; Holschneider, Daniel P.; Abernathy, Avery; Togasaki, Daniel M.; Smith, Alexsandra; Petzinger, Giselle M.; Jakowec, Michael W.

    2012-01-01

    The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson’s disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning. In the social transmission of food preference test, mice showed a significant decrease in preference for familiar food 30 days post-MPTP compared to controls. Mice at both 7 and 30 days post-MPTP-lesioning had increased fear extinction compared to controls. HPLC analysis of tissues homogenates showed dopamine and serotonin were depleted in the striatum, frontal cortex, and amygdala. No changes in anxiety or depression were detected by the tail suspension, sucrose preference, light-dark preference, or hole-board tests. In conclusion, acute MPTP-lesioning regimen in mice causes impairments in associative memory and conditioned fear, no mood changes, and depletion of dopamine and serotonin throughout the brain. PMID:18718537

  17. Divalent Metal Ions Enhance DOPAL-induced Oligomerization of Alpha-Synuclein

    PubMed Central

    Jinsmaa, Yunden; Sullivan, Patricia; Gross, Daniel; Cooney, Adele; Sharabi, Yehonatan; Goldstein, David S.

    2014-01-01

    Parkinson disease (PD) features profound striatal dopamine depletion and Lewy bodies containing abundant precipitated alpha-synuclein. Mechanisms linking alpha-synucleinopathy with the death of dopamine neurons remain incompletely understood. One such link may be 3,4-dihydroxyphenylacetaldehyde (DOPAL). All of the intra-neuronal metabolism of dopamine passes through DOPAL, which is toxic. DOPAL also potently oligomerizes alpha-synuclein and alpha-synuclein oligomers are thought to be pathogenic in PD. Another implicated factor in PD pathogenesis is metal ions, and alpha-synuclein contains binding sites for these ions. In this study we tested whether divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein in cell-free system and in PC12 cells conditionally over-expressing alpha-synuclein. Incubation with divalent metal ions augmented DOPAL-induced oligomerization of alpha-synuclein (Cu2+>Fe2+>Mn2+), whereas monovalent Cu1+ and trivalent Fe3+ were without effect. Other dopamine metabolites, dopamine itself, and metal ions alone or in combination with dopamine, also had no effect. Antioxidant treatment with ascorbic acid and divalent cation chelation with EDTA attenuated the augmentation by Cu2+ of DOPAL-induced alpha-synuclein oligomerization. Incubation of PC12 cells with L-DOPA markedly increased intracellular DOPAL content and promoted alpha-synuclein dimerization. Co-incubation with Cu2+ amplified (p=0.01), while monoamine oxidase inhibition prevented, L-DOPA-related dimerization of alpha-synuclein (p=0.01). We conclude that divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein. Drugs that interfere with this interaction might constitute a novel approach for future treatment or prevention approaches. PMID:24670480

  18. Divalent metal ions enhance DOPAL-induced oligomerization of alpha-synuclein.

    PubMed

    Jinsmaa, Yunden; Sullivan, Patricia; Gross, Daniel; Cooney, Adele; Sharabi, Yehonatan; Goldstein, David S

    2014-05-21

    Parkinson disease (PD) features profound striatal dopamine depletion and Lewy bodies containing abundant precipitated alpha-synuclein. Mechanisms linking alpha-synucleinopathy with the death of dopamine neurons remain incompletely understood. One such link may be 3,4-dihydroxyphenylacetaldehyde (DOPAL). All of the intra-neuronal metabolism of dopamine passes through DOPAL, which is toxic. DOPAL also potently oligomerizes alpha-synuclein and alpha-synuclein oligomers are thought to be pathogenic in PD. Another implicated factor in PD pathogenesis is metal ions, and alpha-synuclein contains binding sites for these ions. In this study we tested whether divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein in cell-free system and in PC12 cells conditionally over-expressing alpha-synuclein. Incubation with divalent metal ions augmented DOPAL-induced oligomerization of alpha-synuclein (Cu(2+)>Fe(2+)>Mn(2+)), whereas monovalent Cu(1+) and trivalent Fe(3+) were without effect. Other dopamine metabolites, dopamine itself, and metal ions alone or in combination with dopamine, also had no effect. Antioxidant treatment with ascorbic acid and divalent cation chelation with EDTA attenuated the augmentation by Cu(2+) of DOPAL-induced alpha-synuclein oligomerization. Incubation of PC12 cells with L-DOPA markedly increased intracellular DOPAL content and promoted alpha-synuclein dimerization. Co-incubation with Cu(2+) amplified (p=0.01), while monoamine oxidase inhibition prevented, L-DOPA-related dimerization of alpha-synuclein (p=0.01). We conclude that divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein. Drugs that interfere with this interaction might constitute a novel approach for future treatment or prevention approaches. PMID:24670480

  19. Extracellular dopamine and its metabolites in the nucleus accumbens of Fisher and Lewis rats: Basal levels and cocaine-induced changes

    SciTech Connect

    Strecker, R.E.; Eberle, W.F. [State Univ. of New York, Stony Brook, NY (United States); Ashby, C.R. Jr. [Brookhaven National Lab., Upton, NY (United States)

    1995-11-01

    Rats of the Lewis (LEW) strain show a greater preference for drugs of abuse than do Fisher 344 (F344) rats. The in vivo microdialysis procedure was used to examine basal and cocaine-evoked extracellular (EC) levels of dopamine (DA), DOPAC, and HVA in the nucleus accumbens (NAc) of F344 and LEW rats. The basal EC levels of the DA metabolites DOPAC and HVA in the NAc were markedly lower in LEW than in F344 rats. Although the increase in ECDA after 3, 10 or 30 mg/kg, i/p. of cocaine was similar in both strains, LEW rats had a smaller peak DA elevation followed by a slower return to basal DA levels at the 30 mg/kg dose. The neurochemical differences observed may contribute to the strain differences in the behavioral response to cocaine. 20 refs., 3 figs.

  20. Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats.

    PubMed

    Pahuja, Richa; Seth, Kavita; Shukla, Anshi; Shukla, Rajendra Kumar; Bhatnagar, Priyanka; Chauhan, Lalit Kumar Singh; Saxena, Prem Narain; Arun, Jharna; Chaudhari, Bhushan Pradosh; Patel, Devendra Kumar; Singh, Sheelendra Pratap; Shukla, Rakesh; Khanna, Vinay Kumar; Kumar, Pradeep; Chaturvedi, Rajnish Kumar; Gupta, Kailash Chand

    2015-05-26

    Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats. PMID:25825926

  1. Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

    PubMed Central

    Van't Veer, Ashlee; Bechtholt, Anita J; Onvani, Sara; Potter, David; Wang, Yujun; Liu-Chen, Lee-Yuan; Schütz, Günther; Chartoff, Elena H; Rudolph, Uwe; Cohen, Bruce M; Carlezon, William A

    2013-01-01

    Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR?/?) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KORlox/lox). Autoradiography demonstrated complete ablation of KOR binding in the KOR?/? mutants, and reduced binding in the DAT-KORlox/lox mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR?/? mice appeared normal in the open field and light/dark box tests, DAT-KORlox/lox mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR?/? mutants, but was exaggerated in DAT-KORlox/lox mutants. Increased sensitivity to cocaine in the DAT-KORlox/lox mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR?/? mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function. PMID:23446450

  2. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice.

    PubMed

    Schulz, J B; Matthews, R T; Muqit, M M; Browne, S E; Beal, M F

    1995-02-01

    Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease. PMID:7530297

  3. Regional variation in phasic dopamine release during alcohol and sucrose self-administration in rats.

    PubMed

    Shnitko, Tatiana A; Robinson, Donita L

    2015-01-21

    While dopamine input to the dorsal striatum is well-known to be critical for action selection, including alcohol-motivated behaviors, it is unknown whether changes in phasic dopamine accompany these behaviors. Long-term alcohol abuse is believed to promote alterations in the neurocircuitry of reward learning in both ventral and dorsal striatum, potentially through increasing dopamine release. Using fast-scan cyclic voltammetry, we measured phasic dopamine release in the dorsal and ventral striatum during alcoholic and nonalcoholic reward-seeking behavior and reward-related cues in rats trained on a variable-interval schedule of reinforcement. We observed robust phasic dopamine release in the dorsolateral striatum after reinforced lever presses and inconsistent dopamine release in the dorsomedial striatum. Contrary to our expectations, alcohol did not enhance dopamine release in rats drinking alcoholic rewards. Cue-induced dopamine release was also observed in the nucleus accumbens core of rats drinking the reward solutions. These data demonstrate that alcoholic and nonalcoholic reward self-administration on a variable-interval schedule of reinforcement in rats is accompanied by phasic dopamine release time-locked to reinforcement in the dorsolateral striatum and the nucleus accumbens, but not the dorsomedial striatum. PMID:25493956

  4. Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse

    PubMed Central

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

    2013-01-01

    Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely-moving animals using in vivo microdialysis, chronoamperometry and FSCV. After a brief introduction of dopamine anatomy and signal transduction, and a section on current theories of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during 1) response-dependent and –independent administration of abused drugs, 2) drug-conditioned stimuli and operant behavior in self-administration paradigms, 3) drug withdrawal, and 4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over stimuli associated with natural reinforcers, which may result in aberrant goal-directed behaviors contributing to drug addiction. PMID:21161749

  5. Addiction: Beyond dopamine reward circuitry

    SciTech Connect

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

    2011-09-13

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

  6. Terminal effects of optogenetic stimulation on dopamine dynamics in rat striatum.

    PubMed

    Bass, Caroline E; Grinevich, Valentina P; Kulikova, Alexandra D; Bonin, Keith D; Budygin, Evgeny A

    2013-04-15

    In this study, the first in-depth analysis of optically induced dopamine release using fast-scan cyclic voltammetry on striatal slices from rat brain was performed. An adeno-associated virus that expresses Channelrhodopsin-2 was injected in the substantia nigra. Tissue was collected and sectioned into 400?m-thick coronal slices 4 weeks later. Blue laser light (473nm) was delivered through a fiber optic inserted into slice tissue. Experiments revealed some difference between maximal amplitudes measured from optically and electrically evoked dopamine effluxes. Specifically, there was an increase in the amplitude of dopamine release induced by electrical stimulation in comparison with light stimulations. However, we found that dopamine release is more sensitive to changes in the pulse width in the case of optical stimulation. Light-stimulated dopamine was increased as the stimulation pulse widened. There was no difference with repeated stimulations at five minute intervals between stimulation sources and dopamine signal was stable during recording sessions, while one minute intervals resulted in a decline in the amplitude from both sources. Optical stimulation can also produce an artifact that is distinguishable from dopamine by the cyclic voltammogram. These results confirm that optical stimulation of dopamine is a sound approach for future pharmacological studies in slices. PMID:23391758

  7. Comparison of the effects of haloperidol, remoxipride and raclopride on “pre”- and postsynaptic dopamine receptors in the rat brain

    Microsoft Academic Search

    Olle Magnusson; Christopher J. Fowler; Bodil Mohringe; Agneta WijkstriJm; Sven-Ove Ögren

    1988-01-01

    The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed ‘GBL-reversal’) was used to define the effects of these compounds on “presynaptic” dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly

  8. Genetic Variance Contributes to Dopamine and Opioid Receptor Antagonist-Induced Inhibition of Intralipid (Fat) Intake in Inbred and Outbred Mouse Strains

    PubMed Central

    Dym, Cheryl T.; Bae, Veronica; Kraft, Tamar; Yakubov, Yakov; Winn, Amanda; Sclafani, Anthony; Bodnar, Richard J.

    2010-01-01

    Preference for and intake of solid and emulsified fat (Intralipid) solutions vary across different mouse strains. Fat intake in rodents is inhibited by dopamine and opioid receptor antagonists, but any variation in these responses as a function of genetic background is unknown. Therefore, the present study compared the ability of dopamine D1-like (SCH23390) and general opioid (naltrexone) receptor antagonism to alter intake of fat emulsions (Intralipid) in mice. Two-h intakes of 5% Intralipid were measured (5–120 min) in seven inbred (BALB/c, C57BL/6, C57BL/10, DBA/2, SJL, SWR, 129P3) and one outbred (CD-1) mouse strains following treatment with vehicle, SCH23390 (50–1600 nmol/kg, ip) and naltrexone (0.001–5 mg/kg, sc). SCH23390 significantly, dose-dependently and differentially reduced Intralipid intake at all five (DBA/2, SWR, CD-1), four (SJL, C57BL/6), three (129P3) and one (C57BL/10) of the doses tested, but failed to affect Intralipid intake in BALB/c mice. Naltrexone significantly, dose-dependently and differentially reduced Intralipid intake at all four (DBA/2), three (SWR, SJL), two (CD-1, C57BL/10) and one (C57BL/6, 129P3) of the doses tested, and also failed to affect Intralipid intake in BALB/cJ mice. SCH23390 and naltrexone were respectively 13.3-fold and 9.3-fold more potent in inhibiting Intralipid intake in the most sensitive (DBA/2) relative to the least sensitive (BALB/c) mouse strains. A strong positive relationship (r=0.91) was observed for the abilities of SCH23390 and naltrexone to inhibit Intralipid intake across strains. These findings indicate that dopaminergic and opioid signaling mechanisms differentially control Intralipid intake across different mouse strains, suggesting important genetic and pharmacological interactions in the short-term control of rewarding and post-ingestive consequences of fat intake. PMID:20026311

  9. Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity.

    PubMed

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

    2009-06-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate-putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure. PMID:19457119

  10. Feeding S-adenosyl- l-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes

    Microsoft Academic Search

    Carmen García-Ruiz; Albert Morales; Anna Colell; Antonio Ballesta; Joan Rodés; Neil Kaplowitz; José C. Fernandez-Checa

    1995-01-01

    Mitochondrial glutathione plays an important role in maintaining a functionally competent organelle. Previous studies have shown that ethanol feeding selectively depletes the mitochondrial glutathione pool, more predominantly in mitochondria from perivenous hepatocytes. Because S-adenosyl-l-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of

  11. Water Depletion Threatens Agriculture

    NASA Astrophysics Data System (ADS)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  12. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. Oleoylethanolamide exerts partial and dose-dependent neuroprotection of substantia nigra dopamine neurons

    Microsoft Academic Search

    B. Galan-Rodriguez; J. Suarez; R. Gonzalez-Aparicio; F. J. Bermudez-Silva; R. Maldonado; P. Robledo; F. Rodriguez de Fonseca; E. Fernandez-Espejo

    2009-01-01

    Oleoylethanolamide (OEA), agonist of nuclear PPAR-? receptors and antagonist of vanilloid TRPV1 receptors, has been reported to show cytoprotective properties. In this study, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. First, PPAR-? receptors were confirmed to be located in the nigrostriatal circuit, these receptors being expressed by dopamine

  14. Striatal Dopamine and Working Memory

    PubMed Central

    Lal, Rayhan; O'Neil, James P.; Baker, Suzanne; Jagust, William J.

    2009-01-01

    Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks. PMID:18550595

  15. Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking

    PubMed Central

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

    2014-01-01

    We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis - yielding a dopamine movie - is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters 1-7. This aspect of the analysis – temporal-variation- is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of 5 main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique ‘HYPR’ spatial filter 8 that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model 7 to a conventional model 9. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented. PMID:23963311

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

    PubMed

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

    2013-01-01

    We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis--yielding a dopamine movie--is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters. This aspect of the analysis--temporal-variation--is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of five main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique 'HYPR' spatial filter that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model to a conventional model. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented. PMID:23963311

  17. Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially alter subcortical dopamine utilization and the behavioral response to stress

    Microsoft Academic Search

    Jeffrey N. Carlson; Kathleen E. Visker; Richard W. Keller; Stanley D. Glick

    1996-01-01

    The effects of left and right prefrontal cortical dopamine (DA) depletion on circling behavior, stress-escape behavior and subcortical DA function were examined in rats exhibiting left or right turning biases. 6-Hydroxydopamine lesions of the medial prefrontal cortex (PFC) caused significant DA depletions when assessed in separate studies at 3 days and 3–4 weeks. However, depletions were smaller at 3–4 weeks

  18. Ghrelin acts as an interface between physiological state and phasic dopamine signaling.

    PubMed

    Cone, Jackson J; McCutcheon, James E; Roitman, Mitchell F

    2014-04-01

    Brief, high-concentration (phasic) spikes in nucleus accumbens dopamine critically participate in aspects of food reward. Although physiological state (e.g., hunger, satiety) and associated hormones are known to affect dopamine tone in general, whether they modulate food-evoked, phasic dopamine specifically is unknown. Here, we used fast-scan cyclic voltammetry in awake, behaving rats to record dopamine spikes evoked by delivery of sugar pellets while pharmacologically manipulating central receptors for the gut "hunger" hormone ghrelin. Lateral ventricular (LV) ghrelin increased, while LV ghrelin receptor antagonism suppressed the magnitude of dopamine spikes evoked by food. Ghrelin was effective when infused directly into the lateral hypothalamus (LH), but not the ventral tegmental area (VTA). LH infusions were made in close proximity to orexin neurons, which are regulated by ghrelin and project to the VTA. Thus, we also investigated and found potentiation of food-evoked dopamine spikes by intra-VTA orexin-A. Importantly, intra-VTA blockade of orexin receptors attenuated food intake induced by LV ghrelin, thus establishing a behaviorally relevant connection between central ghrelin and VTA orexin. Further analysis revealed that food restriction increased the magnitude of dopamine spikes evoked by food independent of any pharmacological manipulations. The results support the regulation of food-evoked dopamine spikes by physiological state with endogenous fluctuations in ghrelin as a key contributor. Our data highlight a novel mechanism by which signals relating physiological state could influence food reinforcement and food-directed behavior. PMID:24695709

  19. Effect of metadoxine on striatal dopamine levels in C57 black mice.

    PubMed

    Fornai, F; Grazia Alessandrě, M; Bonuccelli, U; Scalori, V; Corsini, G U

    1993-05-01

    In the present study, we examined the effect of metadoxine on striatal levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in male C57 Black mice. Striatal content was assayed after systemic administration of metadoxine ranging from 1 micrograms kg-1 to 500 mg kg-1. Striatal dopamine increased 1 h after treatment with metadoxine (150 mg kg-1), but the most notable effect was obtained 24 h after the drug administration. At this time a plateau was reached; the two major metabolites of dopamine showed the same trend. Seven days after metadoxine administration, striatal dopamine approached the control values. Over the same time intervals, striatal 5-HT increased to a lesser extent and 5-hydroxy-indoleacetic acid did not differ significantly from controls. Striatal dopamine increased significantly at a dose of 250 micrograms kg-1 up to a dose of 1 mg kg-1 metadoxine; no further increment was observed between 1 and 500 mg kg-1 metadoxine. Administration of each component at doses equimolar to 1 mg metadoxine showed that pyridoxine produced only a mild increase in striatal dopamine compared with controls. We suggest that the metadoxine-induced striatal dopamine increase is obtained by increasing synthesis of dopamine. PMID:8099970

  20. Prenatal Dopamine and Neonatal Behavior and Biochemistry

    PubMed Central

    Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria; Figueiredo, Barbara; Deeds, Osvelia; Ascencio, Angela; Schanberg, Saul; Kuhn, Cynthia

    2008-01-01

    Depressed pregnant women (N=126) were divided into high and low prenatal maternal dopamine (HVA) groups based on a tertile split on their dopamine levels at 20 weeks gestation. The high versus the low dopamine group had lower CES-D scores, higher norepinephrine levels at the 20 week gestational age visit and higher dopamine and serotonin levels at both the 20 the 32 week gestational age visits. The neonates of the mothers with high versus low prenatal dopamine levels also had higher dopamine and serotonin levels as well as lower cortisol levels. Finally, the neonates in the high dopamine group had better autonomic stability and excitability scores on the Brazelton Neonatal Behavior Assessment Scale. Thus, prenatal maternal dopamine levels appear to be negatively related to prenatal depression scores and positively related to neonatal dopamine and behavioral regulation, although these effects are confounded by elevated serotonin levels. PMID:18774177

  1. MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

    SciTech Connect

    Zhu Guoqi; Chen Ying; Huang Yuying [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); Li Qinglin [Key laboratory of XinAn Medicine, Anhui University of Traditional Chinese Medicine, Hefei 230038 (China); Behnisch, Thomas, E-mail: behnish@fudan.edu.cn [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China)

    2011-08-01

    Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated fEPSPs after i.p. MPTP-injection.

  2. Dopamine, affordance and active inference.

    PubMed

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

    2012-01-01

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

  3. NR4A gene expression is dynamically regulated in the ventral tegmental area dopamine neurons and is related to expression of dopamine neurotransmission genes.

    PubMed

    Eells, Jeffrey B; Wilcots, Josiah; Sisk, Scott; Guo-Ross, Shirley X

    2012-03-01

    The NR4A transcription factors NR4A1, NR4A2, and NR4A3 (also known as Nur77, Nurr1, and Nor1, respectively) share similar DNA-binding properties and have been implicated in regulation of dopamine neurotransmission genes. Our current hypothesis is that NR4A gene expression is regulated by dopamine neuron activity and that induction of NR4A genes will increase expression of dopamine neurotransmission genes. Eticlopride and ?-butyrolactone (GBL) were used in wild-type (+/+) and Nurr1-null heterozygous (+/-) mice to determine the mechanism(s) regulating Nur77 and Nurr1 expression. Laser capture microdissection and real-time PCR was used to measure Nurr1 and Nur77 mRNA levels in the ventral tegmental area (VTA). Nur77 expression was significantly elevated 1 h after both GBL (twofold) and eticlopride (fourfold). In contrast, GBL significantly decreased Nurr1 expression in both genotypes, while eticlopride significantly increased Nurr1 expression only in the +/+ mice. In a separate group of mice, haloperidol injection significantly elevated Nur77 and Nor1, but not Nurr1 mRNA in the VTA within 1 h and significantly increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression by 4 h. These data demonstrate that the NR4A genes are dynamically regulated in dopamine neurons with maintenance of Nurr1 expression requiring dopamine neuron activity while both attenuation of dopamine autoreceptors activation and dopamine neuronal activity combining to induce Nur77 expression. Additionally, these data suggest that induction of NR4A genes could regulate TH and DAT expression and ultimately regulate dopamine neurotransmission. PMID:21932041

  4. Phasic mesolimbic dopamine release tracks reward seeking during expression of Pavlovian-to-instrumental transfer

    PubMed Central

    Wassum, Kate M.; Ostlund, Sean B.; Loewinger, Gabriel C.; Maidment, Nigel T.

    2012-01-01

    Background Recent theories addressing mesolimbic dopamine’s role in reward processing emphasize two apparently distinct functions, one in reinforcement learning (i.e. prediction error) and another in incentive motivation (i.e. the invigoration of reward-seeking elicited by reward-paired cues). Here we evaluate the latter. Methods Using fast-scan cyclic voltammetry, we monitored, in real-time, dopamine release in the nucleus accumbens core of rats (n=9) during a Pavlovian-to-instrumental transfer task in which the effects of a reward-predictive cue on an independently-trained instrumental action were assessed. Voltammetric data were parsed into slow and phasic components to determine whether these forms of dopamine signaling were differentially related to task performance. Results We found that a reward-paired cue, which increased reward-seeking actions, induced an increase in phasic mesolimbic dopamine release and produced slower elevations in extracellular dopamine. Interestingly, phasic dopamine release was temporally-related to and positively correlated with lever-press activity, generally, while slow dopamine changes were not significantly related to such activity. Importantly, the propensity of the reward-paired cue to increase lever-pressing was predicted by the amplitude of phasic dopamine release events, indicating a possible mechanism through which cues initiate reward-seeking actions. Conclusions These data suggest that those phasic mesolimbic dopamine release events thought to signal reward prediction error may also be related to the incentive motivational impact of reward-paired cues on reward-seeking actions. PMID:23374641

  5. In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector

    Microsoft Academic Search

    RJ Samulski; JD Elsworth; MG Kaplitt; P Leone; X Xiao; J Li; A Freese; JR Taylor; RH Roth; JR Sladek Jr; KL O’Malley; DE Redmond Jr

    1998-01-01

    An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopamine-depleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded

  6. Low cumulative manganese exposure affects striatal GABA but not dopamine.

    PubMed

    Gwiazda, R H; Lee, D; Sheridan, J; Smith, D R

    2002-05-01

    The introduction of the anti-knock methylcyclopentadienyl manganese (Mn) tricarbonyl (MMT) in gasoline has raised concerns about the potential for manganese neurotoxicity. Because subpopulations such as the elderly in the early stages of neurodegenerative disease may be at increased risk for manganese toxicity, a pre-Parkinsonism rat model was used to evaluate whether sub-chronic manganese exposure can aggravate the neurochemical and behavioral dysfunctions characteristic of Parkinsonism. Sub-threshold levels of dopamine depletion of 3.5, 53 and 68% were generated via intrastriatal unilateral 6-hydroxydopamine (6-OHDA) doses. A sub-chronic dosing regimen of low cumulative manganese exposure (4.8 mg Mn/kg body weight, 3 i.p. injections per week x 5 weeks) was started 4 weeks after 6-OHDA treatments. Neurochemical and neuromotor (functional observational battery (FOB)) measures were evaluated. Manganese produced significant (P < 0.05) reductions of 30-60% in motor function. This effect was exacerbated in the presence of a pre-Parkinsonism condition [Neurotox. Teratol. 22 (2000) 851]. Manganese did not affect striatal dopamine, but resulted in significant increases in striatal y-aminobutyric acid (GABA) of 16 and 22% (P < 0.01) in both striati and a borderline non-significant 4% increase in frontal cortex (P = 0.076). Manganese treatment produced increased aspartate (P < 0.01) in the manganese and 6-OHDA treated striatum. In light of previous studies predominantly showing dopamine depletion with elevated manganese exposures, the significant effects of manganese on striatal GABA but not on striatal dopamine at the low cumulative exposure administered here suggest a progression in manganese toxicity with increasing cumulative dose, whereby GABA levels are adversely affected before striatal dopamine levels. Because these neurochemical disruptions were accompanied by motor dysfunction that was exacerbated in the presence of a pre-Parkinsonism condition, an increased environmental burden of manganese may have deleterious effects on populations with sub-threshold neurodegeneration in the basal ganglia (e.g. pre-Parkinsonism). PMID:12164549

  7. Differential effect of dopamine catabolism and uptake inhibition on dopamine-induced calcium dysregulation and viability loss 1 1 Mention of a trade name, proprietary product, or specific equipment does not constitute a guarantee by the US Department of Agriculture and does not imply its approval to the exclusion of other products that may be suitable

    Microsoft Academic Search

    Ippolita Cantuti-Castelvetri; James A Joseph

    1999-01-01

    The present study was aimed at evaluating of the effects of dopamine (DA) toxicity on PC12 cells’ calcium homeostasis, cellular viability, and free radical levels. Moreover, the effect of receptor inhibition, and DA metabolism and reuptake antagonism on all parameters was also evaluated. Acute treatment with DA impaired the ability of PC12 cells to buffer excess calcium after K+-depolarization, decreased

  8. Dopamine gates sensory representations in cortex

    PubMed Central

    Tian, Ju

    2014-01-01

    The prefrontal cortex (PFC) maintains information about relevant sensory stimuli, in a process thought to rely on dopamine release. In a recent paper, Jacob et al. (J Neurosci 33: 13724–13734, 2013) demonstrated one way in which dopamine might facilitate this process. The authors recorded from PFC neurons in monkeys during local application of dopamine. They found that dopamine increases the gain of sensory-evoked responses in putative pyramidal neurons in PFC, potentially by inhibiting local interneurons. PMID:24401705

  9. A Dopamine D1 Receptor-Dependent ?-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice

    Microsoft Academic Search

    Nikhil M Urs; Tanya L Daigle; Marc G Caron

    2011-01-01

    Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These effects likely involve functionally selective mechanisms. Indeed, G protein-coupled receptor desensitization and adaptor protein ?-arrestin 2 (?arr2) through its interaction with the ?-opioid receptor regulates the analgesic but not the

  10. Identification of two functionally distinct endosomal recycling pathways for dopamine d2 receptor

    Microsoft Academic Search

    Yun Li; Brittany D Roy; Wei Wang; Li Zhang; Lifeng Zhang; Stephen B Sampson; Yupeng Yang; Da-Ting Lin

    2012-01-01

    Dopamine D(2) receptor (DRD2) is important for normal function of the brain reward circuit. Lower DRD2 function in the brain increases the risk for substance abuse, obesity, attention deficit\\/hyperactivity disorder, and depression. Moreover, DRD2 is the target of most antipsychotics currently in use. It is well known that dopamine-induced DRD2 endocytosis is important for its desensitization. However, it remains controversial

  11. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.

    PubMed

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-01-01

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-? accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-?-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer. PMID:26174737

  12. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition

    PubMed Central

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-01-01

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-? accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-?-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer. PMID:26174737

  13. Age differences in sensitivity to H 2O 2- or no-induced reductions in K +-evoked dopamine release from superfused striatal slices: Reversals by PBN or Trolox

    Microsoft Academic Search

    J. A. Joseph; R. Villalobos-Molina; N. Denisova; S. Erat; R. Cutler; J. Strain

    1996-01-01

    Previous research has indicated that many age-related functional alterations may be the result of a decreased ability of the organism to respond to oxidative stress (OS). However, this hypothesis is based on indirect indices of function (e.g., increased vulnerability of hepatocytes from senescent animals to H2O2-induced DNA damage, increases in lipofuscin accumulation). More direct tests of this hypothesis, especially as

  14. Acute 3-nitropropionic acid intoxication induces striatal astrocytic cell death and dysfunction of the blood-brain barrier: involvement of dopamine toxicity

    Microsoft Academic Search

    Hitoo Nishino; Michiko Kumazaki; Atsuo Fukuda; Ichiro Fujimoto; Yasunobu Shimano; Hideki Hida; Terumi Sakurai; Shripad B Deshpande; Hideo Shimizu; Shigehiro Morikawa; Toshiro Inubushi

    1997-01-01

    Mechanisms underlying the selective vulnerability of the lateral striatal area to the toxic effects of 3-nitropropionic acid (3-NPA) were investigated in rats. A single exposure to 3-NPA (20 mg\\/kg, s.c.) induced no deficits in behavior and histology, but subsequent injection produced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 30% of

  15. Charge-depletion meter

    SciTech Connect

    Schneider, J.F.

    1984-11-27

    This invention relates to a charge-depletion meter apparatus having a current-to-frequency converter to sense and convert the current drain of a battery source to a digital signal which is divided and then accumulated in a counter. An LCD display unit displays the accumulated charge which is received from the counter.

  16. The Influence of Dopamine on Automatic and Controlled Semantic Activation in Parkinson's Disease

    PubMed Central

    Arnott, Wendy L.; Copland, David A.; Chenery, Helen J.; Murdoch, Bruce E.; Silburn, Peter A.; Angwin, Anthony J.

    2011-01-01

    Two semantic priming tasks, designed to isolate automatic and controlled semantic activation, were utilized to investigate the impact of dopamine depletion on semantic processing in Parkinson's disease (PD). Seven people with PD (tested whilst on and off levodopa medication) and seven healthy adults participated in the study. The healthy adult participants demonstrated intact automatic and controlled semantic activation. Aberrant controlled semantic activation was observed in the PD group on levodopa; however, automatic semantic activation was still evident. In contrast, automatic semantic activation was not evident in the PD group off levodopa. These results further clarify the impact of PD on semantic processing, demonstrating that dopamine depletion can cause disturbances in both automatic and controlled semantic activation. PMID:22135759

  17. Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing

    PubMed Central

    Nelson, AJD; Thur, KE; Marsden, CA; Cassaday, HJ

    2011-01-01

    Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0?mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0?µg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates. PMID:21262855

  18. D1 dopamine receptor coupling to PLC? regulates forward locomotion in mice.

    PubMed

    Medvedev, Ivan O; Ramsey, Amy J; Masoud, Shababa T; Bermejo, Marie Kristel; Urs, Nikhil; Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Gainetdinov, Raul R; Salahpour, Ali

    2013-11-13

    Several studies have reported the coupling of dopamine signaling to phospholipase C ? (PLC?) both in vitro and in vivo. However, the precise physiological relevance of this signaling pathway in mediating dopamine behaviors is still unclear. Here we report that stimulation of dopamine receptor signaling in vivo with systemic administration of apomorphine, amphetamine, and cocaine leads to increased production of inositol triphosphate (IP3) in the mouse striatum. Using selective antagonists and dopamine D1 and D2 receptor knock-out animals, we show that the production of IP3 is mediated by the D1 receptor, but not the D2 receptor. A selective blocker of PLC?, U73122, was used to assess the physiological relevance of D1-mediated IP3 production. We show that U73122 inhibits the locomotor-stimulating effects of apomorphine, amphetamine, cocaine, and SKF81297. Furthermore, U73122 also suppresses the spontaneous hyperactivity exhibited by dopamine transporter knock-out mice. Importantly, the effects of U73122 are selective to dopamine-mediated hyperactivity, as this compound does not affect hyperactivity induced by the glutamate NMDA receptor antagonist MK801. Finally, we present evidence showing that an imbalance of D1- and D2-mediated signaling following U73122 treatment modifies the locomotor output of animals from horizontal locomotor activity to vertical activity, further highlighting the importance of the PLC? pathway in the regulation of forward locomotion via dopamine receptors. PMID:24227722

  19. Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: involvement of dopamine D2 and 5-HT2A receptors.

    PubMed

    Nakaya, Kota; Nakagawasai, Osamu; Arai, Yuichiro; Onogi, Hiroshi; Sato, Atsushi; Niijima, Fukie; Tan-No, Koichi; Tadano, Takeshi

    2011-03-17

    It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D(2) antagonist sulpiride (40 mg/kg) and 5-HT(2A/2C) antagonist ketanserin (2 and 4 mg/kg) but not with the selective D(1) antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D(2) or 5-HT(2A) receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD. PMID:21130810

  20. Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

    SciTech Connect

    Martin, J.R.

    1985-01-01

    The present study was undertaken to determine whether there is an alteration of dopamine receptor sensitivity following opiate administration, and whether this alteration has any influence on the development of opiate tolerance and dependence. Behavioral hypersensitivity to direct-acting dopamine agonists was observed in mice following acute or chronic morphine administration. Acute levorphanol administration also resulted in potentiation of dopamine agonist-induced behaviors. An increase in density of dopamine receptors, as measured by (/sup 3/H)butyrophenone binding accompanied the development of behavioral hypersensitivity. This increase was localized to the striatum, an area important in the mediation of dopamine-agonist induced behaviors. Naloxone or LiCl coadministered with the opiates prevented the development of hypersensitivity and the increase in density of dopamine receptors. Coadministration of lithium enhanced the development of acute and chronic tolerance. Lithium enhanced the development of dependence as determined by naloxone-induced hypothermia in chronically morphine-treated mice. Apomorphine enhanced naloxone-induced withdrawal in acutely dependent mice. This enhancement was blocked by coadministration of lithium with the opiates. These results suggest that dopamine receptor supersensitivity influences the degree of tolerance and dependence.

  1. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation.

    PubMed

    Devoto, Paola; Fattore, Liana; Antinori, Silvia; Saba, Pierluigi; Frau, Roberto; Fratta, Walter; Gessa, Gian Luigi

    2014-08-19

    Previous investigations indicate that the dopamine-?-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naďve animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation. PMID:25135633

  2. Differential interaction of neuroleptics with apomorphine-induced behavior in rats as a function of changing levels of dopamine receptor stimulation.

    PubMed

    Megens, Anton A H P; Hendrickx, Herman M R; Lavreysen, Hilde; Langlois, Xavier

    2013-12-01

    Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed. PMID:24071734

  3. Depletion of the nuclear Fermi sea

    E-print Network

    A. Rios; A. Polls; W. H. Dickhoff

    2009-04-14

    The short-range and tensor components of the bare nucleon-nucleon interaction induce a sizeable depletion of low momenta in the ground state of a nuclear many-body system. The self-consistent Green's function method within the ladder approximation provides an \\textit{ab-initio} description of correlated nuclear systems that accounts properly for these effects. The momentum distribution predicted by this approach is analyzed in detail, with emphasis on the depletion of the lowest momentum state. The temperature, density, and nucleon asymmetry (isospin) dependence of the depletion of the Fermi sea is clarified. A connection is established between the momentum distribution and the time-ordered components of the self-energy, which allows for an improved interpretation of the results. The dependence on the underlying nucleon-nucleon interaction provides quantitative estimates of the importance of short-range and tensor correlations in nuclear systems.

  4. The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice.

    PubMed

    Sershen, H; Wolinsky, T; Douyon, R; Hashim, A; Wiener, H L; Lajtha, A; Coons, E E; Serby, M

    1991-01-01

    To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand. PMID:7580173

  5. Anti-aggressive effect elicited by coca-paste in isolation-induced aggression of male rats: influence of accumbal dopamine and cortical serotonin.

    PubMed

    Meikle, María Noel; Prieto, José Pedro; Urbanavicius, Jessika; López, Ximena; Abin-Carriquiry, Juan Andrés; Prunell, Giselle; Scorza, María Cecilia

    2013-09-01

    Coca-paste (CP), an illicit drug of abuse, has been frequently associated with aggressive and impulsive behaviors in humans. However, preclinical studies have not been carried out in order to characterize CP effects on aggression. The acute effect of CP, cocaine and caffeine (the main adulterant present in seized samples) on aggression was assessed using the isolation-induced aggression paradigm in male rats. The dopaminergic (DA) neurotransmission in the nucleus accumbens (NAcc) and serotonergic (5-HT) activity in the frontal cortex were explored. CP and cocaine induced a similar anti-aggressive effect on isolated rats although CP-treated animals showed a shorter latency to the first attack. Aggressive behavior was not increased per se by caffeine. Social investigation time was slightly reduced only by cocaine while exploratory activity and time spent walking were increased by the three drugs. Accumbal DA levels were significantly augmented by CP, cocaine and caffeine, although differences in DOPAC and HVA levels were evidenced. A decrease in DA turnover was only observed after CP and cocaine administration. Increased cortical 5-HT levels with a concomitant decrease in 5-HT turnover were observed after CP and cocaine whereas caffeine did not alter it. As cocaine but not caffeine reduced aggression, it seems like cocaine content was mainly responsible for CP anti-aggressive action; however, the presence of caffeine in CP may have a role in the shorter latency to attack compared to cocaine. Despite the increase in NAcc DA, the enhancement of cortical 5-HT levels can likely underlie the anti-aggression observed in CP-treated animals. PMID:23891757

  6. Sequential depletion of rat testicular lipids with long-chain and very long-chain polyenoic fatty acids after X-ray-induced interruption of spermatogenesis[S

    PubMed Central

    Oresti, Gerardo M.; Ayuza Aresti, Pablo L.; Gigola, Graciela; Reyes, Luis E.; Aveldańo, Marta I.

    2010-01-01

    When a single dose of X-rays is applied to the adult rat testis, stem spermatogonia are damaged, and spermatogenesis is interrupted. Supported by Sertoli cells, spermatogenic cells that endure irradiation complete their differentiation and gradually leave the testis as spermatozoa. In this study, the in vivo changes taking place a number of weeks after irradiation revealed cell-specific features of testicular lipid classes. A linear drop, taking about six weeks, in testis weight, nonlipid materials, free cholesterol, and 22:5n-6-rich glycerophospholipids took place with germ cell depletion. Sphingomyelins and ceramides with nonhydroxy very long-chain polyenoic fatty acids (n-VLCPUFA) disappeared in four weeks, together with the last spermatocytes, whereas species with 2-hydroxy VLCPUFA lasted for six weeks, disappearing with the last spermatids and spermatozoa. The amount per testis of 22:5n-6-rich triacylglycerols, unchanged for four weeks, fell between weeks 4 and 6, associating these lipids with spermatids and their residual bodies, detected as small, bright lipid droplets. In contrast, 22:5n-6-rich species of cholesterol esters and large lipid droplets increased in seminiferous tubules up to week 6, revealing they are Sertoli cell products. At week 30, the lipid and fatty acid profiles reflected the resulting permanent testicular involution. Our data highlight the importance of Sertoli cells in maintaining lipid homeostasis during normal spermatogenesis. PMID:20529883

  7. Adipokinetic hormone-induced influx of extracellular calcium into insect fat body cells is mediated through depletion of intracellular calcium stores.

    PubMed

    Van Marrewijk, W J; Van den Broek, A T; Van der Horst, D J

    1993-11-01

    Adipokinetic hormone I (AKH I) needs extracellular Ca2+ for its activating action on glycogen phosphorylase in locust fat body in vitro. TMB-8 reduces this AKH effect significantly, indicating that for a major part, hormone action also requires the mobilization of Ca2+ from intracellular stores. Using 45Ca2+, AKH was shown to stimulate both the influx and the efflux of Ca2+. Thapsigargin also enhances the influx of extracellular Ca2+ into the fat body cells, indicating that the stimulating effect of AKH on Ca2+ influx may be mediated through depletion of intracellular Ca2+ stores as well. AKH is known to enhance cAMP levels in locust fat body. We show that elevation of cAMP with forskolin or theophylline leads to activation of glycogen phosphorylase, both in the presence and in the absence of extracellular Ca2+. The present data are discussed in an attempt to elucidate further the mechanism underlying transduction of the hormonal signal in locust fat body. PMID:8130079

  8. A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain.

    PubMed

    Xie, Zhihua; Miller, Gregory M

    2009-07-01

    This study reveals a novel receptor mechanism for methamphetamine action in dopamine transporter (DAT) regulation. Trace amine-associated receptor 1 (TAAR1) is expressed in brain dopaminergic nuclei and is activated by methamphetamine in vitro. Here, we show that methamphetamine interaction with TAAR1 inhibits [(3)H]dopamine uptake, enhances or induces [(3)H]dopamine efflux, and triggers DAT internalization. In time course assays in which methamphetamine and [(3)H]dopamine were concurrently loaded into cells or synaptosomes or in pretreatment assays in which methamphetamine was washed away before [(3)H]dopamine loading, methamphetamine caused a distinct inhibition in [(3)H]dopamine uptake in TAAR1 + DAT-cotransfected cells and in wild-type mouse and rhesus monkey striatal synaptosomes. This distinct uptake inhibition was not observed in DAT-only transfected cells or in TAAR1 knockout mouse striatal synaptosomes. In [(3)H]dopamine efflux assays using the same cell and synaptosome preparations, methamphetamine enhanced [(3)H]dopamine efflux at a high loading concentration of [(3)H]dopamine (1 muM) or induced [(3)H]dopamine efflux at a low loading concentration of [(3)H]dopamine (10 nM) in a TAAR1-dependent manner. In DAT biotinylation assays using the same cell and synaptosome preparations, we observed that 1 muM methamphetamine induced DAT internalization in a TAAR1-dependent manner. All these TAAR1-mediated effects of methamphetamine were blocked by the protein kinase inhibitors H89 [N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline] and/or 2-{8-[(dimethylamino) methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methylindol-3-yl)maleimide (Ro32-0432), suggesting that methamphetamine interaction with TAAR1 triggers cellular phosphorylation cascades and leads to the observed effects of methamphetamine on DAT. These findings demonstrate a mediatory role of TAAR1 in methamphetamine action in DAT regulation and implicate this receptor as a potential target of therapeutics drugs for methamphetamine addiction. PMID:19364908

  9. Cellular Programming and Reprogramming: Sculpting Cell Fate for the Production of Dopamine Neurons for Cell Therapy

    PubMed Central

    Aguila, Julio C.; Hedlund, Eva; Sanchez-Pernaute, Rosario

    2012-01-01

    Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate. PMID:22988464

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

    PubMed

    van der Schaaf, Marieke E; van Schouwenburg, Martine R; Geurts, Dirk E M; Schellekens, Arnt F A; Buitelaar, Jan K; Verkes, Robbert Jan; Cools, Roshan

    2014-03-01

    Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine. PMID:23183711

  11. Glycine transporter-1 inhibition promotes striatal axon sprouting via NMDA receptors in dopamine neurons.

    PubMed

    Schmitz, Yvonne; Castagna, Candace; Mrejeru, Ana; Lizardi-Ortiz, José E; Klein, Zoe; Lindsley, Craig W; Sulzer, David

    2013-10-16

    NMDA receptor activity is involved in shaping synaptic connections throughout development and adulthood. We recently reported that brief activation of NMDA receptors on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching. To test whether this mechanism was relevant to axon regrowth in adult animals, we examined the reinnervation of dorsal striatum following nigral dopamine neuron loss induced by unilateral intrastriatal injections of the toxin 6-hydroxydopamine. We used a pharmacological approach to enhance NMDA receptor-dependent signaling by treatment with an inhibitor of glycine transporter-1 that elevates levels of extracellular glycine, a coagonist required for NMDA receptor activation. All mice displayed sprouting of dopaminergic axons from spared fibers in the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion, but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was approximately twice as dense as in untreated mice. The treated mice also displayed higher levels of striatal dopamine and a complete recovery from lateralization in a test of sensorimotor behavior. We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons. Glycine transport inhibitors promote functionally relevant sprouting of surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson's disease. PMID:24133278

  12. Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra

    SciTech Connect

    Hargraves, R.; Freed, W.J.

    1987-03-09

    This study examined the effects of continuously supplied dopamine delivered directly into the dopamine-deficient striatum. Rats received unilateral lesions of the substantia nigra by stereotaxic administration of 6-hydroxydopamine and were tested for apomorphine-induced rotational behavior and general activity. Osmotic mini-pumps were filled with dopamine in various concentrations, implanted subcutaneously and connected to a cannula implanted directly into the striatum. The system delivered solution at a rate of .5 ..mu..l/hr for two weeks. Dopamine in a dosage of 0.5 ..mu..g/per hour reduced apomorphine-induced rotational behavior by a mean of 52 +/- 5.8% (mean +/- SEM n=20) with a maximal individual decrease of 99%. There was no change in general activity or increase in stereotype behavior. Infusions of vehicle solutions did not decrease rotational behavior. Spread of the infused dopamine and its metabolites was estimated by adding /sup 3/H-dopamine to the pumps in tracer quantities. Radioactivity was highly concentrated at the infusion site and decreased rapidly within a few mm from the infusion site. Continuous infusion methods may eventually prove to be effective in the treatment of nigro-striatal degenerative disease. 12 references, 4 figures.

  13. Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

    PubMed

    Wieland, Sebastian; Schindler, Sebastian; Huber, Cathrin; Köhr, Georg; Oswald, Manfred J; Kelsch, Wolfgang

    2015-07-01

    Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of <1 s. Compatible with predictions of dynamic value assignment, the synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum. PMID:26156995

  14. Reinforcing properties of fencamfamine: involvement of dopamine and opioid receptors.

    PubMed

    Planeta, C da S; Aizenstein, M L; DeLucia, R

    1995-01-01

    Fencamfamine (FCF) is a psychostimulant classified as an indirect dopamine agonist. The conditioning place preference (CPP) paradigm was used to investigate the reinforcing properties of FCF. After initial preferences had been determined, animals were conditioned with FCF (1.75, 3.5, or 7.0 mg/kg; IP). Only at the dose of 3.5 mg/kg FCF produced a significant place preference. Pretreatment with SCH23390 (0.05 mg/kg; SC) or naloxone (1.0 mg/kg; SC) 10 min before FCF (3.5 mg/kg, IP) blocked both FCF-induced hyperactivity and CPP. Pretreatment with metoclopramide (10.0 mg/kg; IP) or pimozide (1.0 mg/kg, IP), respectively, 30 min or 4 h before FCF (3.5 mg/kg; IP), which blocked the FCF-induced locomotor activity, failed to influence place conditioning produced by FCF. In conclusion, the present study suggests that dopamine D1 and opioid receptors are related to FCF reinforcing effect, while dopamine D2 subtype receptor was ineffective in modifying FCF-induced CPP. PMID:7700952

  15. The multilingual nature of dopamine neurons.

    PubMed

    Trudeau, Louis-Eric; Hnasko, Thomas S; Wallén-Mackenzie, Asa; Morales, Marisela; Rayport, Steven; Sulzer, David

    2014-01-01

    The ability of dopamine (DA) neurons to release other transmitters in addition to DA itself has been increasingly recognized, hence the concept of their multilingual nature. A subset of DA neurons, mainly found in the ventral tegmental area, express VGLUT2, allowing them to package and release glutamate onto striatal spiny projection neurons and cholinergic interneurons. Some dopaminergic axon terminals release GABA. Glutamate release by DA neurons has a developmental role, facilitating axonal growth and survival, and may determine in part the critical contribution of the ventral striatum to psychostimulant-induced behavior. Vesicular glutamate coentry may have synergistic effects on vesicular DA filling. The multilingual transmission of DA neurons across multiple striatal domains and the increasing insight into the role of glutamate cotransmission in the ventral striatum highlight the importance of analyzing DA neuron transmission at the synaptic level. PMID:24968779

  16. The evaluation of AZ66, an optimized sigma receptor antagonist, against methamphetamine-induced dopaminergic neurotoxicity and memory impairment in mice.

    PubMed

    Seminerio, Michael J; Hansen, Rolf; Kaushal, Nidhi; Zhang, Han-Ting; McCurdy, Christopher R; Matsumoto, Rae R

    2013-06-01

    Sigma (?) receptors have recently been identified as potential targets for the development of novel therapeutics aimed at mitigating the effects of methamphetamine. Particularly, ? receptors are believed to mitigate some of the neurotoxic effects of methamphetamine through modulation of dopamine, dopamine transporters and body temperature. Furthermore, recent evidence suggests that targeting ? receptors may prevent cognitive impairments produced by methamphetamine. In the present study, an optimized ? receptor antagonist, AZ66, was evaluated against methamphetamine-induced neurotoxicity and cognitive dysfunction. AZ66 was found to be highly selective for ? receptors compared to 64 other sites tested. Pretreatment of male, Swiss Webster mice with i.p. dosing of AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test, which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. Taken together, these results suggest that targeting ? receptors may provide neuroprotection against the neurotoxicity and cognitive impairments produced by methamphetamine. PMID:22932447

  17. In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human