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Overexpression of GRK6 rescues l-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats.  


l-DOPA therapy in Parkinson's disease often results in side effects such as l-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to l-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naïve than in chronically l-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to l-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute l-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr(308). Finally, GRK6 reduced accumulation of ?FosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID. PMID:25687550

Ahmed, M Rafiuddin; Bychkov, Evgeny; Kook, Seunghyi; Zurkovsky, Lilia; Dalby, Kevin N; Gurevich, Eugenia V




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...


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

PubMed Central

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

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.



Dopamine depletion induces distinct compensatory gene expression changes in DARPP-32 signal transduction cascades of striatonigral and striatopallidal neurons  

PubMed Central

Functional alterations in striatal projection neurons play a critical role in the development of motor symptoms in Parkinson’s disease (PD), but their molecular adaptation to dopamine depletion remains poorly understood. In particular, type and extent of regulation in post-synaptic signal transduction pathways that determine the responsiveness of striatal projection neurons to incoming stimuli, are currently unknown. Using cell-type specific transcriptome analyses in a rodent model of chronic dopamine depletion we identified large scale gene expression changes including neurotransmitter receptors, signal transduction cascades and target proteins of dopamine signaling in striatonigral and striatopallidal neurons. Within the dopamine and cyclic adenosine 3’,5’-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) cascade of enzymes that plays a central role in signal integration of dopaminoceptive neurons multiple catalytic and regulatory subunits change their mRNA expression levels. In addition to the number of genes the fact that the alterations occur at multiple levels stresses the biological relevance of transcriptional regulation for adaptations of post-synaptic signaling pathways. The overall pattern of changes in both striatonigral and striatopallidal neurons is compatible with homeostatic mechanisms. In accordance with the distinct biological effects of dopamine D1 and D2 receptor stimulation, the alterations of the transcriptional profiles most likely result in prodopaminergic phosphorylation patterns. Our data provide insight into the disease related plasticity of functional genomic networks in vivo that might contribute to the protracted preclinical phase of PD. In addition, the data have potential implications for the symptomatic treatment of the disease. PMID:19474310

Meurers, Bernhard H.; Dziewczapolski, Gustavo; Shi, Tao; Bittner, Anton; Kamme, Fredrik; Shults, Clifford W.



Cortical Regulation of Striatal Medium Spiny Neuron Dendritic Remodeling in Parkinsonism: Modulation of Glutamate Release Reverses Dopamine Depletion–Induced Dendritic Spine Loss  

PubMed Central

Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion–induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease. PMID:20118184

Garcia, Bonnie G.; Neely, M. Diana



The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice  

Microsoft Academic Search

Summary.  In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson’s\\u000a disease iron accumulates in substantia nigra pars compacta which has been suggested to participate in oxidative stress induced\\u000a neurodegeneration. Pretreatment with iron chelators desferal, clioquinol, VK-28 and M30 are neuroprotective in both models.\\u000a To determine the specificity of chelation neuroprotective activity we have examined the effect of D-penicillamine, a relatively

M. B. H. Youdim; E. Grünblatt; S. Mandel



Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease.  


The present study was undertaken to investigate the neuroprotective effects of resveratrol (RES) on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. PD is an age-related neurodegenerative disorder in which the role of reactive oxygen species (ROS) is strongly implicated. RES, a polyphenolic antioxidant compound enriched in grapes, has been shown to have antioxidant and anti-inflammatory actions and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male Wistar rats were pretreated with RES (20mg/kg body weight i.p.) once daily for 15 days and subjected to unilateral intrastriatal injection of 6-OHDA (10 microg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity and were killed after 4 weeks of 6-OHDA infusion for the estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT], and superoxide dismutase [SOD]. RES was found to be successful in upregulating the antioxidant status and lowering the dopamine loss. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), and activity of phospholipase A2 in 6-OHDA group was attenuated significantly in RES-pretreated group when compared with 6-OHDA-lesioned group. These results were supported by the immunohistochemical findings in the substantia nigra that has shown the protection of neurons by RES from deleterious effects of 6-OHDA. Thus, RES may be used to reduce the deterioration caused by free radicals thereby preventing subsequent behavioral, biochemical, and histopathological changes that occur during PD. PMID:20167206

Khan, Mohd Moshahid; Ahmad, Ajmal; Ishrat, Tauheed; Khan, M Badruzzaman; Hoda, Md Nasrul; Khuwaja, Gulrana; Raza, Syed Shadab; Khan, Andleeb; Javed, Hayate; Vaibhav, Kumar; Islam, Fakhrul



Dopamine Precursor Depletion Influences Pain Affect Rather than Pain Sensation  

PubMed Central

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states. PMID:24760082

Schulz, Enrico; Baumkötter, Jochen; Ploner, Markus



Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine  

Microsoft Academic Search

w SUMMARY Repeated administration of high doses of methamphetamine produced long- term decreases in dopamine (DA) levels and in the number of DA uptake sites in the rat striatum. These two effects were dose-related and did not appear to be due to the continued presence of drug in striatai tissue. Long-lasting depletions induced by methamphetamine were selective for striatal DA




Homeostatic Plasticity of Striatal Neurons Intrinsic Excitability following Dopamine Depletion  

PubMed Central

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, IA. Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of IA represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks. PMID:19730738

Azdad, Karima; Chàvez, Marcelo; Bischop, Patrick Don; Wetzelaer, Pim; Marescau, Bart; De Deyn, Peter Paul; Gall, David; Schiffmann, Serge N.



Cholesterol depletion induces autophagy  

SciTech Connect

Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

Cheng, Jinglei [Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ohsaki, Yuki [Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Tauchi-Sato, Kumi [Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Fujita, Akikazu [Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Fujimoto, Toyoshi [Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan)]. E-mail:



Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion.  


Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. The formalin test revealed that rats with neonatal dopamine depletion exhibited a significant increase in nociceptive response during interphase (6-15min post formalin injection) and phase 2 (16-75min post formalin injection). This increase in nociceptive response to the formalin injection was not reversed by pretreatment with methamphetamine, which ameliorates motor hyperactivity observed in adolescent rats with neonatal 6-OHDA treatment. The von-Frey filament and tail flick tests failed to reveal significant differences in withdrawal thresholds between neonatal 6-OHDA-treated and vehicle-treated rats. The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I-II and V-VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of spontaneous motor hyperactivity induced by neonatal dopamine depletion. PMID:25592423

Ogata, M; Noda, K; Akita, H; Ishibashi, H



Depletion of retinal dopamine does not affect the ERG b-wave increment threshold function in goldfish in vivo.  


Increment threshold functions of the electroretinogram (ERG) b-wave were obtained from goldfish using an in vivo preparation to study intraretinal mechanisms underlying the increase in perceived brightness induced by depletion of retinal dopamine by 6-hydroxydopamine (6-OHDA). Goldfish received unilateral intraocular injections of 6-OHDA plus pargyline on successive days. Depletion of retinal dopamine was confirmed by the absence of tyrosine-hydroxylase immunoreactivity at 2 to 3 weeks postinjection as compared to sham-injected eyes from the same fish. There was no difference among normal, sham-injected or 6-OHDA-injected eyes with regard to ERG waveform, intensity-response functions or increment threshold functions. Dopamine-depleted eyes showed a Purkinje shift, that is, a transition from rod-to-cone dominated vision with increasing levels of adaptation. We conclude (1) dopamine-depleted eyes are capable of photopic vision; and (2) the ERG b-wave is not diagnostic for luminosity coding at photopic backgrounds. We also predict that (1) dopamine is not required for the transition from scotopic to photopic vision in goldfish; (2) the ERG b-wave in goldfish is influenced by chromatic interactions; (3) horizontal cell spinules, though correlated with photopic mechanisms in the fish retina, are not necessary for the transition from scotopic to photopic vision; and (4) the OFF pathway, not the ON pathway, is involved in the action of dopamine on luminosity coding in the retina. PMID:7918220

Lin, Z S; Yazulla, S



Dopamine and norepinephrine depletion in ring doves fed DDE, dieldrin, and Aroclor 1254  

USGS Publications Warehouse

The levels of dopamine and norepinephrine were measured in one-half of the brain of ring doves fed a control diet or a diet containing 2, 20, or 200 ppm DDE; 1, 4, or 16 ppm dieldrin; or 1, 10, or 100 ppm Aroclor 1254. Levels of DDE, dieldrin, or Aroclor 1254 were determined in the other half of each brain. The intermediate and high levels of each chemical caused depletions in both neurotransmitters, and brain residues of each chemical were negatively correlated with levels of neurotransmitters. The highest concentrations of DDE, dieldrin, and Aroclor 1254 depressed averages of dopamine to 42.4, 41.4, and 45.2% of the control level and norepinephrine to 61.6, 62.0, and 56.9% of controls, respectively. Depletions of dopamine and norepinephrine could result in abnormal behavior of contaminated birds in the wild, and the detection of such depletions could become an important tool in assessing contaminant-induced behavioral aberrations in birds.

Heinz, G.H.; Hill, E.F.; Contrera, J.F.



Differential sensitivity of cranial and limb motor function to nigrostriatal dopamine depletion  

PubMed Central

The present study determined the differential effects of unilateral striatal dopamine depletion on cranial motor versus limb motor function. Forty male Long Evans rats were first trained on a comprehensive motor testing battery that dissociated cranial versus limb motor function and included: cylinder forepaw placement, single pellet reaching, vermicelli pasta handling; sunflower seed opening, pasta biting acoustics, and a licking task. Following baseline testing, animals were randomized to either a 6-hydroxydopamine (6-OHDA) (n = 20) or control (n = 20) group. Animals in the 6-OHDA group received unilateral intrastriatal 6-OHDA infusions to induce striatal dopamine depletion. Six-weeks following infusion, all animals were re-tested on the same battery of motor tests. Near infrared densitometry was performed on sections taken through the striatum that were immunohistochemically stained for tyrosine hydroxylase (TH). Animals in the 6-OHDA condition showed a mean reduction in TH staining of 88.27%. Although 6-OHDA animals were significantly impaired on all motor tasks, limb motor deficits were more severe than cranial motor impairments. Further, performance on limb motor tasks was correlated with degree of TH depletion while performance on cranial motor impairments showed no significant correlation. These results suggest that limb motor function may be more sensitive to striatal dopaminergic depletion than cranial motor function and is consistent with the clinical observation that therapies targeting the nigrostriatal dopaminergic system in Parkinson’s disease are more effective for limb motor symptoms than cranial motor impairments. PMID:23018122

Plowman, Emily K.; Maling, Nicholas; Rivera, Benjamin J.; Larson, Krista; Thomas, Nagheme J.; Fowler, Stephen C.; Manfredsson, Fredric P.; Shrivastav, Rahul; Kleim, Jeffrey A.



Immunocytochemical characterization of catecholaminergic neurons in the rat striatum following dopamine-depleting lesions.  


It is possible either permanently or transiently to deplete the rat striatum of dopamine. Following such depletions, striatal neurons immunoreactive for tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC) or dopamine appear. The presence of dopamine-producing neurons in the striatum has relevance for the treatment of Parkinson's disease, but whether these catecholaminergic phenotypes all produce dopamine is unclear. In the present study we establish that after unilateral 6-hydroxydopamine lesions or methamphetamine administration, striatal TH-immunoreactive neurons differ in size, morphology and location from those that are immunopositive for AADC or dopamine. The TH-positive cells which were localized either to ventral parts of the striatum or to the central and dorsal areas of the caudate-putamen generally have the morphological features of projection neurons, whereas those containing AADC or dopamine were confined to subcallosal positions in the dorsal medial quadrant of the caudate-putamen and resemble small, local-circuit neurons. The fact that AADC-immunoreactive neurons overlap in size, morphology and location with the cells that produce dopamine suggests strongly that this population is dopaminergic. However, the simultaneous appearance of neurons that contain the TH enzyme but clearly do not make dopamine raises questions about the functional role of these cells and the cellular mechanisms responsible for their induction following striatal dopamine loss. PMID:10564366

Meredith, G E; Farrell, T; Kellaghan, P; Tan, Y; Zahm, D S; Totterdell, S



Glutathione Deficiency in Gclm Null Mice Results in Complex I Inhibition and Dopamine Depletion Following Paraquat Administration  

PubMed Central

Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson’s disease (PD) and in animal models of PD. The goal of this study was to determine whether chronic glutathione (GSH) deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks, A. I., Chadwick, C. A., Gelbard, H. A., Cory-Slechta, D. A., and Federoff, H. J. [1999]. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 823, 1–10; McCormack, A. L., Thiruchelvam, M., Manning-Bog, A. B., Thiffault, C., Langston, J. W., Cory-Slechta, D. A., and Di Monte, D. A. [2002]. Environmental risk factors and Parkinson’s disease: Selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol. Dis. 10, 119–127.) Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm), leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm ?/?) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition, and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm ?/? mice of ages 3–5 or 14–16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity, and CoASH remained unchanged. Administration of paraquat (10mg/kg, twice/week, 3 weeks) to 3- to 5-month-old Gclm ?/? mice resulted in significantly decreased aconitase activity, complex I activity, and dopamine levels but not in 3- to 5-month-old Gclm +/+ mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm ?/? mice was observed in the striatum but not in the cortex. The results suggest that chronic deficiency of GSH in Gclm ?/? mice was not sufficient to result in complex I inhibition or dopamine depletion perhaps due to homeostatic mechanisms but required an additional oxidative stress insult as shown with paraquat exposure. PMID:23704229

Patel, Manisha



LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity  

PubMed Central

Objective Mutations in leucine-rich repeat kinase 2 (LRRK2) pose a significant genetic risk in familial and sporadic Parkinson's disease (PD). R1441 mutation (R1441G/C) in its GTPase domain is found in familial PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis and synaptic vesicle recycling remain unclear. Methods To explore the pathogenic effects of LRRK2R1441G mutation on nigrostriatal synaptic nerve terminals and locomotor activity, we generated C57BL/6N mice with homozygous LRRK2R1441G knockin (KI) mutation, and examined for early changes in nigrostriatal region, striatal synaptosomal [3H]-DA uptake and locomotor activity after reserpine-induced DA depletion. Results Under normal conditions, mutant mice showed no differences, (1) in amount and morphology of nigrostriatal DA neurons and neurites, (2) tyrosine hydroxylase (TH), DA uptake transporter (DAT), vesicular monoamine transporter-2 (VMAT2) expression in striatum, (3) COX IV, LC3B, Beclin-1 expression in midbrain, (4) LRRK2 expression in total cell lysate from whole brain, (5) ?-synuclein, ubiquitin, and tau protein immunostaining in midbrain, (6) locomotor activity, compared to wild-type controls. However, after a single intraperitoneal reserpine dose, striatal synaptosomes from young 3-month-old mutant mice demonstrated significantly lower DA uptake with impaired locomotor activity and significantly slower recovery from the effects of reserpine. Interpretation Although no abnormal phenotype was observed in mutant LRRK2R1441G mice, the KI mutation increases vulnerability to reserpine-induced striatal DA depletion and perturbed DA homeostasis resulting in presynaptic dysfunction and locomotor deficits with impaired recovery from reserpine. This subtle nigrostriatal synaptic vulnerability may reflect one of the earliest pathogenic processes in LRRK2-associated PD. PMID:25356398

Liu, Hui-Fang; Lu, Song; Ho, Philip Wing-Lok; Tse, Ho-Man; Pang, Shirley Yin-Yu; Kung, Michelle Hiu-Wai; Ho, Jessica Wing-Man; Ramsden, David B; Zhou, Zhong-Jun; Ho, Shu-Leong



Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation.  


Methamphetamine-induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity-regulated, cytoskeleton-associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine-induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic- or tonic-like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic-like, but not tonic-like, stimulation induced immediate-early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine-pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic-like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine-induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long-term consequences of methamphetamine-induced dopamine loss on basal ganglia functions. PMID:23480199

Howard, Christopher D; Pastuzyn, Elissa D; Barker-Haliski, Melissa L; Garris, Paul A; Keefe, Kristen A



Multisite Intracerebral Microdialysis to Study the Mechanism of L-DOPA Induced Dopamine and Serotonin Release in the Parkinsonian Brain  

PubMed Central

L-DOPA is currently one of the best medications for Parkinson’s disease. It was assumed for several years that its benefits and side effects were related to the enhancement of dopamine release in the dopamine-depleted striatum. The use of intracerebral microdialysis combined with a pharmacological approach has led to the discovery that serotonergic neurons are responsible for dopamine release induced by L-DOPA. The subsequent use of multisite microdialysis has further revealed that L-DOPA-stimulated dopamine release is widespread and related to the serotonergic innervation. The present Review emphasizes the functional impact of extrastriatal release of dopamine induced by L-DOPA in both the therapeutic and side effects of L-DOPA. PMID:23541043



Magnesium depletion enhances cisplatin-induced nephrotoxicity  

Microsoft Academic Search

Purpose: Nephrotoxicity and magnesium (Mg)-depletion are well-known side effects to cisplatin (CP) treatment. The purpose of this present study was to investigate the role of Mg on CP induced changes in renal function. CP induced renal dysfunction was achieved by treatment with CP or vehicle (2.5 mg\\/kg) once weekly for 3 weeks. Since the CP-induced renal damage, including tubular reabsorption defects, is

H. Lajer; M. Kristensen; H. H. Hansen; S. Nielsen; J. Frøkiær; L. F. Østergaard; S. Christensen; G. Daugaard; T. E. N. Jonassen



[Pathological gambling induced by dopamine agonists].  


Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease. PMID:21809260

Gahr, M; Connemann, B J; Schönfeldt-Lecuona, C J



Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling.  


Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH-pretreated animals and the 6-hydroxydopamine model of Parkinson's disease suggests that a disruption of phasic DA signaling, which is important for learning and goal-directed behavior, may be such a link. However, previous studies used electrical stimulation to elicit phasic-like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH-induced DA terminal loss on both electrically evoked phasic-like DA signals and so-called 'spontaneous' phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these subsecond DA changes may play a role in enhancing reward-cue associations. METH pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by ~55%. Analysis of phasic-like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH-induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH-induced striatal DA depletions and cognitive deficits. PMID:23574406

Howard, Christopher D; Daberkow, David P; Ramsson, Eric S; Keefe, Kristen A; Garris, Paul A



Scoliosis in rats with experimentally-induced hemiparkinsonism: dependence upon striatal dopamine denervation.  

PubMed Central

Rats suffering from experimental hemiparkinsonism induced by a unilateral injection of 6-hydroxydopamine into the left area ventralis tegmenti showed a strong ipsilateral deviation and scoliosis-like skeletal deformity. The rats often showed single rotatory curves affecting the thoracic and lumbar regions, although cases with multiple curves were also found. The severity of the scoliosis was closely related to a decrease in extracellular striatal dopamine measured with microdialysis and to the development of postsynaptic dopamine receptor supersensitivity, functionally evaluated with rotational behaviour elicited with apomorphine. Indeed, rats with the strongest dopamine depletion (greater than 95%) and the strongest rotational responses showed the sharpest spinal deviation and skeletal deformity. These findings agree with the clinical observations that scoliosis occurs in patients with Parkinson's disease and its direction is correlated with the side of the major signs and symptoms of parkinsonism. Images PMID:2303830

Herrera-Marschitz, M; Utsumi, H; Ungerstedt, U



Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice  

PubMed Central

SUMMARY A subset of patients with Parkinson’s disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson’s disease dementia; PDD). Brains from PDD patients show extensive cholinergic loss as well as dopamine (DA) depletion. We used a mutant mouse model to directly test whether combined cholinergic and DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3-sensitive choline transporter (CHTHET) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA depletion in CHTHET and wild-type (WT) littermates via intra-striatal infusion of 6-hydroxydopamine (6-OHDA), or used vehicle as control. Executive function and memory were evaluated using rodent versions of cognitive tasks commonly used with human subjects: the set-shifting task and spatial and novel-object recognition paradigms. Our studies revealed impaired acquisition of attentional set in the set-shifting paradigm in WT-6OHDA and CHTHET-vehicle mice that was exacerbated in the CHTHET-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHTHET-6OHDA mice compared with all other groups. Treatment with acetylcholinesterase (AChE) inhibitors physostigmine (0.05 or 0.1 mg/kg) and donepezil (0.1 and 0.3 mg/kg) reversed the impaired object recognition of the CHTHET-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh and DA depletion as compared with either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD. PMID:22864020

Zurkovsky, Lilia; Bychkov, Evgeny; Tsakem, Elviche L.; Siedlecki, Carley; Blakely, Randy D.; Gurevich, Eugenia V.



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

PubMed Central

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

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.; Desrivières, 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



Alteration of Daily and Circadian Rhythms following Dopamine Depletion in MPTP Treated Non-Human Primates  

PubMed Central

Disturbances of the daily sleep/wake cycle are common non-motor symptoms of Parkinson's disease (PD). However, the impact of dopamine (DA) depletion on circadian rhythms in PD patients or non-human primate (NHP) models of the disorder have not been investigated. We evaluated alterations of circadian rhythms in NHP following MPTP lesion of the dopaminergic nigro-striatal system. DA degeneration was assessed by in vivo PET ([11C]-PE2I) and post-mortem TH and DAT quantification. In a light?dark cycle, control and MPTP-treated NHP both exhibit rest-wake locomotor rhythms, although DA-depleted NHP show reduced amplitude, decreased stability and increased fragmentation. In all animals, 6-sulphatoxymelatonin peaks at night and cortisol in early morning. When the circadian system is challenged by exposure to constant light, controls retain locomotor rest-wake and hormonal rhythms that free-run with stable phase relationships whereas in the DA-depleted NHP, locomotor rhythms are severely disturbed or completely abolished. The amplitude and phase relations of hormonal rhythms nevertheless remain unaltered. Use of a light-dark masking paradigm shows that expression of daily rest-wake activity in MPTP monkeys requires the stimulatory and inhibitory effects of light and darkness. These results suggest that following DA lesion, the central clock in the SCN remains intact but, in the absence of environmental timing cues, is unable to drive downstream rhythmic processes of striatal clock gene and dopaminergic functions that control locomotor output. These findings suggest that the circadian component of the sleep-wake disturbances in PD is more profoundly affected than previously assumed. PMID:24465981

Fifel, Karim; Vezoli, Julien; Dzahini, Kwamivi; Claustrat, Bruno; Leviel, Vincent; Kennedy, Henry; Procyk, Emmanuel; Dkhissi-Benyahya, Ouria; Gronfier, Claude; Cooper, Howard M.



Intrastriatal excitotoxic lesion or dopamine depletion of the neostriatum differentially impairs response execution in extrapersonal space.  


Dysfunction of the neostriatum, a primary feature of several neurodegenerative disorders, including Parkinson's disease and Huntington's disease, has been found to result in impaired localisation of, and reaction to, contralateral stimuli. On the basis of previous findings, it is hypothesised that, with increasing eccentricity of the response option, striatal cell loss may impair response localisation at the furthest levels of eccentricity, whereas dopamine (DA) depletion may not impact adversely upon responses executed in this extrapersonal space. In order to elucidate more fully the function of the striatum, the present study examined the differential impact of unilateral DA depletion or excitoxic lesion on response execution in ipsilateral and contralateral space at up to four levels of eccentricity. The results confirmed that, after both types of striatal dysfunction, the sensory ability to detect stimuli remains intact, whereas the ability to direct responses in absolute contralateral space is impaired. Distinct differences in the profiles of impairment were, however, evident, with a marked increase in response omissions observed after DA depletion, which may reflect decreased motivational processing, and recovery of function observed in rats with excitotoxic lesions, which suggests the ability to re-learn. Furthermore, the data demonstrate that, after cell loss, responding in near contralateral space is controlled by competing striata, whereas responding in extrapersonal space relies on the contralateral hemisphere. These results have implications for understanding the role of the striatum in egocentrically defined response localisation, as well as for unravelling the behavioural impact of striatal cell loss or aberrant DA transmission observed in neurodegenerative diseases. PMID:22925170

Lelos, M J; Harrison, D J; Dunnett, S B



Age moderates the effect of acute dopamine depletion on passive avoidance learning.  


Despite extensive links between reinforcement-based learning and dopamine (DA), studies to date have not found consistent effects of acute DA reduction on reinforcement learning in both men and women. Here, we tested the effects of reducing DA on reward- and punishment-based learning using the deterministic passive avoidance learning (PAL) task. We tested 16 (5 female) adults (ages 22-40) in a randomized, cross-over design to determine whether reducing global DA by administering an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[-]), would affect PAL task performance. We found that P/T[-] beverage effects on PAL performance were modulated by age. Specifically, we found that P/T depletion significantly improved learning from punishment with increasing participant age. Participants committed 1.49 fewer passive avoidance errors per additional year of age (95% CI, -0.71 - -2.27, r=-0.74, p=0.001). Moreover, P/T depletion improved learning from punishment in adults (ages 26-40) while it impaired learning from punishment in emerging adults (ages 22-25). We observed similar, but non-significant trends in learning from reward. While there was no overall effect of P/T-depletion on reaction time (RT), there was a relationship between the effect of P/T depletion on PAL performance and RT; those who responded more slowly on the P/T[-] beverage also made more errors on the P/T[-] beverage. When P/T-depletion slowed RT after a correct response, there was a worsening of PAL task performance; there was no similar relationship for the RT after an incorrect response and PAL task performance. Moreover, among emerging adults, changes in mood on the P/T[-] beverage negatively correlated with learning from reward on the P/T[-] beverage. Together, we found that both reward- and punishment-based learning are sensitive to central catecholamine levels, and that these effects of acute DA reduction vary with age. PMID:25636601

Kelm, Mary Katherine; Boettiger, Charlotte Ann



Dopamine alleviates salt-induced stress in Malus hupehensis.  


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

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



Structural analysis of dopamine- and amphetamine-induced depolarization currents in the human dopamine transporter.  


Amphetamine (AMPH) induces depolarizing currents through the human dopamine transporter (hDAT). Recently we discovered that the S(+) enantiomer of AMPH induces a current through hDAT that persists long after its removal from the external milieu. The persistent current is less prominent for R(-)AMPH and essentially absent for dopamine (DA)-induced currents. Related agents such as methamphetamine also exhibit persistent currents, which are present in both frog oocyte and mammalian HEK expression systems. Here, we study hDAT-expressing Xenopus laevis oocytes voltage-clamped and exposed from outside to DA, S(+)AMPH, R(-)AMPH, and related synthesized compounds, including stereoisomers. The goal of the study was to determine how structural transitioning from dopamine to amphetamine influences hDAT potency and action. At saturating concentrations, S(+)AMPH or R(-)AMPH induce a sharply rising depolarizing current from -60 mV that is comparable in amplitude to DA-induced currents. The magnitude and duration of the currents and the presence or absence of persistent currents depend on the concentration, duration of exposure, and chemical structure and enantiomeric versions of the agents. PMID:25594379

Tang, Qiong-Yao; Kolanos, Renata; De Felice, Louis J; Glennon, Richard A



Diet-induced obesity: dopamine transporter function, impulsivity and motivation  

PubMed Central

OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity. PMID:23164701

Narayanaswami, V; Thompson, AC; Cassis, LA; Bardo, MT; Dwoskin, LP



Rat globus pallidus neurons: functional classification and effects of dopamine depletion.  


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. Synapse 69:41-51, 2015. © 2014 Wiley Periodicals, Inc. PMID:25196543

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



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


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

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



Single Photon Emission Computerized Tomography Imaging of Amphetamine-Induced Dopamine Release in Drug-Free Schizophrenic Subjects  

Microsoft Academic Search

The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release

Marc Laruelle; Anissa Abi-Dargham; Christopher H. van Dyck; Roberto Gil; Cyril D. D'Souza; Joseph Erdos; Elinore McCance; William Rosenblatt; Christine Fingado; Sami S. Zoghbi; Ronald M. Baldwin; John P. Seibyl; John H. Krystal; Dennis S. Charney; Robert B. Innis



Pumping induced depletion from two streams Dongmin Sun a  

E-print Network

Author's personal copy Pumping induced depletion from two streams Dongmin Sun a , Hongbin Zhan b-domain and becomes identical to that of Hunt [Hunt B. Unsteady stream depletion from ground water pumping. Ground of the shortest distance from the pumping well to the other stream over the shortest distance between the two

Zhan, Hongbin


Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia  

E-print Network

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 ...

Taylor, Norman E.


Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by l-BSO and apoptosis  

Microsoft Academic Search

Dopamine (DA), while an essential neurotransmitter, is also a known neurotoxin that potentially plays an etiologic role in several neurodegenerative diseases. DA metabolism and oxidation readily produce reactive oxygen species (ROS) and DA can also be oxidized to a reactive quinone via spontaneous, enzyme-catalyzed or metal-enhanced reactions. A number of these reactions are cytotoxic, yet the precise mechanisms by which

Alan H Stokes; Denise Y Lewis; Lawrence H Lash; W. Gray Jerome; Ken W Grant; Michael Aschner; Kent E Vrana



Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity.  


Pramipexole, a novel non-ergoline dopamine (DA) agonist, has been applied successfully for treatment of Parkinson's disease (PD). We report here that pramipexole can protect dopaminergic cell line Mes23.5 against dopamine- and levodopa-induced cytotoxicity possibly through a mechanism related to antioxidant activity. In the MES 23.5 cultures, DA and L-DOPA induce a dose- and time-dependent cytotoxicity, as determined by tetrazolium salt and trypan blue assays. Furthermore, an in situ terminal deoxynucleotidyl transferase assay demonstrates that DA-induced cell death is apoptotic. Pretreatment with pramipexole in a concentration range (4-100 microM) significantly attenuates DA- or L-DOPA-induced cytotoxicity and apoptosis, an action which is not blocked by D3 antagonist U-99194 A or D2 antagonist raclopride. Pramipexole also protects MES 23.5 cells from hydrogen peroxide-induced cytotoxicity in a dose-dependent manner. In cell-free system, pramipexole can effectively inhibit the formation of melanin, an end product resulting from DA or L-DOPA oxidation. These results indicate that pramipexole exerts its neuroprotective effect possibly through a mechanism, which is independent of DA receptors but related to antioxidation or scavenging of free radicals (e.g. hydrogen peroxide). As a direct DA agonist and potentially neuroprotective agent, pramipexole remains attractive in the treatment of PD. PMID:10227583

Zou, L; Jankovic, J; Rowe, D B; Xie, W; Appel, S H; Le, W



Dopamine depletion of the striatum causes a cell-type specific reorganization of GluN2B- and GluN2D-containing NMDA receptors.  


The GluN2B subunit of NMDA receptors (NMDARs) is an attractive drug target for therapeutic intervention in Parkinson's disease (PD). We have used whole-cell patch clamp recordings in brain slices to examine the contribution of GluN2B and GluN2D to functional NMDARs in the striatum of the unilateral 6-hydroxydopamine-lesioned mouse model of PD. We found that current/voltage relationships of NMDAR-mediated excitatory post synaptic currents were altered in a population of medium spiny projection neurons (MSNs) in the dopamine-depleted striatum. Using antagonists for GluN2B- and GluN2D-containing NMDARs, we found that GluN2B contributes to functional NMDARs in MSNs in the intact striatum and in the striatum of control mice. The function of GluN2B-containing NMDARs is however reduced in MSNs from the dopamine-depleted striatum. GluN2D is absent in MSNs from intact striatum and from control mice, but the contribution of this subunit to functional NMDARs is increased in the dopamine-depleted striatum. These changes in the subunit composition of NMDARs are associated with a decreased protein level of GluN2B and an increased level of GluN2D in the dopamine-depleted striatum. In cholinergic interneurons from the intact striatum and control mice, both GluN2B and GluN2D contribute to functional NMDARs. The functions of GluN2D, and to some extent GluN2B, are reduced in the dopamine-depleted striatum. Our findings demonstrate a cell-type specific reorganization of GluN2B and GluN2D in a mouse model of PD and suggest GluN2D as a potential target for the management of the disease. PMID:25619731

Zhang, Xiaoqun; Chergui, Karima



Subthalamotomy-induced changes in dopamine receptors in parkinsonian monkeys.  


Subthalamotomy allows a reduction of doses of l-DOPA in dyskinetic patients while its antiparkinsonian benefits are preserved. However, the mechanisms of the potentiation of this response to medication remain to be elucidated. Hence, dopamine D1 and D2 receptors as well as the dopamine transporter were investigated using receptor binding autoradiography. D1 and D2 receptors as well as preproenkephalin and preprodynorphin mRNA levels were measured by in situ hybridization. Four dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys that underwent unilateral subthalamotomy were compared to four controls, four saline-treated and four l-DOPA-treated MPTP monkeys. Dopamine, its metabolites and its transporter were extensively and similarly decreased in all parkinsonian monkeys. D1 receptor specific binding was decreased in the striatum of all MPTP monkeys. The l-DOPA-induced decrease in D1 receptor specific binding was reversed in the striatum ipsilateral to subthalamotomy. D1 receptor mRNA levels followed a similar pattern. D2 receptor specific binding and mRNA levels remained unchanged in all groups. Striatal preproenkephalin mRNA levels were overall increased in MPTP monkeys; the STN-lesioned parkinsonian group had significantly lower values than the saline-treated and l-DOPA-treated parkinsonian monkeys in the dorsolateral putamen. Striatal preprodynorphin mRNA levels remained unchanged in MPTP monkeys compared to controls whereas it increased in all monkeys treated with l-DOPA compared to controls; subthalamotomy induced a decrease in the dorsolateral putamen ipsilateral to surgery. The improved motor response to l-DOPA after subthalamotomy in the parkinsonian monkeys investigated may be associated with an increased synthesis and expression of D1 receptors ipsilateral to STN lesion of the direct pathway. PMID:25172808

Jourdain, Vincent A; Morin, Nicolas; Morissette, Marc; Grégoire, Laurent; Di Paolo, Thérèse



D-1 dopamine receptors mediate dopamine-induced pancreatic exocrine secretion in anesthetized dogs.  


Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3 mumol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1 mumol. SCH23390 (3-30 nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. However, domperidone (3 mumol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A Schild analysis of the data indicates that the inhibitory constant value for SCH23390 to inhibit DA-stimulated secretion was 6.9 nmol. In addition, the stimulatory effects of SKF38393 (0.1-10 mumol) and YM435 (0.3-30 nmol), selective D-1 DA receptor agonists, and LY171555 (1-10 mumol), a selective D-2 DA receptor agonist, on pancreatic secretion were demonstrated. The rank order of agonist potency was YM435 > DA > SKF38393 > LY171555. These results suggest that DA-induced pancreatic exocrine secretion is mediated by activation of D-1 DA receptors. PMID:8529053

Iwatsuki, K; Horiuchi, A; Ren, L M; Chiba, S



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

PubMed Central

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

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



Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress.  


In Parkinson's disease, neuroprotective therapy to rescue dopamine neurons has been proposed. Ginsenoside Rg1, one of the biologically active ingredients of ginseng, may be a candidate neuroprotective drug. In the present study, the mechanism underlying the neuroprotection provided by ginsenosde Rg1 was studied against apoptosis induced by exogenous dopamine in PC12 cells. Pretreatment with ginsenoside Rg1 markedly reduced the generation of dopamine-induced reactive oxygen species and the release of mitochondrial cytochrome c into the cytosol, and subsequently inhibited the activation of caspase-3. In addition, Rg1 pretreatment also reduced inducible nitric oxide (NO) synthase protein level and NO production. These results suggested that ginsenoside Rg1 may attenuate dopamine-induced apoptotic cell death through suppression of intracellular oxidative stress, and that it may rescue or protect dopamine neurons in Parkinson's disease. PMID:12877931

Chen, Xiao-Chun; Zhu, Yuan-Gui; Zhu, Li-An; Huang, Chun; Chen, Ying; Chen, Li-Min; Fang, Fang; Zhou, Yi-Can; Zhao, Chao-Hui



Dopamine-induced amylase secretion from guinea-pig submandibular gland.  

PubMed Central

1. The effects of dopamine, 5-hydroxydopamine (5-OHDA) and noradrenaline on amylase secretion from the guinea-pig submandibular gland were investigated under in vitro conditions. 2. All three amines greatly enhanced amylase secretion. Blockade of dopamine beta-hydroxylase did not inhibit the response to dopamine. 3. Noradrenaline and dopamine stimulated amylase release from salivary glands of reserpine-treated animals, whereas 5-OHDA had no stimulatory effect on secretion in guinea-pigs pretreated with reserpine. 4. Haloperidol completely inhibited dopamine-induced enzyme discharge, but did not affect noradrenaline-initiated secretion. 5. Apomorphine caused a slight enzyme release by itself; it diminished the dopamine secretory effect, but did not modify that of noradrenaline. 6. Pimozide and fluspirilene attenuated the dopamine-induced enzyme discharge, but compared with haloperidol they were less effective. 7. It is concluded that dopamine exerts a secretagogic action different from that of noradrenaline. The possible presence of a specific dopamine receptor in salivary glands is discussed. PMID:169937

Bloom, G D; Carlsöö, B; Danielsson, A



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

E-print Network

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

Morris, Evan D,


Dopamine and noradrenaline receptor stimulation: Reversal of reserpine-induced suppression of motor activity  

Microsoft Academic Search

The motor activity of reserpine treated mice was recorded after drug treatments causing stimulation of dopamine or noradrenaline receptors or both. The dopamine receptor stimulating agent apomorphine elicited an activation with stereotypies whereas the noradrenaline receptor stimulating agent clonidine was inefficient. Combined treatment with apomorphine and clonidine induced marked stimulation with jumping. Biochemically, clonidine did not significantly interfere with the

Nils-Erik Andén; Ulf Strömbom; Torgny H. Svensson



Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress  

Microsoft Academic Search

In Parkinson's disease, neuroprotective therapy to rescue dopamine neurons has been proposed. Ginsenoside Rg1, one of the biologically active ingredients of ginseng, may be a candidate neuroprotective drug. In the present study, the mechanism underlying the neuroprotection provided by ginsenosde Rg1 was studied against apoptosis induced by exogenous dopamine in PC12 cells. Pretreatment with ginsenoside Rg1 markedly reduced the generation

Xiao-Chun Chen; Yuan-Gui Zhu; Li-An Zhu; Chun Huang; Ying Chen; Li-Min Chen; Fang Fang; Yi-Can Zhou; Chao-Hui Zhao



Styrene-induced hepatotoxicity in mice depleted of glutathione.  


In mice depleted of glutathione (GSH) by pretreatment with an inhibitor of GSH synthesis, buthionine sulfoximine (BSO; 1 hr before styrene, 2 mmol/kg or higher doses, ip), styrene (0.96-5.76 mmol/kg, po) produced hepatotoxicity characterized by an increase in serum alanine transaminase activity and cetrilobular necrosis of hepatocytes. Treatment with inhibitors of hepatic cytochrome P-450-dependent monooxygenases such as carbon disulfide, methoxsalen, piperonyl butoxide, and SKF-525A prevented or tended to reduce the hepatotoxic effect of styrene given in combination with BSO. Styrene 7,8-oxide (3.84 mmol/kg, po), a known metabolite of styrene, in combination with BSO caused an earlier and larger increase in SALT than that caused by an equimolar dose of styrene in combination with BSO. These results suggest that metabolism of styrene, possibly to styrene 7,8-oxide, is a necessary step in styrene-induced hepatotoxicity in GSH-depleted mice. Before the onset of hepatotoxicity, styrene in combination with BSO produced a larger and more prolonged depletion of hepatic GSH than that seen after the sole treatment with BSO or prolonged depletion of hepatic GSH than that seen after the sole treatment with BSO or styrene, but no depletion of hepatic protein sulfhydryls was induced by styrene in combination with BSO. PMID:7712112

Mizutani, T; Irie, Y; Nakanishi, K



Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease  

Microsoft Academic Search

BackgroundParkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis

Sonia Gandhi; Annika Vaarmann; Zhi Yao; Michael R. Duchen; Nicholas W. Wood; Andrey Y. Abramov



Effects of green tea polyphenols on dopamine uptake and on MPP +-induced dopamine neuron injury  

Microsoft Academic Search

As antioxidants, polyphenols are considered to be potentially useful in preventing chronic diseases in man, including Parkinson's disease (PD), a disease involving dopamine (DA) neurons. Our studies have demonstrated that polyphenols extracted from green tea (GT) can inhibit the uptake of 3H-dopamine (3H-DA) and 1-methyl-4-phenylpyridinium (MPP+) by DA transporters (DAT) and partially protect embryonic rat mesencephalic dopaminergic (DAergic) neurons from

Tianhong Pan; Jian Fei; Xiaoda Zhou; Joseph Jankovic; Weidong Le



Relationship between cocaine-induced subjective effects and dopamine transporter occupancy  

SciTech Connect

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}.

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



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


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

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



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


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

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



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

SciTech Connect

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.

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



The Magnitude of Brain Dopamine Depletion from Prenatal Cocaine Exposure Is a Function of Uterine Position  

Microsoft Academic Search

Cocaine’s teratogenicity remains equivocal in the literature. The variance in cocaine-induced teratogenic data led us to consider that the intrauterine exposure to cocaine is not homogenous and that sampling methods presently utilized in the literature lead to inconsistent results. Cocaine’s vasoconstrictive actions, in concert with regional variance in the uterine milieu of the rodent, were postulated to differentially reduce the

Jack W Lipton; Heather C Robie; Zaodung Ling; Debra E Weese-Mayer; Paul M Carvey



Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers.  


Dopamine signaling in nucleus accumbens is essential for cocaine reward. Interestingly, imaging studies have reported blunted dopamine increases in striatum (assessed as reduced binding of [(11)C]raclopride to D2/D3 receptors) in detoxified cocaine abusers. Here, we evaluate whether the blunted dopamine response reflected the effects of detoxification and the lack of cocaine-cues during stimulant exposure. For this purpose we studied 62 participants (43 non-detoxified cocaine abusers and 19 controls) using positron emission tomography and [(11)C]raclopride (radioligand sensitive to endogenous dopamine) to measure dopamine increases induced by intravenous methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, methylphenidate increased dopamine in dorsal (effect size 1.4; P<0.001) and ventral striatum (location of accumbens) (effect size 0.89; P<0.001), but in cocaine abusers methylphenidate's effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use. PMID:24912491

Volkow, N D; Tomasi, D; Wang, G-J; Logan, J; Alexoff, D L; Jayne, M; Fowler, J S; Wong, C; Yin, P; Du, C



Cystamine induces AIF-mediated apoptosis through glutathione depletion.  


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

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



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

PubMed Central

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 (PrPC). 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 PrPC 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 PrPC, 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 PrPC, which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrPC 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 PrPC solubility and its subcellular localization. PMID:25698927

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



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

PubMed Central

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

Kachadourian, Remy; Day, Brian J.



Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system  

PubMed Central

Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson’s disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. ?-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3H-WIN 35,428 binding and 3H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. PMID:17291500

Hatcher, Jaime M.; Richardson, Jason R.; Guillot, Thomas S.; McCormack, Alison L.; Di Monte, Donato A.; Jones, Dean P.; Pennell, Kurt D.; Miller, Gary W.



Increased dopamine tone during meditation-induced change of consciousness.  


This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level. PMID:11958969

Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola; Brooks, David; Alving, Jørgen; Lou, Hans C



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

E-print Network

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 ...

Hernandez, Ledia F.


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


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

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



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


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

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



Pyrethroid pesticide-induced alterations in dopamine transporter function  

SciTech Connect

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

Elwan, Mohamed A. [Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Richardson, Jason R. [Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Guillot, Thomas S. [Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Caudle, W. Michael [Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322 (United States); Miller, Gary W. [Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322 (United States) and Department of Environmental and Occupational Health, School of Medicine, Emory University, Atlanta, GA 30322 (United States)]. E-mail:



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

PubMed Central

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

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



Quantification of Depletion-Induced Adhesion of Red Blood Cells  

NASA Astrophysics Data System (ADS)

Red blood cells (RBCs) are known to form aggregates in the form of rouleaux due to the presence of plasma proteins under physiological conditions. The formation of rouleaux can also be induced in vitro by the addition of macromolecules to the RBC suspension. Current data on the adhesion strength between red blood cells in their natural discocyte shapes mostly originate from indirect measurements such as flow chamber experiments, but data is lacking at the single cell level. Here, we present measurements on the dextran-induced aggregation of red blood cells using atomic force microscopy-based single cell force spectroscopy. The effects of dextran concentration and molecular weight on the interaction energy of adhering RBCs were determined. The results on adhesion energy are in excellent agreement with a model based on the depletion effect and previous experimental studies. Furthermore, our method allowed to determine the adhesion force, a quantity that is needed in theoretical investigations on blood flow.

Steffen, P.; Verdier, C.; Wagner, C.



Increased dopamine tone during meditation-induced change of consciousness  

Microsoft Academic Search

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to

Troels W Kjaer; Camilla Bertelsen; Paola Piccini; David Brooks; Jørgen Alving; Hans C Lou



Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates  

PubMed Central

Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6?mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT. PMID:24287719

Baumann, Michael H; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A; Partilla, John S; Ali, Syed F; Stockner, Thomas; Rothman, Richard B; Sandtner, Walter; Sitte, Harald H



A transgenic mouse model of neuroepithelial cell specific inducible overexpression of dopamine D1-receptor  

PubMed Central

Dopamine and its receptors appear in the brain during early embryonic period suggesting a role for dopamine in brain development. In fact, dopamine receptor imbalance resulting from impaired physiological balance between D1- and D2-receptor activities can perturb brain development and lead to persisting changes in brain structure and function. Dopamine receptor imbalance can be produced experimentally using pharmacological or genetic methods. Pharmacological methods tend to activate or antagonize the receptors in all cell types. In the traditional gene knockout models the receptor imbalance occurs during development and also at maturity. Therefore, assaying the effects of dopamine imbalance on specific cell types (e.g. precursor versus postmitotic cells) or at specific periods of brain development (e.g. pre- or postnatal periods) is not feasible in these models. We describe a novel transgenic mouse model based on the tetracycline dependent inducible gene expression system in which dopamine D1-receptor transgene expression is induced selectively in neuroepithelial cells of the embryonic brain at experimenter-chosen intervals of brain development. In this model, doxycycline-induced expression of the transgene causes significant overexpression of the D1-receptor and significant reductions in the incorporation of the S-phase marker bromodeoxyuridine into neuroepithelial cells of the basal and dorsal telencephalon indicating marked effects on telencephalic neurogenesis. The D1-receptor overexpression occurs at higher levels in the medial ganglionic eminence than the lateral ganglionic eminence or cerebral wall. Moreover, although the transgene is induced selectively in the neuroepithelium, D1-receptor protein overexpression appears to persist in postmitotic cells. The mouse model can be modified for neuroepithelial cell-specific inducible expression of other transgenes or induction of the D1-receptor transgene in other cells in specific brain regions by crossbreeding the mice with transgenic mouse lines available already. PMID:20674683

Fujimoto, Kumiko; Araki, Kiyomi; McCarthy, Deirdre M.; Sims, John R.; Ren, Jia-Qian; Zhang, Xuan; Bhide, Pradeep G.



Zinc induces depletion and aggregation of endogenous TDP-43.  


Ubiquitinated neuronal aggregates containing TDP-43 are pathological hallmarks in the spectrum of frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS). In affected neurons, TDP-43 undergoes C-terminal fragmentation, phosphorylation, and ubiquitination and forms aggregates in the cytoplasm or nucleus. Although in vitro studies have been able to recapitulate these features using transfected cell culture models, little is known about the biochemical mechanisms that underlie pathological changes to endogenous TDP-43. As altered metal ion homeostasis and increased oxidative stress are central features of neurodegeneration, including FTLD and ALS, we sought to determine the affects of these factors on endogenous TDP-43 metabolism in mammalian cells. Treatment of SY5Y neuronal-like cells expressing endogenous TDP-43 with zinc (Zn) induced depletion of TDP-43 expression and formation of inclusions that were TDP-43 positive. TDP-43 was also detected in the cytosol of Zn-affected cells but this was not aggregated. No evidence of C-terminal fragmentation, phosphorylation, or ubiquitination was observed. The depletion and aggregation of TDP-43 were associated with the specific action of Zn but were not seen with copper, iron, or H(2)O(2). These studies describe for the first time specific induction of endogenous TDP-43 aggregation in neuronal-like cells and suggest that specific Zn-associated processes could affect TDP-43 metabolism in neurodegenerative diseases. PMID:20138212

Caragounis, Aphrodite; Price, Katherine Ann; Soon, Cynthia P W; Filiz, Gulay; Masters, Colin L; Li, Qiao-Xin; Crouch, Peter J; White, Anthony R



Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND.  


Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

Gaskill, Peter J; Calderon, Tina M; Coley, Jacqueline S; Berman, Joan W



Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND  

PubMed Central

Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.



Pathological gambling induced by dopamine antagonists: a case report.  


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

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



Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity  

Microsoft Academic Search

Dopamine (DA) and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily\\u000a due to the generation of highly reactive DA and DOPA quinones. Quinone formation is closely linked to other representative\\u000a hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome\\u000a system, in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease and

Ikuko Miyazaki; Masato Asanuma



Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease  

PubMed Central

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

Park, Ariane; Stacy, Mark



Distinct Mechanisms Mediating Methamphetamine-Induced Neuronal Apoptosis and Dopamine Terminal Damage Share the Neuropeptide Substance P in the Striatum of Mice  

PubMed Central

Methamphetamine (METH) is an addictive psychostimulant that induces damage to the dopamine terminals and the apoptosis of some neurons of the striatum. Our laboratory demonstrated using either a single bolus dose (30 mg/kg) or a binge (10 mg/kg 4× at 2-h intervals) of METH that pharmacological blockade of the substance P receptor (neurokinin-1) attenuates METH-induced damage to both the presynaptic dopamine terminals and the apoptosis of some neurons of the striatum. To determine the phenotype of striatal neuron ablated by METH, we combined TUNEL (Terminal Deoxyncleotidyl Transferase-Mediated dUTP Nick End Labeling) with immunofluorescence for selective markers of projection and interneurons. METH induces the loss of approximately 20% of the projection neurons. The cholinergic and ?-aminobutyric acid (GABA)-parvalbumin interneurons sustain losses of 30% and 50%, respectively. The somatostatin/neuropeptide Y (NPY)/nitric oxide synthase (NOS) interneurons are not impacted by METH. To investigate the mechanism by which substance P mediates METH-induced damage in this part of the brain, we ablated the striatal interneurons that express the neurokinin-1 receptor (NK-1R) with the selective neurotoxin substance P-SAP. Ablation of the NK-1R-expressing interneurons prevented METH-induced apoptosis in the striatum but was without effect on depletion of dopamine terminal markers. We propose that substance P mediates the apoptosis of some striatal neurons via the intrastriatal activation of nitric oxide synthesis. In contrast, substance P may mediate damage of the dopamine terminals via an extrastriatal mechanism involving the substantia nigra and cortical glutamate release. PMID:17105911




The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release  

Microsoft Academic Search

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both

Sondra T. Bland; Mark R. Hutchinson; Steven F. Maier; Linda R. Watkins; Kirk W. Johnson



SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats.  


Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions. PMID:24661728

Chen, Lin; Deltheil, Thierry; Turle-Lorenzo, Nathalie; Liberge, Martine; Rosier, Corinne; Watabe, Isabelle; Sreng, Leam; Amalric, Marianne; Mourre, Christiane



Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide  

SciTech Connect

The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of ({sup 3}H) SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for ({sup 3}H) SCH-23390 binding, and no change in the K{sub D}. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of ({sup 3}H) spiroperidol to striatal homogenates by 70-80%.

Saleh, M.I.M.



Dopamine and paraquat enhance ?-synuclein-induced alterations in membrane conductance  

PubMed Central

We have previously demonstrated that ?-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although ?-synuclein is thought to play a central role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease, multiple system atrophy and diffuse Lewy body disease the mechanism of action is not completely understood. In this study we sought to determine whether multiple factors act together with ?-synuclein to engender cell vulnerability through an augmentation of membrane conductance. Here we employed a cell model that mimics dopaminergic neurons coupled with ?-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of ?-synuclein-induced toxicity in the presence of combined treatment with dopamine and paraquat, two molecules known to incite oxidative stress. In addition we show that combined dopamine and paraquat treatment increases the expression of heme oxygenase-1, an antioxidant response protein. Finally, we demonstrate for the first time that combined treatment of dopaminergic cells with paraquat and dopamine enhances ?-synuclein-induced leak channel properties resulting in increased membrane conductance. Importantly, these increases are most robust when both paraquat and dopamine are present suggesting the need for multiple oxidative insults to augment ?-synuclein-induced disruption of membrane integrity. PMID:21735318

Feng, Li Rebekah; Maguire-Zeiss, Kathleen A.



Dopamine or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease  

Microsoft Academic Search

Dopamine (DA)- or L-dihydroxyphenylalanine- (L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse\\u000a reaction induced by longterm L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerousin vitro andin vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen\\u000a species generated in the enzymatical oxidation or auto-oxidation of

Masato Asanuma; Ikuko Miyazaki; Norio Ogawa



Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors  

PubMed Central

Methylphenidate (MPD) administration alters the subcellular distribution of vesicular monoamine transporter-2 (VMAT-2)-containing vesicles in rat striatum. This report reveals previously undescribed pharmacological features of MPD by elucidating its receptor-mediated effects on VMAT-2-containing vesicles that co-fractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and on striatal dopamine (DA) release. MPD administration increased DA transport into, and decreased the VMAT-2 immunoreactivity of, the membrane-associated vesicle subcellular fraction. These effects were mimicked by the D2 receptor agonist, quinpirole, and blocked by the D2 receptor antagonist, eticlopride. Both MPD and quinpirole increased vesicular DA content. However, MPD increased, whereas quinpirole decreased, K+-stimulated DA release from striatal suspensions. Like MPD, the muscarinic receptor agonist, oxotremorine, increased K+-stimulated DA release. Both eticlopride and the muscarinic receptor antagonist, scopolamine, blocked MPD-induced increases in K+-stimulated DA release while the N-methyl-D-aspartate receptor antagonist, MK-801, was without effect. This suggests that D2 receptors mediate both the MPD-induced redistribution of vesicles away from synaptosomal membranes and the MPD-induced upregulation of vesicles remaining at the membrane. This results in a redistribution of DA within the striatum from the cytoplasm into vesicles, leading to increased DA release. However, D2 receptor activation alone is not sufficient to mediate the MPD-induced increases in striatal DA release as muscarinic receptor activation is also required. These novel findings provide insight into the mechanism of action of MPD, regulation of DA sequestration/release, and treatment of disorders affecting DA disposition including attention-deficit hyperactivity disorder, substance abuse, and Parkinson's disease. PMID:18591219

Volz, Trent J.; Farnsworth, Sarah J.; Rowley, Shane D.; Hanson, Glen R.; Fleckenstein, Annette E.



Coarse-Grained Molecular Dynamics Simulations of Depletion-Induced Interactions for Soft Matter Systems  

E-print Network

Given the ubiquity of depletion effects in biological and other soft matter systems, it is desirable to have coarse-grained Molecular Dynamics simulation approaches appropriate for the study of complex systems. This paper examines the use of two common truncated Lennard-Jones (WCA) potentials to describe a pair of colloidal particles in a thermal bath of depletants. The shifted-WCA model is the steeper of the two repulsive potentials considered, while the combinatorial-WCA model is the softer. It is found that the depletion-induced well depth for the combinatorial-WCA model is significantly deeper than the shifted-WCA model because the resulting overlap of the colloids yields extra accessible volume for depletants. For both shifted- and combinatorial-WCA simulations, the second virial coefficients and pair potentials between colloids are demonstrated to be well approximated by the Morphometric Thermodynamics (MT) model. This agreement suggests that the presence of depletants can be accurately modelled in MD simulations by implicitly including them through simple, analytical MT forms for depletion-induced interactions. Although both WCA potentials are found to be effective generic coarse-grained simulation approaches for studying depletion effects in complicated soft matter systems, combinatorial-WCA is the more efficient approach as depletion effects are enhanced at lower depletant densities. The findings indicate that for soft matter systems that are better modelled by potentials with some compressibility, predictions from hard-sphere systems could greatly underestimate the magnitude of depletion effects at a given depletant density.

Tyler N. Shendruk; Martin Bertrand; James L. Harden; Gary W. Slater; Hendrick W. de Haan



Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey.  


Despite the importance and frequency of levodopa-induced dyskinesias, little is known about their causal mechanisms. In this study, electrophysiological single-unit recordings of the neuronal activity of the globus pallidus internalis (GPi), the main basal ganglia output structure, and the globus pallidus externalis (GPe) were recorded continuously in both normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated subhuman primates before and after the administration of three dopamine agonists--apomorphine (a dopaminergic mixed agonist), SKF-38393 (a D1 partial agonist) and piribedil (a D2/D3 agonist)--at doses known to induce dyskinesias in the parkinsonian monkey. Changes in both the firing frequency and the firing pattern were analysed in relation to behavioural modifications. In both the normal and the parkinsonian monkey, the three agonists induced a decrease in the mean firing frequency of GPi neurones, although dyskinesias were induced only in the parkinsonian animals. In this situation, the improvement of parkinsonian motor abnormalities was correlated with the decrease in GPi firing frequency, whereas firing pattern changes were concomitant with the onset of dyskinesias. Moreover, firing frequency seemed to be decreased excessively during dyskinesias. The results indicate that the electrophysiological mechanism of dyskinesia involves an excessive decrease in GPi firing frequency and a modification of the firing pattern. However, the similarity between the induced decrease in firing frequency in normal and parkinsonian animals underlines the need for dopamine depletion in the induction of dyskinesias. PMID:11222455

Boraud, T; Bezard, E; Bioulac, B; Gross, C E



A Role for D1 Dopamine Receptors in Striatal Methamphetamine-Induced Neurotoxicity  

PubMed Central

Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia. PMID:23994061

Friend, Danielle M.; Keefe, Kristen A.



Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.  


Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity. PMID:24378745

Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Dagher, Alain; Leyton, Marco; Benkelfat, Chawki



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

PubMed Central

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

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.



Two Intracellular Pathways Mediate Metabotropic Glutamate Receptor-Induced Ca2 Mobilization in Dopamine Neurons  

Microsoft Academic Search

Activation of metabotropic glutamate receptors (mGluRs) causes membrane hyperpolarization in midbrain dopamine neurons. This hyperpolarization results from the opening of Ca 2-sensitive K channels, which is mediated by the release of Ca 2 from intracellular stores. Neurotransmitter-induced mobilization of Ca 2 is generally ascribed to the action of inositol 1,4,5-triphosphate (IP3 ) in neurons. Here we show that the mGluR-mediated

Hitoshi Morikawa; Kamran Khodakhah; John T. Williams


Calcium Store Depletion Induces Persistent Perisomatic Increases in the Functional Density  

E-print Network

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

Alford, Simon


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

E-print Network

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

Rubloff, Gary W.


Dopamine-induced depolarizing responses associated with negative slope conductance in LB-cluster neurones of Aplysia.  

PubMed Central

1. Current- and voltage-clamp methods were used to evaluate the intracellular and ionic mechanisms involved in dopamine-induced slow depolarizations recorded from neurones of the LB cluster in the abdominal ganglion of Aplysia kurodai. 2. In voltage-clamped cells, dopamine induced a slow inward current that, over the range studied (-40 to -110 mV), decreased in amplitude with hyperpolarization of the cell, but failed to invert when the cell was hyperpolarized beyond the reversal potential for K+,(E)K. 3. Bathing the ganglion in 3-isobutyl-1-methylxanthine (IBMX) caused a significant increase in the dopamine response. 4. Most of the responses to dopamine were markedly augmented in Ca2+-free media, but were depressed in Na+-free media. 5. An intracellular injection of cyclic adenosine 3',5'-monophosphate (cyclic AMP) into the same cell type produced an inward current which, like the response to dopamine, diminished in amplitude with hyperpolarization of the cell. 6. Like the dopamine response, the cyclic AMP response increased in the presence of IBMX, was enhanced in Ca2+-free media, was depressed in Na+-free media, and was unaffected by changes in external potassium. 7. In a few cells, although the cyclic AMP-induced responses disappeared in Na+-free media, the dopamine-induced slow inward current responses did not. However, these Na+-free resistant responses disappeared completely in Na+- and Ca2+-free media. 8. It was concluded that most of the dopamine-induced inward current responses were produced by an increase in permeability, mainly to Na+, triggered by a receptor-controlled increase in intracellular cyclic AMP. PMID:2476551

Matsumoto, M; Sasaki, K; Sato, M; Shozushima, M; Takashima, K



Parkin Controls Dopamine Utilization in Human Midbrain Dopaminergic Neurons Derived from Induced Pluripotent Stem Cells  

PubMed Central

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. Through the generation and analyses of induced pluripotent stem cells (iPSCs) from normal subjects and PD patients with parkin mutations, we show here that loss of parkin in human midbrain DA neurons greatly increased the transcription of monoamine oxidases and oxidative stress, significantly reduced DA uptake and increased spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescued all the phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of dopaminergic neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. PMID:22314364

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



Total body glutathione depletion induces oxidative stress and disrupts the immune function in mice  

Microsoft Academic Search

The effect of total body glutathione (GSH) depletion induced by L-buthionine-(S,R)-sulfoximine (BSO) treatment on the murine immune system has not been studied previously. BSO was administered via drinking water for 14 days to induce total body GSH depletion. A significant decrease in total GSH (TGSH) of the immune organs such as spleen, liver, peritoneal macrophages as well as blood was

Maher Y. Abdalla; Iman M. Hassan; Noor H. Mustafa; Lubna H. Tahtamouni; Iman M. Ahmad



Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia  

PubMed Central

In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form deprivation) or ? 10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 µl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n=16; n=5, respectively) or lenses (n=20; n=6) were removed for 2 hours immediately after. Saline injections prior to vision were done as controls (form deprivation: n=11; lenses: n=10). Two other saline-injected groups wore the lenses (n=12) or diffusers (n=4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 hours after the injection. Refractive errors were measured at the end of the experiment using a Hartinger’s refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 µm; p=0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 µm respectively, vs 264 µm). The increased elongation in the spiperone-injected form deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 µm; p<0.01). Finally, spiperone inhibited the vision-induced transient choroidal thickening in form deprived eyes, while SCH-23390 did not. These results indicate that the dopaminergic mechanisms mediating the protective effects of brief periods of unrestricted vision differ for form deprivation versus negative lens-wear, which may imply different growth control mechanisms between the two. PMID:21872586

Nickla, Debora L.; Totonelly, Kristen



D1 but not D4 dopamine receptors are critical for MDMA-induced neurotoxicity in mice.  


MDMA, an addictive psychostimulant-consumed worldwide, has the ability to induce neurotoxic effects and addiction in laboratory animals and in humans through its effects on monoaminergic systems. MDMA-induced neurotoxicity in mice occurs primarily in dopaminergic neurons and does not significantly affect the serotonergic system. As the neurotoxic effects of MDMA in mice involve excessive dopamine (DA) release, DA receptors are highly likely to play a role in MDMA neurotoxicity, but the specific dopamine receptor subtypes involved have not previously been determined definitively. In this study, dopamine D1 and D4 receptor knock-out mice (D1R(-/-) and D4R(-/-)) were used to determine whether these receptors are involved in MDMA neurotoxicity. D1R inactivation attenuated MDMA-induced hyperthermia, decreased the reduction of dopamine and dopamine metabolite levels, and protected against dopamine terminal loss and reactive astrogliosis as determined in the striatum, 7 days after MDMA treatment. In sharp contrast, inactivation of D4R did not prevent hyperthermia or the neurotoxic effects of MDMA. Altogether, these results indicate that D1R, but not D4R, plays a significant role in the dopaminergic striatal neurotoxicity observed after exposure to MDMA. PMID:24257898

Granado, N; Ares-Santos, S; Moratalla, R



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


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 CB1 receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-Ping; Liu, Qing-Song



Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output.  


In Parkinson's disease (PD), the dopamine (DA) neuron loss in the substantia nigra and the DA axon loss in the dorsal striatum are severe, but DA neurons in the ventral tegmental area and DA axons in middle and ventral striatal subregions are less affected. Severe DA loss leads to DA receptor supersensitivity, but it was not known whether the supersensitivity of the DA D1 receptors (D1Rs) on the striatonigral axon terminal is determined by the severe striatal or nigral DA loss. This question is important because these two possibilities affect the extent of the striatonigral terminals with supersensitive D1Rs and hence the strength of the direct pathway output. Here we have investigated this question in the transcription factor Pitx3 mutant mice that have a PD-like DA loss pattern. We found that the presynaptic D1R function was upregulated globally: the D1R-mediated facilitation was equally enhanced for the striatonigral GABA output originated in the dorsal striatum where the DA loss is severe and the somatic D1Rs are supersensitive, and for the striatonigral GABA output originated in the middle and ventral striatum where the DA loss is moderate and the somatic D1Rs are not supersensitive. These results suggest that severe nigral DA loss is sufficient to induce functional upregulation of the D1Rs on striatonigral axon terminals. Consequently, in PD, the globally enhanced D1Rs on striatonigral axon terminals originated in broad striatal subregions may strongly enhance the striatonigral GABA output upon D1R stimulation, potentially contributing to D1R agonism's profound motor-stimulating effects. PMID:25552639

Ding, Shengyuan; Li, Li; Zhou, Fu-Ming



Coarse-grained molecular dynamics simulations of depletion-induced interactions for soft matter systems  

NASA Astrophysics Data System (ADS)

Given the ubiquity of depletion effects in biological and other soft matter systems, it is desirable to have coarse-grained Molecular Dynamics (MD) simulation approaches appropriate for the study of complex systems. This paper examines the use of two common truncated Lennard-Jones (Weeks-Chandler-Andersen (WCA)) potentials to describe a pair of colloidal particles in a thermal bath of depletants. The shifted-WCA model is the steeper of the two repulsive potentials considered, while the combinatorial-WCA model is the softer. It is found that the depletion-induced well depth for the combinatorial-WCA model is significantly deeper than the shifted-WCA model because the resulting overlap of the colloids yields extra accessible volume for depletants. For both shifted- and combinatorial-WCA simulations, the second virial coefficients and pair potentials between colloids are demonstrated to be well approximated by the Morphometric Thermodynamics (MT) model. This agreement suggests that the presence of depletants can be accurately modelled in MD simulations by implicitly including them through simple, analytical MT forms for depletion-induced interactions. Although both WCA potentials are found to be effective generic coarse-grained simulation approaches for studying depletion effects in complicated soft matter systems, combinatorial-WCA is the more efficient approach as depletion effects are enhanced at lower depletant densities. The findings indicate that for soft matter systems that are better modelled by potentials with some compressibility, predictions from hard-sphere systems could greatly underestimate the magnitude of depletion effects at a given depletant density.

Shendruk, Tyler N.; Bertrand, Martin; Harden, James L.; Slater, Gary W.; de Haan, Hendrick W.



Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia  

PubMed Central

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans. PMID:20532043

Aguilar-Valles, Argel; Flores, Cecilia; Luheshi, Giamal N.



Shock induced multi-mode damage in depleted uranium  

SciTech Connect

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.

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



A search for relativistic electron induced stratospheric ozone depletion  

NASA Technical Reports Server (NTRS)

Possible ozone changes at 1 mb associated with the time variation and precipitation of relativistic electrons are investigated by examining the NIMBUS 7 SBUV ozone data set and corresponding temperatures derived from NMC data. No ozone depletion was observed in high-latitude summer when temperature fluctuations are small. In winter more variation in ozone occurs, but large temperature changes make it difficult to identify specific ozone decreases as being the result of relativistic electron precipitation.

Aikin, Arthur C.



Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.  


Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis. PMID:25554644

Chalmers, Samantha A; Chitu, Violeta; Herlitz, Leal C; Sahu, Ranjit; Stanley, E Richard; Putterman, Chaim



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


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

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



Demon voltammetry and analysis software: Analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures  

PubMed Central

The fast sampling rates of fast scan cyclic voltammetry make it a favorable method for measuring changes in brain monoamine release and uptake kinetics in slice, anesthetized, and freely moving preparations. The most common analysis technique for evaluating changes in dopamine signaling uses well-established Michaelis-Menten kinetic methods that can accurately model dopamine release and uptake parameters across multiple experimental conditions. Nevertheless, over the years, many researchers have turned to other measures to estimate changes in dopamine release and uptake, yet to our knowledge no systematic comparison amongst these measures has been conducted. To address this lack of uniformity in kinetic analyses, we have created the Demon Voltammetry and Analysis software suite, which is freely available to academic and non-profit institutions. Here we present an explanation of the Demon Acquisition and Analysis features, and demonstrate its utility for acquiring voltammetric data under in vitro, in vivo anesthetized, and freely moving conditions. Additionally, the software was used to compare the sensitivity of multiple kinetic measures of release and uptake to cocaine-induced changes in electrically evoked dopamine efflux in nucleus accumbens core slices. Specifically, we examined and compared tau, full width at half height, half-life, T20, T80, slope, peak height, calibrated peak dopamine concentration, and area under the curve to the well-characterized Michaelis-Menten parameters, dopamine per pulse, maximal uptake rate, and apparent affinity. Based on observed results we recommend tau for measuring dopamine uptake and calibrated peak dopamine concentration for measuring dopamine release. PMID:21392532

Yorgason, Jordan T.; España, Rodrigo A.; Jones, Sara R.



Involvement of the dorsal hippocampal dopamine D2 receptors in histamine-induced anxiogenic-like effects in mice.  


Anxiety-related behaviors increase histamine and dopamine release in the brain. On the other hand, central histamine counteracts reward and reinforcement processes mediated by the mesolimbic dopamine system. We investigated the effects of the histaminergic system and dopamine D2 receptors agents and their interactions on anxiety-related behaviors using the elevated plus-maze (EPM). The intra-hippocampal (Intra-CA1) microinjection of histamine (10 ?g/mouse) decreased the percentage of open arm time (%OAT) and open arm entries (%OAE) but not the locomotor activity, indicating an anxiogenic-like response. Quinpirole (0.5 and 2 ?g/mouse) or sulpiride (0.3 and 1 ?g/mouse) when injected into the dorsal hippocampus also induced anxiety-like behavior, however, the drugs reversed the anxiogenic response induced by the effective dose of histamine (10 ?g/mouse). Taken together and under the present experimental design, our results indicate that activation of the dorsal hippocampal histaminergic receptors causes anxiety-like behaviors altered by dopamine D2 receptor agonist and antagonist. Histamine can decrease dopaminergic tone in the dorsal hippocampus through decreasing the endogenous dopamine release, whereas quinpirole does the same via the postsynaptic DA receptors' activation. Sulpiride however renders the same effect through autoreceptors' blockade and potentiated dopamine transmission. Thus, quinpirole and sulpiride seem to compensate the effects of the intra-CA1 injection of exogenous histamine, and tend to exert anxiolytic effects in the presence of histamine. PMID:23872092

Piri, Morteza; Ayazi, Elham; Zarrindast, Mohammad Reza



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


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

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



Subchronic low dose ?-vinyl GABA (vigabatrin) inhibits cocaine-induced increases in nucleus accumbens dopamine  

Microsoft Academic Search

Rationale  ?-Vinyl GABA (GVG) irreversibly inhibits GABA-transaminase. This non-receptor mediated inhibition requires de novo synthesis\\u000a for restoration of functional GABA catabolism.\\u000a \\u000a \\u000a \\u000a Objectives  Given its preclinical success for treating substance abuse and the increased risk of visual field defects (VFD) associated\\u000a with cumulative lifetime exposure, we explored the effects of sub-chronic low dose GVG on cocaine-induced increases in nucleus\\u000a accumbens (NAcc) dopamine (DA).

Wynne K. Schiffer; Douglas Marsteller; Stephen L. Dewey



L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum  

PubMed Central

L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa. PMID:24429495

Porras, Gregory; De Deurwaerdere, Philippe; Li, Qin; Marti, Matteo; Morgenstern, Rudolf; Sohr, Reinhard; Bezard, Erwan; Morari, Michele; Meissner, Wassilios G.



Prevention of Calbindin Recruitment into Nigral Dopamine Neurons from MPTP-Induced Degeneration in Macaca fascicularis  

Microsoft Academic Search

\\u000a Dopaminergic neurons in the substantia nigra pars compacta that express the calcium-binding protein calbindin selectively\\u000a survive the cell death period in Parkinson’s disease. On the basis of this finding, we examined the preventive effect of calbindin\\u000a recruitment into nigral dopamine neurons on toxic insults induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).\\u000a A recombinant adenoviral vector encoding the calbindin gene was injected unilaterally into

Masahiko Takada; Ken-ichi Inoue; Shigehiro Miyachi; Haruo Okado; Atsushi Nambu


Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat.  


Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity. PMID:23932919

Hansen, Henrik H; Jensen, Majbrit M; Overgaard, Agnete; Weikop, Pia; Mikkelsen, Jens D



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

Microsoft Academic Search

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

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



Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia  

PubMed Central

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

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



Cholecystokinin facilitates methamphetamine-induced dopamine overflow in rat striatum and fetal ventral mesencephalic grafts.  


The purpose of this study was to investigate the interactions of sulfated (S) and unsulfated (US) cholecystokinin (CCK) and methamphetamine (MA)-induced dopamine (DA) overflow in rat striatum. High-speed chronoamperometric recording techniques, using Nafion-coated carbon fiber electrodes, were used to evaluate extracellular DA concentration. CCK-8S, CCK-8US, MA, and DA were locally applied directly to the striatum of urethane-anesthetized Sprague-Dawley rats. We found that CCK potentiated MA-induced DA release in the anterior striatum. This response is probably mediated through CCK-A receptors because CCK-8S, but not CCK-8US, enhanced MA-induced responses. Replacement of Ca2+ with Mg2+ in the drug barrel antagonized this reaction, suggesting that the modulation of MA-induced DA release by CCK is Ca2+ dependent. Both MA-induced DA release and CCK modulatory effects disappeared in the striatum after unilaterally lesioning the medial forebrain boundle with 6-hydroxydopamine (6-OHDA). We had previously found that the zone of normalized dopamine clearance in 6-OHDA-lesioned rats was considerably larger than that of normalized release in the anterior striatum after fetal ventral mesencephalic (VM) transplantation, which may be a result of partial reinnervation from the transplant. In the present study, we found that the modulation of DA release by CCK was restored only in the zone of normalized release after fetal nigral transplantation; CCK did not increase MA-induced DA release throughout the larger partially innervated area. In conclusion, these findings suggest that not only DA release processes but also CCK modulatory mechanisms are restored in the anterior striatum after fetal VM transplantation. PMID:7867757

Wang, Y; Perng, S L; Lin, J C; Tsao, W L



Increased L-DOPA-derived dopamine following selective MAO-A or-B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation  

PubMed Central

Background and Purpose Selective MAO type B (MAO-B) inhibitors are effective in potentiation of the clinical effect of L-DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO-A) in rat brain. We sought to clarify the roles of MAO-A and MAO-B in deamination of DA formed from exogenous L-DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter-3 (OCT-3) inhibition by decinium-22 on extracellular DA levels following L-DOPA. Experimental Approach Striatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6-hydroxydopamine or 5,7-dihydroxytryptamine respectively. Microdialysate DA levels after systemic L-DOPA were measured after inhibition of MAO-A or MAO-B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence. Key Results Rasagiline increased DA extracellular levels following L-DOPA to a greater extent in double-than in single-lesioned rats (2.8-and 1.8-fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10-fold. MAO-A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO-B was localized in glia and to a small extent in MSNs. Inhibition of OCT-3 increased DA levels in the double-more than the single-lesion animals. Conclusions and Implications In striatum devoid of dopaminergic and serotonergic inputs, most deamination of L-DOPA-derived DA is mediated by MAO-A in MSN and a smaller amount by MAO-B in both MSN and glia. OCT-3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT-3 are potential future targets for anti-Parkinsonian treatments. PMID:23992249

Sader-Mazbar, O; Loboda, Y; Rabey, M J; Finberg, J P M



Polychlorinated Biphenyl-Induced Reduction of Dopamine Transporter Expression as a Precursor to Parkinson's Disease-Associated Dopamine Toxicity  

Microsoft Academic Search

Epidemiological and laboratory studies have suggested that exposure to polychlorinated biphenyls (PCBs) may be a risk factor for Parkinson's disease. The purpose of this study was to examine the potential mechanisms by which PCBs may disrupt normal functioning of the nigrostriatal dopamine (DA) system. We utilized an environmentally relevant exposure of PCBs (7.5 or 15 mg\\/kg\\/day Aroclor 1254:1260 for 30

W. Michael Caudle; Jason R. Richardson; Kristin C. Delea; Thomas S. Guillot; Minzheng Wang; Kurt D. Pennell; Gary W. Miller



Prenatal l-DOPA exposure produces lasting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference  

Microsoft Academic Search

Dopamine, its receptors and transporter are present in the brain beginning from early in the embryonic period. Dopamine receptor activation can influence developmental events including neurogenesis, neuronal migration and differentiation raising the possibility that dopamine imbalance in the fetal brain can alter development of the brain and behavior. We examined whether elevated dopamine levels during gestation can produce persisting changes

Jia-Qian Ren; Yan Jiang; Zhihui Wang; Deirdre McCarthy; Anjali M. Rajadhyaksha; Thomas F. Tropea; Barry E. Kosofsky; Pradeep G. Bhide



Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice  

PubMed Central

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors. PMID:24155877

Hayashizaki, Seiji; Hirai, Shinobu; Ito, Yumi; Honda, Yoshiko; Arime, Yosefu; Sora, Ichiro; Okado, Haruo; Kodama, Tohru; Takada, Masahiko



Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors  

SciTech Connect

The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

Di Paolo, T.; Falardeau, P.



Effect of Temperature on Dopamine Transporter Function and Intracellular Accumulation of Methamphetamine: Implications for Methamphetamine-Induced Dopaminergic Neurotoxicity  

Microsoft Academic Search

Hyperthermia exacerbates and hypothermia attenuates metham- phetamine (METH)-induced dopamine (DA) neurotoxicity. The mechanisms underlying these temperature effects are unknown. Given the essential role of the DA transporter (DAT) in the ex- pression of METH-induced DA neurotoxicity, we hypothesized that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT. To

Tao Xie; Una D. McCann; Saejeong Kim; Jie Yuan; George A. Ricaurte



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

Microsoft Academic Search

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

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



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


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

Gao, Feng-Hou; Liu, Feng; Wei, Wei; Liu, Li-Bin; Xu, Mang-Hua; Guo, Zhu-Ying; Li, Wei; Jiang, Bin; Wu, Ying-Li



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

PubMed Central

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

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



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

NASA Astrophysics Data System (ADS)

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.

Babincová, Melánia; Babinec, Peter



Molecular and cellular bases for the protective effects of dopamine D1 receptor antagonist, SCH23390, against methamphetamine-induced  

E-print Network

i Molecular and cellular bases for the protective effects of dopamine D1 receptor antagonist, SCH23390, against methamphetamine-induced neurotoxicity in the rat brain Geneviève Beauvais Ecole doctorale Abbreviations VI List of Figures IX List of Tables X 1. General introduction 1 1.1 History of methamphetamine 1

Paris-Sud XI, Université de



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, ...


Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels  

ERIC Educational Resources Information Center

The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah



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


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

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



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


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

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



Alterations in membrane transport function and cell viability induced by ATP depletion in primary cultured rabbit renal proximal tubular cells.  


This study was undertaken to elucidate the underlying mechanisms of ATP depletion-induced membrane transport dysfunction and cell death in renal proximal tubular cells. ATP depletion was induced by incubating cells with 2.5 mM potassium cyanide (KCN)/0.1 mM iodoacetic acid (IAA), and membrane transport function and cell viability were evaluated by measuring Na(+)-dependent phosphate uptake and trypan blue exclusion, respectively. ATP depletion resulted in a decrease in Na(+)-dependent phosphate uptake and cell viability in a time-dependent manner. ATP depletion inhibited Na(+)-dependent phosphate uptake in cells, when treated with 2 mM ouabain, a Na(+) pump-specific inhibitor, suggesting that ATP depletion impairs membrane transport functional integrity. Alterations in Na(+)-dependent phosphate uptake and cell viability induced by ATP depletion were prevented by the hydrogen peroxide scavenger such as catalase and the hydroxyl radical scavengers (dimethylthiourea and thiourea), and amino acids (glycine and alanine). ATP depletion caused arachidonic acid release and increased mRNA levels of cytosolic phospholipase A(2) (cPLA(2)). The ATP depletion-dependent arachidonic acid release was inhibited by cPLA(2) specific inhibitor AACOCF(3). ATP depletion-induced alterations in Na(+)-dependent phosphate uptake and cell viability were prevented by AACOCF(3). Inhibition of Na(+)-dependent phosphate uptake by ATP depletion was prevented by antipain and leupetin, serine/cysteine protease inhibitors, whereas ATP depletion-induced cell death was not altered by these agents. These results indicate that ATP depletion-induced alterations in membrane transport function and cell viability are due to reactive oxygen species generation and cPLA(2) activation in renal proximal tubular cells. In addition, the present data suggest that serine/cysteine proteases play an important role in membrane transport dysfunction, but not cell death, induced by ATP depletion. PMID:19885021

Lee, Sung Ju; Kwon, Chae Hwa; Kim, Yong Keun




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...


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

E-print Network

Depletion-induced surface alignment of asymmetric diblock copolymer in selective solvents Rong Wang online 31 July 2008 Phase separation of asymmetric diblock copolymer near surfaces in selective solvents hard surfaces or the film thickness W and the block copolymer concentration fP. Morphologies


Chronic unpredictable stress augments +3,4-methylenedioxymethamphetamine-induced monoamine depletions: The role of corticosterone  

Microsoft Academic Search

Exposure to stress alters the behavioral and neurochemical effects of drugs of abuse. However, it is unknown if chronic stress can affect the serotonergic depletions induced by the psychostimulant drug 3,4-methylenedioxymethamphetamine (MDMA). Rats were exposed to 10 days of chronic unpredictable stress (CUS) which resulted in the predicted elevation of basal plasma corticosterone concentrations. On the 11th day, rats received

B. N. Johnson; B. K. Yamamoto



Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat  

PubMed Central

Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant ?-synuclein vectors did not induce rotational behavior, although ?-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau- rather than ?-synuclein-related damage in this model. Both tau and ?-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons. PMID:16137567

Klein, Ronald L.; Dayton, Robert D.; Lin, Wen-Lang; Dickson, Dennis W.



Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines.  


General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions. PMID:20580531

Kuepper, Rebecca; Morrison, Paul D; van Os, Jim; Murray, Robin M; Kenis, Gunter; Henquet, Cécile



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


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

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



Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243  

Microsoft Academic Search

Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0mg\\/kg). The non-selective dopamine agonist pergolide, a

John D. Salamone; Brian B. Carlson; Clifford Rios; Elizabeth Lentini; Merce Correa; Ania Wisniecki; Adrienne Betz



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


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 [(18)F]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 [(18)F]fallypride displacement and the spatial extent of stress-induced [(18)F]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 [(18)F]fallypride displacement nor the spatial extent of stress-induced [(18)F]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

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



Effect of a History of Major Depressive Disorder on Smoking-Induced Dopamine Release  

PubMed Central

Background Dopamine (DA) system dysfunction is implicated in the pathophysiology of Major Depressive Disorder (MDD). We sought to determine if cigarette smokers with a history of MDD and current mild depressive symptoms have abnormal smoking-induced DA release (measured indirectly as change in 11C-raclopride binding potential [BPND]). Methods Fifty-six cigarette smokers either with (n = 10) or without (n = 46) a history of MDD (MDD+ and MDD?, respectively) underwent bolus-plus-continuous-infusion 11C-raclopride positron emission tomography, during which they smoked a regular cigarette. Pre- to post- smoking changes in 11C-raclopride BPND were compared between groups. Also, correlations were determined between change in BPND and depression, anxiety, and withdrawal rating scale scores for the MDD+ group. Results The MDD+ group had a significantly greater reduction in 11C-raclopride BPND (?16.3%) than the MDD? group (?8.4%) (ANCOVA, p = 0.03). Significant negative correlations were found between depression/anxiety and change in 11C-raclopride BPND (r = ?0.77, p < 0.01 and r = ?0.74, p = 0.01, respectively). Conclusions MDD+ smokers have greater smoking-induced DA release than MDD? smokers, and higher depression/anxiety levels are associated with greater smoking-induced DA release. These findings support the theory that MDD+ smokers have DA system dysfunction including heightened smoking-induced DA release. PMID:19640507

Brody, Arthur L.; Olmstead, Richard E.; Abrams, Anna L.; Costello, Matthew R.; Khan, Aliyah; Kozman, Daniel; Saxena, Sanjaya; Farahi, Judah; London, Edythe D.; Mandelkern, Mark A.



Smoking-induced change in intrasynaptic dopamine concentration: Effect of treatment for Tobacco Dependence  

PubMed Central

The aim of this study was to determine whether standard treatments for Tobacco Dependence affect smoking-induced changes in intrasynaptic dopamine (DA) concentration. Forty-three otherwise healthy adult cigarette smokers (10 to 40 cigarettes per day) were treated with either practical group counseling (PGC) psychotherapy (n = 14), bupropion HCl (n = 14), or matching pill placebo (n = 15) (random assignment) for 8 weeks. Before and after treatment, each subject underwent a bolus-plus-continuous-infusion 11C-raclopride positron emission tomography (PET) scanning session, during which he or she smoked a regular cigarette. The PET scanning outcome measure of interest was percent change in smoking-induced 11C-raclopride binding potential (BPND) in the ventral caudate/nucleus accumbens (VCD/NAc), as an indirect measure of DA release. Although the entire study sample had a smaller mean smoking-induced reduction in VCD/NAc BPND after treatment (compared to before treatment), this change was highly correlated with smaller total cigarette puff volumes (and not other treatment variables). These data indicate that smoking-induced DA release is dose-dependent, and is not significantly affected by reductions in daily smoking levels or treatment type. PMID:20682457

Brody, Arthur L.; London, Edythe D.; Olmstead, Richard E.; Allen-Martinez, Zoe; Shulenberger, Stephanie; Costello, Matthew R.; Abrams, Anna L.; Scheibal, David; Farahi, Judah; Shoptaw, Steven; Mandelkern, Mark A.



Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells.  


High levels of plasma free fatty acid are thought to contribute to the loss of pancreatic beta-cells in type 2 diabetes. In particular, saturated fatty acid such as palmitate or stearate can induce apoptosis in cultured beta cells (lipotoxicity). Endoplasmic reticulum stress is a critical mediator of free fatty acid-induced lipotoxicity. Recently, disorders in mitochondrial respiratory metabolism have been linked to lipotoxicity. Since iron is a critical component of respiratory metabolism, this study is initiated to determine whether abnormal iron metabolism is involved in palmitate-induced beta cell death. Immunoblotting analysis showed that treatment of INS-1 beta cells with palmitate reduced the level of transferrin receptor 1 (TfR1), but increased the level of heavy chain ferritin (FTH). In addition, palmitate reduced intracellular labile iron pool. Whereas iron depletion through treatment with iron-chelators deferoxamine or deferasirox augmented palmitate-induced cell death, iron supplementation with ferric chloride, ferrous sulfate, or holo-transferrin significantly protected cells against palmitate-induced death. Furthermore, overexpression of TfR1 reduced palmitate-induced cell death, whereas knockdown of TfR1 augmented cell death. In particular, treatment with deferoxamine increased the level of endoplasmic reticulum (ER) stress markers phospho-PERK, phospho-eIF2?, CHOP and phospho-c-Jun N-terminal kinase. Treatment with chemical chaperone significantly protected cells against deferoxamine-induced apoptosis. Iron supplementation also protected cells against palmitate-induced primary islet death. These data suggest that iron depletion plays an important role in palmitate-induced beta cell death through inducing ER stress. Therefore, attempts to block iron depletion might be able to prevent beta cell loss in type 2 diabetes. PMID:25779532

Jung, Ik-Rak; Choi, Sung-E; Jung, Jong-Gab; Lee, Sang-A; Han, Seung Jin; Kim, Hae Jin; Kim, Dae Jung; Lee, Kwan-Woo; Kang, Yup



The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D[subscript 1]-Type, D[subscript 2]-Type, and Nonselective Dopamine Receptor Agonists  

ERIC Educational Resources Information Center

Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D[subscript 1]-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D[subscript…

Bratcher, Natalie A.; Farmer-Dougan, Valeri; Dougan, James D.; Heidenreich, Byron A.; Garris, Paul A.



Footshock facilitates methamphetamine-induced conditioned suppression through HPA axis, not dopamine.  


The present study examined whether footshock can enhance methamphetamine (MAMPH)-induced conditioned suppression and whether this effect involves the dopamine (DA) reward system or hypothalamic-pituitary-adrenal (HPA) axis. We also examined whether the footshock-induced enhancements of MAMPH-induced conditioned suppression are attributable to MAMPH's rewarding or aversive properties. During the footshock phase, all female rats received 0.1mg/kg haloperidol (HAL) and its vehicle (2% tartaric acid solution), or low and high doses of dexamethasone (DEX; 0.5 and 1.0mg/kg) and its vehicle before each footshock (1mA, 2s), or no footshock, in seven trials once per day. The control group did not receive any drugs or footshocks. All of the rats were then allowed 15min access to a 0.1% saccharin solution and then received 2mg/kg MAMPH in five trials once per day. Footshock exhibited an increase in MAMPH-induced taste suppression. The low- and high-dose DEX groups but not the HAL group exhibited a blocking effect of the footshock enhancements of MAMPH-induced taste suppression. The low- and high-dose DEX groups exhibited a significant decrease in corticosterone levels during the footshock treatment phase but not during the testing phase. Altogether, the HPA stress system and not the DA reward system, particularly D2 receptors, appear to mediate the footshock-induced enhancements of MAMPH-induced conditioned taste suppression, which may result from the aversive and not the rewarding properties of MAMPH. The present findings may provide some clinical implications for alternating aversively classical conditioning for psychiatric disorders. PMID:25592442

Huang, Andrew Chih Wei; Wang, Shiun; Wu, José Jiun-Shian; Wang, Cheng Chung



Depletion of the adaptor protein NCK increases UV-induced p53 phosphorylation and promotes apoptosis.  


The cellular response to DNA damage requires the coordination of many proteins involved in diverse molecular processes. Discrete molecular pathways are becoming increasingly well understood, but the interconnectivity and coordination of multiple pathways remains less clear. We now show that NCK, an adapter protein involved in cytoskeletal responses to tyrosine kinase receptor signaling, accumulates in the nucleus in response to DNA damage and this translocation can be blocked by specific inhibition of the ATR protein kinase. Strikingly, HeLa cells depleted of NCK undergo apoptosis shortly after UV irradiation, as monitored by caspase-3 cleavage and PARP cleavage. This rapid, hyperactive apoptosis in NCK depleted cells might be p53 dependent, because loss of NCK also increased UV-induced p53 phosphorylation. Importantly, depletion of SOCS7, which is necessary for NCK nuclear translocation, phenocopies NCK depletion, indicating the nuclear accumulation of NCK is responsible for these molecular events. There are two NCK isoforms that have mostly redundant functions, and although NCK2 appears to have a greater contribution, depletion of NCK1 or NCK2, led to increased p53 phosphorylation and early apoptosis after UV exposure. These data reveal a novel function for NCK in regulating p53 phosphorylation and apoptosis, and provide evidence for interconnectedness of growth factor signaling proteins and the DNA damage response. PMID:24086708

Errington, Timothy M; Macara, Ian G



Depletion of the Adaptor Protein NCK Increases UV-Induced p53 Phosphorylation and Promotes Apoptosis  

PubMed Central

The cellular response to DNA damage requires the coordination of many proteins involved in diverse molecular processes. Discrete molecular pathways are becoming increasingly well understood, but the interconnectivity and coordination of multiple pathways remains less clear. We now show that NCK, an adapter protein involved in cytoskeletal responses to tyrosine kinase receptor signaling, accumulates in the nucleus in response to DNA damage and this translocation can be blocked by specific inhibition of the ATR protein kinase. Strikingly, HeLa cells depleted of NCK undergo apoptosis shortly after UV irradiation, as monitored by caspase-3 cleavage and PARP cleavage. This rapid, hyperactive apoptosis in NCK depleted cells might be p53 dependent, because loss of NCK also increased UV-induced p53 phosphorylation. Importantly, depletion of SOCS7, which is necessary for NCK nuclear translocation, phenocopies NCK depletion, indicating the nuclear accumulation of NCK is responsible for these molecular events. There are two NCK isoforms that have mostly redundant functions, and although NCK2 appears to have a greater contribution, depletion of NCK1 or NCK2, led to increased p53 phosphorylation and early apoptosis after UV exposure. These data reveal a novel function for NCK in regulating p53 phosphorylation and apoptosis, and provide evidence for interconnectedness of growth factor signaling proteins and the DNA damage response. PMID:24086708

Errington, Timothy M.; Macara, Ian G.



Influence of dopamine synthesis on methamphetamine-induced changes in striatal and adrenal tyrosine hydroxylase activity  

Microsoft Academic Search

Methamphetamine in large doses decreases striatal tyrosine hydroxylase activity. This effect is prevented by neuroleptic agents such as chlorpromazine and haloperidol which would suggest that released dopamine may be involved in the response. To test this hypothesis, we have altered dopamine synthesis with a-methyl-p-tyrosine and l-Dopa and found that dopamine synthesis is necessary for the observed depression of striatal TH

J. W. Gibb; F. J. Kogan



Dorsal raphe nuclei integrate allostatic information evoked by depletion-induced sodium ingestion.  


Structures of the lamina terminalis (LT) sense and integrate information reflecting the state of body water and sodium content. Output from the LT projects into a neural network that regulates body fluid balance. Serotonin (5-HT) and the dorsal raphe nuclei (DRN) have been implicated in the inhibitory control of salt intake (i.e., sodium appetite). Signals arriving from the LT evoked by fluid depletion-induced sodium ingestion interact with this inhibitory serotonergic system. We investigated the role of neurons along the LT that directly project to the DRN. We analyzed the pattern of immunoreactivity (ir) of LT cells double-labeled for Fos (a marker of neural activity) and Fluorogold (FG; a retrograde tracer) following sodium depletion-induced sodium intake. Seven days after injection of FG into the DRN, sodium appetite was induced by furosemide injection and overnight access to only a low sodium diet (Furo-LSD) and distilled water. Twenty-four hours later, access to 0.3 M NaCl was given to depleted or sham-depleted rats and sodium intake was measured over the following 60 min. Ninety minutes after the termination of the intake test, the animals were perfused and their brains were processed for immunohistochemical detection of Fos and FG. Compared to sham-depleted animals there was a significantly greater number of Fos-/FG-ir double-labeled cells in the subfornical organ, the organum vasculosum of the lamina terminalis and the median preoptic nucleus in rats that ingested NaCl. Projections from the LT cells may contribute to inhibitory mechanisms involving 5-HT neurons in the DRN that limit the intake of sodium and prevent excess volume expansion. PMID:17544397

Badauê-Passos, Daniel; Godino, Andrea; Johnson, Alan Kim; Vivas, Laura; Antunes-Rodrigues, José



The protective effects of garlic extract against acetaminophen-induced oxidative stress and glutathione depletion.  


Acetaminophen, the most commonly sold over-the-counter antipyretic analgesic, is capable of causing severe and sometimes fatal hepatic damage in humans and experimental animals. The incidence of liver injury due to acetaminophen overdose, either with suicidal intent or by accident, is increasing. Garlic is among those medicinal plants famous for its different health protective effects. In this study, the protective effects of garlic extract on acute acetaminophen-induced liver injury were investigated using freshly isolated rat hepatocytes. The hepatocytes were isolated from Sprague-Dawley male rats by a two step collagenase model. Formation of Reactive Oxygen Species (ROS) and Glutathione (GSH) depletion were studied after addition of acetaminophen to cell suspensions. The effects of garlic extract on prevention of ROS formation as well as GSH depletion was investigated and compared with the effects of N-Acetyl Cysteine (NAC) as the standard treatment. Reactive oxygen species formation was assessed by a spectrofluorometry method and garlic extract was shown to be as effective as NAC in decreasing ROS formation induced by acetaminophen. Glutathione (GSH) levels of hepatocytes were determined using HPLC. Garlic extract was effective in preventing GSH depletion significantly (p < 0.05). It is concluded that garlic extract has an antioxidant effect and can protect hepatocytes from GSH depletion following NAPQI production. PMID:19806806

Anoush, M; Eghbal, M A; Fathiazad, F; Hamzeiy, H; Kouzehkonani, N S



The Rat With Oxygen-Induced Retinopathy Is Myopic With Low Retinal Dopamine  

PubMed Central

Purpose. Dopamine (DA) is a neurotransmitter implicated both in modulating neural retinal signals and in eye growth. Therefore, it may participate in the pathogenesis of the most common clinical sequelae of retinopathy of prematurity (ROP), visual dysfunction and myopia. Paradoxically, in ROP myopia the eye is usually small. The eye of the rat with oxygen-induced retinopathy (OIR) is characterized by retinal dysfunction and short axial length. There have been several investigations of the early maturation of DA in rat retina, but little at older ages, and not in the OIR rat. Therefore, DA, retinal function, and refractive state were investigated in the OIR rat. Methods. In one set of rats, the development of dopaminergic (DAergic) networks was evaluated in retinal cross-sections from rats aged 14 to 120 days using antibodies against tyrosine hydroxylase (TH, the rate-limiting enzyme in the biosynthesis of DA). In another set of rats, retinoscopy was used to evaluate spherical equivalent (SE), electoretinography (ERG) was used to evaluate retinal function, and high-pressure liquid chromatography (HPLC) was used to evaluate retinal contents of DA, its precursor levodopamine (DOPA), and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Results. The normally rapid postnatal ramification of DAergic neurons was disrupted in OIR rats. Retinoscopy revealed that OIR rats were relatively myopic. In the same eyes, ERG confirmed retinal dysfunction in OIR. HPLC of those eyes' retinae confirmed low DA. Regression analysis indicated that DA metabolism (evaluated by the ratio of DOPAC to DA) was an important additional predictor of myopia beyond OIR. Conclusions. The OIR rat is the first known animal model of myopia in which the eye is smaller than normal. Dopamine may modulate, or fail to modulate, neural activity in the OIR eye, and thus contribute to this peculiar myopia. PMID:24168993

Zhang, Nan; Favazza, Tara L.; Baglieri, Anna Maria; Benador, Ilan Y.; Noonan, Emily R.; Fulton, Anne B.; Hansen, Ronald M.; Iuvone, P. Michael; Akula, James D.



Polyamine-depletion induces p27 Kip1 and enhances dexamethasone-induced G 1 arrest and apoptosis in human T lymphoblastic leukemia cells  

Microsoft Academic Search

Glucocorticoid-induced apoptosis is preceded by G1 arrest and supposed to be up-regulated by polyamine-depletion, which also induces G1 arrest. In CEM leukemia cells, dexamethasone showed an antileukemic effect by inducing G1 arrest and apoptosis. DFMO, which depleted cellular polyamines by inhibiting ornithine decarboxylase, induced G1 arrest but without apoptosis, though it enhanced dexamethasone-induced G1 arrest and apoptosis. The G1 arrest

Sang-Hyun Choi; Seong-Woo Kim; Dong-Hee Choi; Bon-Hong Min; Boe-Gwun Chun



Dual task performance after diazepam intake: can resource depletion explain the benzodiazepine-induced amnesia?  

Microsoft Academic Search

It was tested whether a depletion in resources can account for the benzodiazepine-induced memory impairment. In two experiments,\\u000a it was examined whether dividing attention had a disproportionately detrimental effect on learning semantically related and\\u000a unrelated word pairs after diazepam intake. Word pairs had to be learned in both a single task condition and while performing\\u000a a visual discrimination task concurrently

M. E. E. Gorissen; Paul A. T. M. Eling



Individual differences in frontal cortical thickness correlate with the d-amphetamine-induced striatal dopamine response in humans.  


The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 ± 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is. PMID:24048857

Casey, Kevin F; Cherkasova, Mariya V; Larcher, Kevin; Evans, Alan C; Baker, Glen B; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco



GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine  

Microsoft Academic Search

Environments previously associated with drug use can become one of the most common factors triggering relapse to drug-seeking behavior. To better understand the neurochemical mechanisms potentially mediating these cues, we measured nucleus accumbens dopamine levels in animals exposed to environmental cues previously paired with cocaine administration. In animals exposed to a cocaine-paired environment nucleus accumbens dopamine increased by 25%. When

Madina R Gerasimov; Wynne K Schiffer; Eliot L Gardner; Douglas A Marsteller; Ian C Lennon; Stephen J. C Taylor; Jonathan D Brodie; Charles R Ashby; Stephen L Dewey



Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum  

PubMed Central

The neurological effects of organophosphate pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here we characterized the effects of the broadly-used insecticide chlorpyrifos on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. Chlorpyrifos potentiated PKA-dependent phosphorylation of the striatal protein DARPP-32 and the GluR1 subunit of AMPA receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide DEET. This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration. PMID:21848865

Torres-Altoro, Melissa I.; Mathur, Brian N.; Drerup, Justin M.; Thomas, Rachel; Lovinger, David; O’Callaghan, James P.; Bibb, James A.



Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats  

Microsoft Academic Search

The effects of blockade of opioid and dopamine receptors on relapse to heroin-seeking induced by footshock stress and re-exposure to heroin were examined in a reinstatement procedure. Male rats were trained to self-administer heroin (100 µg\\/kg per infusion, IV; four 3-h sessions\\/day for 8–11 consecutive days). Extinction sessions were given for 5–7 days during which saline was substituted for heroin.

Y. Shaham; J. Stewart



Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias  

Microsoft Academic Search

Summary Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with (11C)raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of

Raul de la Fuente-Fernandez; Vesna Sossi; Zhigao Huang; Sarah Furtado; Jian-Qiang Lu; Donald B. Calne; Thomas J. Ruth; A. Jon Stoessl



Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine-induced state-dependent learning in rats.  


In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 ?g/rat) dose-dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 ?g/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 ?g/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 ?g/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 ?g/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine-induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic receptors. PMID:23933216

Piri, M; Rostampour, M; Nasehi, M; Zarrindast, M R



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

Microsoft Academic Search

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

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



PX-12-induced HeLa cell death is associated with oxidative stress and GSH depletion  

PubMed Central

PX-12, as an inhibitor of thioredoxin (Trx), has antitumor activity. However, little is known about the toxicological effect of PX-12 on cervical cancer cells. In the present study, the growth inhibitory effects of PX-12 on HeLa cervical cancer cells in association with reactive oxygen species (ROS) and glutathione (GSH) levels were investigated. Based on MTT assays, PX-12 inhibited the growth of HeLa cells with an IC50 value of ~7 ?M at 72 h. DNA flow cytometry analysis indicated that 5 and 10 ?M PX-12 significantly induced a G2/M phase arrest of the cell cycle. PX-12 also increased the number of dead cells and annexin V-fluorescein isothiocyanate-positive cells, which was accompanied by the loss of mitochondrial membrane potential. All the investigated caspase inhibitors significantly rescued certain cells from PX-12-induced HeLa cell death. With respect to ROS and GSH levels, PX-12 increased ROS levels (including O2•?) in HeLa cells and induced GSH depletion. N-acetyl cysteine markedly reduced the levels of O2•? in PX-12-treated HeLa cells, and prevented apoptotic cell death and GSH depletion in these cells. By contrast, L-buthionine sulfoximine intensified cell death and GSH depletion in PX-12-treated HeLa cells. To conclude, this is the first study to demonstrate that PX-12 inhibits the growth of HeLa cells via G2/M phase arrest, as well as inhibiting apoptosis; the effect was associated with intracellular increases in ROS levels and GSH depletion. PMID:24260080




Macrophage depletion abates Porphyromonas gingivalis-induced alveolar bone resorption in mice.  


The role of the macrophage in the immunopathology of periodontitis has not been well defined. In this study, we show that intraoral inoculation of mice with Porphyromonas gingivalis resulted in infection, alveolar bone resorption, and a significant increase in F4/80(+) macrophages in gingival and submandibular lymph node tissues. Macrophage depletion using clodronate-liposomes resulted in a significant reduction in F4/80(+) macrophage infiltration of gingival and submandibular lymph node tissues and significantly (p < 0.01) less P. gingivalis-induced bone resorption compared with controls in BALB/c and C57BL/6 mice. In both mouse strains, the P. gingivalis-specific IgG Ab subclass and serum cytokine [IL-4, IL-10, IFN-?, and IL-12 (p70)] responses were significantly (p < 0.01) lower in the macrophage-depleted groups. Macrophage depletion resulted in a significant reduction in the level of P. gingivalis infection, and the level of P. gingivalis infection was significantly correlated with the level of alveolar bone resorption. M1 macrophages (CD86(+)), rather than M2 macrophages (CD206(+)), were the dominant macrophage phenotype of the gingival infiltrate in response to P. gingivalis infection. P. gingivalis induced a significant (p < 0.01) increase in NO production and a small increase in urea concentration, as well as a significant increase in the secretion of IL-1?, IL-6, IL-10, IL-12 (p70), eotaxin, G-CSF, GM-CSF, macrophage chemoattractant protein-1, macrophage inflammatory protein-? and -?, and TNF-? in isolated murine macrophages. In conclusion, P. gingivalis infection induced infiltration of functional/inflammatory M1 macrophages into gingival tissue and alveolar bone resorption. Macrophage depletion reduced P. gingivalis infection and alveolar bone resorption by modulating the host immune response. PMID:25070844

Lam, Roselind S; O'Brien-Simpson, Neil M; Lenzo, Jason C; Holden, James A; Brammar, Gail C; Walsh, Katrina A; McNaughtan, Judith E; Rowler, Dennis K; Van Rooijen, Nico; Reynolds, Eric C



Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.  


Arsenic trioxide (ATO; As2O3) induces apoptotic cell death in various cancer cells including lung cancer via the induction of reactive oxygen species (ROS). However, little is known about the toxicological effects of ATO on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ??m). ATO increased ROS levels including O2•- and GSH depleted cell numbers. NAC attenuated the growth inhibition, death and MMP (??m) loss in ATO-treated HPF cells and also decreased the ROS levels in these cells. However, vitamin C enhanced the growth inhibition, death, MMP (??m) loss and GSH depletion by ATO and even strongly increased mitochondrial O2•- levels in ATO-treated HPF cells. BSO showed a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth inhibition, cell death, MMP (??m) loss and GSH depletion. Moreover, superoxide dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO, which was not correlated with ROS and GSH level changes. In conclusion, ATO induced the growth inhibition and death of HPF cells, accompanied by increasing ROS levels and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and BSO enhanced the death. PMID:22684917

You, Bo Ra; Park, Woo Hyun



The effects of chemical sympathectomy on dopamine, noradrenaline and adrenaline content in some peripheral tissues.  

PubMed Central

Dopamine, noradrenaline (NA) and adrenaline (Ad) depletion by 6-hydroxydopamine (6-OHDA) and pargyline plus 6-OHDA was investigated in the cat left ventricle, mesenteric and renal arteries, renal cortex, renal medulla and adrenal medulla. Catecholamine concentrations in plasma were also analyzed in these two experimental conditions. 6-OHDA alone or in combination with pargyline induced parallel decreases of NA and dopamine contents in the left ventricle. In the main trunk and proximal branches of the mesenteric artery and renal artery 6-OHDA selectively reduced NA without a parallel decrease in dopamine content. Previous treatment with pargyline abolished this selectivity. In the kidney of control animals, dopamine content was greater than could be attributed to its presence only in noradrenergic neurones. In the renal cortex 6-OHDA reduced significantly dopamine and NA contents, and in the renal medulla only NA levels were decreased by this drug. Pargyline plus 6-OHDA did not deplete the NA content either in the renal cortex or in the renal medulla, and only reduced significantly the dopamine content in the renal cortex. NA concentrations in plasma were increased by pargyline plus 6-OHDA whilst Ad remained unaffected. In the adrenal medulla only NA content was reduced either by 6-OHDA or pargyline plus 6-OHDA. The present findings suggest a NA-independent dopamine pool in both segments of the mesenteric artery and renal artery but not in the left ventricle. PMID:3931730

Caramona, M. M.; Soares-da-Silva, P.



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


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

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



Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals  

PubMed Central

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

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



Lateral Parabrachial Nucleus Serotonergic Mechanisms and Salt Appetite Induced by Sodium Depletion  

NASA Technical Reports Server (NTRS)

This study investigated the effects of bilateral injections of a serotonin (5-HT) receptor agonist into the lateral parabrachial nucleus on the intake of NaCl and water induced by 24-h water deprivation or by sodium depletion followed by 24 h of sodium deprivation (injection of the diuretic furosemide plus 24 h of d sodium-deficient diet). Rats had stainless steel cannulas implanted bilaterally into the LPBN. Bilateral LPBN injections of the serotonergic 5-HT(1/2) receptor antagonist methysergide (4 micro-g/200 nl at each site) increased hypertonic NaCl intake when tested 24 h after sodium depletion and after 24 h of water deprivation. Water intake also increased after bilateral injections of methysergide into the LPBN. In contrast, the intake of a palatable solution (0.06 M sucrose) under body fluid-replete conditions was not changed after bilateral LPBN methysergide injections. The results show that serotonergic mechanisms in the LPBN modulate water and sodium intake induced by volume depletion and sodium loss. The finding that sucrose intake was not affected by LPBN serotonergic blockade suggests that the effects of the methysergide treatment on the intakes of water and NaCl are not due to a mechanism producing a nonspecific enhancement of all ingestive behaviors.

Menani, Jose Vanderlei; DeLuca, Laurival Antonio, Jr.; Johnson, Alan Kim



Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxy-methamphetamine, p-chloroamphetamine and (+)-fenfluramine  

PubMed Central

The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA?MDMA?(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). [3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ?-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70?nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. These results indicate that the release induced by these compounds is both ‘carrier-mediated' and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes. PMID:9283711

Crespi, Daniela; Mennini, Tiziana; Gobbi, Marco



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

NASA Astrophysics Data System (ADS)

Deformation accelerates the development of grain boundary chromium depletion (GBCD), or sensitization, in type 316 austenitic stainless steels (SS). Quantitative assessment of the degree of sensitization (DOS) using the electrochemical potentiokinetic reactivation (EPR) test indicates that the acceleration in GBCD is a function of the amount of strain in the material and temperature of isothermal sensitization treatment. A systematic increase in strain from 0 to 20 pct yields a continuous increase in EPRDOS values below 700°C, while at higher temperatures, a threshold strain of 6 to 10 pct is required to cause accelerated GBCD development. Straining SS above 20 pct also produces higher amounts of chromium depletion, though the (intergranular) sensitization susceptibility of the material could not be quantitatively evaluated due to the presence of grain matrix or transgranular corrosion. Classical C-curve precipitation-sensitization behavior was also noted for strained and unstrained materials, though strain moved the C-curves to the left. Microstructural evaluation of sensitization revealed a systematic increase in grain boundary and twin boundary corrosion on EPR attack surfaces with strain, which corroborated the deformation-induced acceleration of EPRDOS. A time-temperature-strain dependence of transgranular corrosion was also identified on EPR-etched samples strained above 20 pct. These were also reflected in transmission electron microscope (TEM) observations of higher grain boundary carbide precipitation on strained vs unstrained specimens and site-specific carbide precipitation on deformation sites in the material. Kinetic and thermodynamic modeling of deformation effects on carbide precipitation and depletion development in type 316 SS indicated that strain induces a reduction in the activation barrier to diffusion ( Q) a and thermodynamic barrier to nucleation (? G *) during the precipitation-depletion process. The lowering of Q a with strain caused chromium diffusivity and depletion development to be accelerated in strained vs unstrained materials and appears to be due to increased dislocation pipe diffusion with strain. Reduction of ? G * with strain was related to an increase in the free energy change of the grain boundary (? G) gb and accelerated carbide precipitate nucleation in deformed SS. The effect of strain on the kinetics and thermodynamics of the precipitation-depletion process decreases with increasing temperature.

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



Dopamine affects the change of pain-related electrical activity induced by morphine dependence.  


Morphine is among the most effective analgesics. However, many evidences suggest that, besides the well-know analgesic activity, repeated opioids treatment can induce some side effects such as dependence, hyperalgesia and tolerance. The mechanism of noxious information transmission in the central nervous system after dependence is not clear. An important neurotransmitter, dopamine (DA) participates not only in the process of opioid dependence but also in pain modulation in the central nervous system. In the present study we observed changes of electrical activities of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the caudate nucleus (Cd) following the development of morphine dependence. We also observed the role of DA on these changes. Our results revealed that both the latency of PEN discharges and the inhibitory duration of PIN discharges decreased, and the net increased values of PEN and PIN discharges increased in the Cd of morphine dependent rats. Those demonstrated that electrical activities of both PENs and PINs increased in morphine dependent rats. DA inhibited the electrical activities of PENs and enhanced those of PINs in morphine dependent rats. PMID:22240902

Zhang, Ying; Zhang, Fengmin; Yang, Chunxiao; Jin, Hongbo; Yang, Yongbin; Xu, Manying



Occupancy of Dopamine D2/3 Receptors in Rat Brain by Endogenous Dopamine  

E-print Network

dopamine depletion; reserpine; a-methyl-para-tyrosine; PET; D2/3 receptor; [11 C]MNPA ABSTRACT Estimates. Radioligand binding was compared at baseline and after treatment with reserpine plus a by administration of reserpine plus a-methyl-para-tyrosine. Hence, dopamine depletion did not increase the PET

Shen, Jun


Polymer-Induced Depletion Interaction and Its Effect on Colloidal Sedimentation in Colloid-Polymer Mixtures  

NASA Technical Reports Server (NTRS)

In this paper we focus on the polymer-induced depletion attraction and its effect on colloidal sedimentation in colloid-polymer mixtures. We first report a small angle neutron scattering (SANS) study of the depletion effect in a mixture of hard-sphere-like colloid and non-adsorbing polymer. Then we present results of our recent sedimentation measurements in the same colloid-polymer mixture. A key parameter in controlling the sedimentation of heavy colloidal particles is the interparticle potential U(tau), which is the work required to bring two colloidal particles from infinity to a distance tau under a give solvent condition. This potential is known to affect the average settling velocity of the particles and experimentally one needs to have a way to continuously vary U(tau) in order to test the theory. The interaction potential U(tau) can be altered by adding polymer molecules into the colloidal suspension. In a mixture of colloid and non-adsorbing polymer, the potential U(tau) can develop an attractive well because of the depletion effect, in that the polymer chains are expelled from the region between two colloidal particles when their surface separation becomes smaller than the size of the polymer chains. The exclusion of polymer molecules from the space between the colloidal particles leads to an unbalanced osmotic pressure difference pushing the colloidal particles together, which results in an effective attraction between the two colloidal particles. The polymer-induced depletion attraction controls the phase stability of many colloid-polymer mixtures, which are directly of interest to industry.

Tong, Penger



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


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

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



Mitotic catastrophe and cell death induced by depletion of centrosomal proteins  

PubMed Central

Mitotic catastrophe, which refers to cell death or its prologue triggered by aberrant mitosis, can be induced by a heterogeneous group of stimuli, including chromosome damage or perturbation of the mitotic apparatus. We investigated the mechanism of mitotic catastrophe and cell death induced by depletion of centrosomal proteins that perturbs microtubule organization. We transfected cells harboring wild-type or mutated p53 with siRNAs targeting Aurora A, ninein, TOG, TACC3, ?-tubulin, or pericentriolar material-1, and monitored the effects on cell death. Knockdown of Aurora A, ninein, TOG, and TACC3 led to cell death, regardless of p53 status. Knockdown of Aurora A, ninein, and TOG, led to aberrant spindle formation and subsequent cell death, which was accompanied by several features of apoptosis, including nuclear condensation and Annexin V binding in HeLa cells. During this process, cleavage of poly(ADP-ribose) polymerase-1, caspase-3, and caspase-9 was detected, but cleavage of caspase-8 was not. Cell death, monitored by time-lapse imaging, occurred during both interphase and M phase. In cells depleted of a centrosomal protein (Aurora A, ninein, or TOG), the rate of cell death was higher if the cells were cotransfected with siRNA against BubR1 or Mad2 than if they were transfected with siRNA against Bub1 or a control siRNA. These results suggest that metaphase arrest is necessary for the mitotic catastrophe and cell death caused by depletion of centrosomal proteins. Knockdown of centrosomal proteins led to increased phosphorylation of Chk2. Enhanced p-Chk2 localization was also observed at the centrosome in cells arrested in M phase, as well as in the nuclei of dying cells. Cotransfection of siRNAs against Chk2, in combination with depletion of a centrosomal protein, decreased the amount of cell death. Thus, Chk2 activity is indispensable for apoptosis after mitotic catastrophe induced by depletion of centrosomal proteins that perturbs microtubule organization. PMID:23598415

Kimura, M; Yoshioka, T; Saio, M; Banno, Y; Nagaoka, H; Okano, Y



Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats  

PubMed Central

AIM: To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine (DENA)-induced hepatic carcinogenesis. METHODS: A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) received a single intraperitoneal (i.p.) injection of normal saline. Animals in group 2 (carnitine-supplemented group) were given L-carnitine (200 mg/kg per day) in drinking water for 8 wk. Animals in group 3 (carnitine-depleted group) were given D-carnitine (200 mg/kg per day) and mildronate (200 mg/kg per day) in drinking water for 8 wk. Rats in group 4 (DENA group) were injected with a single dose of DENA (200 mg/kg, i.p.) and 2 wk later received a single dose of carbon tetrachloride (2 mL/kg) by gavage as 1:1 dilution in corn oil. Animals in group 5 (DENA-carnitine depleted group) received the same treatment as group 3 and group 4. Rats in group 6 (DENA-carnitine supplemented group) received the same treatment as group 2 and group 4. RESULTS: Administration of DENA resulted in a significant increase in alanine transaminase (ALT), gamma-glutamyl transferase (G-GT), alkaline phosphatase (ALP), total bilirubin, thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GSHPx), catalase (CAT) and total carnitine content in liver tissues. In the carnitine-depleted rat model, DENA induced a dramatic increase in serum ALT, G-GT, ALP and total bilirubin, as well as a progressive reduction in total carnitine content in liver tissues. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes, TBARS and NOx, and a decrease in total carnitine, GSH, GSHPx, and CAT induced by DENA, compared with the control values. Histopathological examination of liver tissues confirmed the biochemical data, where L-carnitine prevented DENA-induced hepatic carcinogenesis while D-carnitine-mildronate aggravated DENA-induced hepatic damage. CONCLUSION: Data from this study suggest for the first time that: (1) carnitine deficiency is a risk factor and should be viewed as a mechanism in DENA-induced hepatic carcinogenesis; (2) oxidative stress plays an important role but is not the only cause of DENA-induced hepatic carcinogenesis; and (3) long-term L-carnitine supplementation prevents the development of DENA-induced liver cancer. PMID:19294768

Al-Rejaie, Salim S; Aleisa, Abdulaziz M; Al-Yahya, Abdulaziz A; Bakheet, Saleh A; Alsheikh, Abdulmalik; Fatani, Amal G; Al-Shabanah, Othman A; Sayed-Ahmed, Mohamed M



Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine  

Microsoft Academic Search

Positron emission tomography (PET), in combination with 11C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments, 11C-raclopride

Wynne K Schiffer; Jean Logan; Stephen L Dewey



l-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells  

PubMed Central

l-dopa is a precursor for dopamine synthesis and a mainstay treatment for Parkinson's disease. However, l-dopa therapy is not without side effects that may be attributed to non-dopaminergic mechanisms. Synthesized dopamine can be neurotoxic through its enzymatic degradation by monoamine oxidase (MAO) to form the reactive byproduct, hydrogen peroxide and hydroxyl radicals or through auto-oxidation to form highly reactive quinones that can bind proteins and render them non-functional. Since l-dopa could be decarboxylated by aromatic amino acid decarboxylase (AADC) present within both dopamine and serotonin neurons, it was hypothesized that serotonin neurons convert l-dopa into dopamine to generate excessive reactive oxygen species and quinoproteins that ultimately lead to serotonin neuron death. To examine the effects of l-dopa on serotonin neurons, the RN46A-B14 cell line was used. These immortalized serotonergic cell cultures were terminally differentiated and then incubated with varying concentrations of l-dopa. Results show that RN46A-B14 cells contain AADC and can synthesize dopamine after incubation with l-dopa. Furthermore, l-dopa dose-dependently increased intracellular reactive oxygen species (ROS) and cell death. Dopamine, ROS production and cell death were attenuated by co-incubation with the AADC inhibitor, NSD-1015. The MAO inhibitor, pargyline, also attenuated cell death and ROS after l-dopa treatment. Lastly, quinoprotein formation was enhanced significantly by incubation with l-dopa. Taken together, these data illustrate that serotonergic cells can produce dopamine and that the accumulation of dopamine after l-dopa and its subsequent degradation can lead to ROS production and death of RN46A-B14 serotonergic cells. PMID:23196068

Stansley, Branden J.; Yamamoto, Bryan K.



Role of Dopamine Transporter in Methamphetamine-Induced Neurotoxicity: Evidence from Mice Lacking the Transporter  

Microsoft Academic Search

The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary acidic protein (GFAP) expression, and free radical formation were assessed as markers of METH neurotoxicity in the striatum and\\/or hippocampus of wild-type, heterozygote, and homozygote (DAT 2\\/2) mice. Four injections of

Fabio Fumagalli; Raul R. Gainetdinov; Kenneth J. Valenzano; Marc G. Caron



Ca 2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism  

Microsoft Academic Search

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg\\/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus

Lucyna Antkiewicz-Michaluk; Irena Roma?ska; Jerzy Vetulani



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

PubMed Central

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-naïve 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

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.



The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release.  


Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal. PMID:19486648

Bland, Sondra T; Hutchinson, Mark R; Maier, Steven F; Watkins, Linda R; Johnson, Kirk W



Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats  

PubMed Central

Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D4 receptor agonist that activates human dopamine D4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. PMID:15087502

Brioni, Jorge D.; Moreland, Robert B.; Cowart, Marlon; Hsieh, Gin C.; Stewart, Andrew O.; Hedlund, Petter; Donnelly-Roberts, Diana L.; Nakane, Masaki; Lynch, James J.; Kolasa, Teodozyi; Polakowski, James S.; Osinski, Mark A.; Marsh, Kennan; Andersson, Karl-Erik; Sullivan, James P.



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

NASA Astrophysics Data System (ADS)

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.

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



Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model.  


We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, L-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans. PMID:20871981

Shimizu, Shinji; Atsumi, Ryo; Nakazawa, Tsunenori; Izumi, Takashi; Sudo, Kenichi; Okazaki, Osamu; Saji, Hideo



Lipid peroxidation scavengers prevent the carbonylation of cytoskeletal brain proteins induced by glutathione depletion.  


In this study, we investigated the possible link between lipid peroxidation (LPO) and the formation of protein carbonyls (PCOs) during depletion of brain glutathione (GSH). To this end, rat brain slices were incubated with the GSH depletor diethyl maleate (DEM) in the absence or presence of classical LPO scavengers: trolox, caffeic acid phenethyl ester (CAPE), and butylated hydroxytoluene (BHT). All three scavengers reduced DEM-induced lipid oxidation and protein carbonylation, suggesting that intermediates/products of the LPO pathway such as lipid hydroperoxides, 4-hydroxynonenal and/or malondialdehyde are involved in the process. Additional in vitro experiments revealed that, among these products, lipid hydroperoxides are most likely responsible for protein oxidation. Interestingly, BHT prevented the carbonylation of cytoskeletal proteins but not that of soluble proteins, suggesting the existence of different mechanisms of PCO formation during GSH depletion. In pull-down experiments, beta-actin and alpha/beta-tubulin were identified as major carbonylation targets during GSH depletion, although other cytoskeletal proteins such as neurofilament proteins and glial fibrillary acidic protein were also carbonylated. These findings may be important in the context of neurological disorders that exhibit decreased GSH levels and increased protein carbonylation such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. PMID:17551832

Bizzozero, Oscar A; Reyes, Savanna; Ziegler, Jennifer; Smerjac, Suzanne



Oleic acid-induced lung injury in rabbits: effect of fibrinogen depletion with Arvin  

SciTech Connect

The role of fibrinogen in the evolution of the increased permeability after oleic acid-induced lung injury was studied in New Zealand White rabbits. Animals depleted of fibrinogen by treatment with Malayan pit viper venom were compared with untreated rabbits immediately and at 1 and 24 h after injury. The increased permeability to albumin and elevated extravascular lung water (EVLW) associated with lung injury returned to control values by 24 h in untreated animals. Fibrinogen-depleted animals had a higher mortality (10/25 vs. 2/17, P less than 0.02) and showed a greater immediate increase in permeability to albumin that returned to control values at 1 and 24 h after injury, as well as trends toward elevated blood-free dry lung weight and larger increases in EVLW that persisted for 24 h. These findings indicate that fibrinogen-related proteins play an important role in controlling the microvascular injury that is produced by oleic acid. However, when these proteins are depleted, other mechanisms partially control the leak at later stages of the repair process.

Allard, M.F.; Doerschuk, C.M.; Brumwell, M.L.; Belzberg, A.; Hogg, J.C.



Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study  

PubMed Central

Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry



Modification of Leech Behavior Patterns by Reserpine-Induced Amine Depletion  

Microsoft Academic Search

A single injection of 100 pg reserpine into the crop of the medicinal leech, Hirudo medicinalis, reduced CNS serotonin and dopamine levels to less than 1% of control values within 3 d. High-pressure liquid chromatography- (HPLC) deter- mined CNS serotonin and dopamine levels remained maxi- mally depressed for approximately 1 month following re- serpine injection. Subsequently, amine levels recovered slowly,

Bruce A. O'Gara; Heechin Chae; Lisa B. Latham; W. Otto



Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats  

PubMed Central

Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction. PMID:25076877

Palm, Sara; Momeni, Shima; Lundberg, Stina; Nylander, Ingrid; Roman, Erika



Inhibition of dopamine synthesis with alpha-methyl- p-tyrosine abolishes the enhancement of methamphetamine-induced extracellular dopamine levels in the amygdala of rats with excitotoxic lesions of the entorhinal cortex  

Microsoft Academic Search

This study was performed to investigate the mechanisms underlying the augmentation of methamphetamine (MAP)-induced dopamine (DA) release in the entorhinal cortex-lesioned rats. Quinolinic acid or phosphate buffered saline was infused into the left entorhinal cortex of adolescent rats (postnatal day 7 weeks). After 4 weeks of lesioning, acute MAP (2 mg\\/kg, i.p.)-induced DA release in the amygdala was significantly enhanced

Takashi Uehara; Tomiki Sumiyoshi; Hiroko Itoh; Masayoshi Kurachi



Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans.  


Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD. PMID:25029430

Lorthioir, Aurélien; Joannidès, Robinson; Rémy-Jouet, Isabelle; Fréguin-Bouilland, Caroline; Iacob, Michèle; Roche, Clothilde; Monteil, Christelle; Lucas, Danièle; Renet, Sylvanie; Audrézet, Marie-Pierre; Godin, Michel; Richard, Vincent; Thuillez, Christian; Guerrot, Dominique; Bellien, Jérémy



Administration of the D2 Dopamine Receptor Antagonist Sulpiride into the Shell, but not the Core, of the Nucleus Accumbens Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking  

Microsoft Academic Search

Enhanced dopamine transmission in the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug-seeking behavior. However, the contribution of each dopamine receptor subtype to this behavior remains unclear. The present experiments were designed to assess the role of D2-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Rats

Sharon M Anderson; Heath D Schmidt; R Christopher Pierce



Variants of the dopamine D2 receptor and risperidone-induced hyperprolactinemia in children and adolescents  

PubMed Central

Objective To investigate the association between hyperprolactinemia and variants of the dopamine D2 receptor (DRD2) gene in children and adolescents in long-term treatment with risperidone. Methods Medically healthy 7–17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were selected for a cross-sectional evaluation. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical record. The effect of the TaqIA variants of the DRD2 on the risk of risperidone-induced hyperprolactinemia was the primary outcome measure. Results Hyperprolactinemia was present in 50% of 107 patients (87% males) treated with risperidone for an average of 2.9 years. Age, stage of sexual development, and the dose of risperidone independently predicted a higher prolactin concentration, whereas the dose of psychostimulants was negatively correlated with it. However, these four predictors became nonsignificant when risperidone serum concentration was entered into the model. Adverse events potentially related to hyperprolactinemia were more common in participants with elevated prolactin concentration in girls (45%) compared with boys (10%). After controlling for risperidone concentration and the dose of psychostimulants, the TaqIA A1 and the A-241G alleles were associated with higher prolactin concentration, whereas the -141C Ins/Del AQ1and C957T variants had no significant effect. In addition, adverse events potentially related to hyperprolactinemia were four times more common in TaqIA A1 allele carriers. Conclusion Prolactin concentration is closely related to central DRD2 blockade, as reflected by risperidone serum concentration. Furthermore, the TaqIA and A-241G variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia and its potential adverse events. PMID:19339912

Calarge, Chadi A.; Ellingrod, Vicki L.; Acion, Laura; Miller, Del D.; Moline, Jessica; Tansey, Michael J.; Schlechte, Janet A.



Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis.  


Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK?BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension. PMID:24019399

Chen, Yue; Asico, Laureano D; Zheng, Shuo; Villar, Van Anthony M; He, Duofen; Zhou, Lin; Zeng, Chunyu; Jose, Pedro A




PubMed Central

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

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



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


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

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



Measuring Cigarette Smoking-Induced Cortical Dopamine Release: A [(11)C]FLB-457 PET Study.  


Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response. PMID:25502631

Wing, Victoria C; Payer, Doris E; Houle, Sylvain; George, Tony P; Boileau, Isabelle



Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons  

PubMed Central

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

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



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


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

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



Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential  

PubMed Central

Realizing the full therapeutic potential of mesenchymal stromal/stem cells (MSCs) awaits improved understanding of mechanisms controlling their fate. Using MSCs cultured as spheroids to recapitulate a three-dimensional cellular environment, we show that perturbing the mesenchymal regulators, platelet-derived growth factor (PDGF) receptors or fibronectin, reverts MSCs toward mesodermal progenitors with endothelial potential that can potently induce neovascularization in vivo. MSCs within untreated spheroids retain their mesenchymal spindle shape with abundant smooth muscle ?-actin filaments and fibronectin-rich matrix. Inhibiting PDGF receptors or depleting fibronectin induces rounding and depletes smooth muscle ?-actin expression; these cells have characteristics of mesenchymoangioblasts, with enhanced expression of mesendoderm and endoderm transcription factors, prominent upregulation of E-cadherin, and Janus kinase signaling-dependent expression of Oct4A and Nanog. PDGF receptor-inhibited spheroids also upregulate endothelial markers platelet endothelial cell adhesion molecule 1 and vascular endothelial-cadherin and secrete many angiogenic factors, and in vivo they potently stimulate neovascularization, and their MSCs integrate within functional blood vessels that are perfused by the circulation. Thus, MSC potency and vascular induction are regulated by perturbing mesenchymal fate. PMID:24022915

Ball, S G; Worthington, J J; Canfield, A E; Merry, C L R; Kielty, C M



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

PubMed Central

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

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



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

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

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



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.  


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 [(3)H]DA uptake without changes in the Km. Y88F and K92M enhanced IC50 values for DA inhibition of [(3)H]DA uptake and [(3)H]WIN35,428 binding but decreased IC50 for cocaine and GBR12909 inhibition of [(3)H]DA uptake, suggesting that these residues are critical for substrate and these inhibitors. Y470F, Y470A, Y88F and K92M attenuated zinc-induced increase of [(3)H]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

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



Role of the 5-HT1A autoreceptor in the enhancement of fluvoxamine-induced increases in prefrontal dopamine release by adrenalectomy/castration in mice.  


We have found that fluvoxamine-induced increases in prefrontal dopamine release are enhanced by adrenalectomy/castration and 5-HT1A receptors are involved in the enhancement. This study examined which 5-HT1A autoreceptors or postsynaptic receptor play a key role in the enhancement in mice. Adrenalectomy/castration-induced enhancement of fluvoxamine-induced increase in the dopamine release was not blocked by local perfusion with the 5-HT1A receptor antagonist WAY100635 (10 ?M), while it was blocked by systemic administration of WAY100635 at low dose (0.1 mg/kg) which blocked preferentially autoreceptor-mediated responses. These finding suggests that 5-HT1A autoreceptors play a key role in the enhancement of prefrontal dopamine release. PMID:25727963

Hasebe, Shigeru; Hiramatsu, Naoki; Ago, Yukio; Mori, Kazuya; Watabe, Yuji; Hashimoto, Hitoshi; Takuma, Kazuhiro; Matsuda, Toshio



Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia  

PubMed Central

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n?=?7), tris buffer (n?=?6) or a randomized DNA oligonucleotide (n?=?7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease. PMID:21779401

Holahan, Matthew R.; Madularu, Dan; McConnell, Erin M.; Walsh, Ryan; DeRosa, Maria C.



Involvement of oxidative stress in paraquat-induced metallothionein synthesis under glutathione depletion.  


The inhibition of glutathione (GSH) synthesis by L-buthionine-SR-sulfoximine (BSO) causes aggravation of hepatotoxicity of paraquat (PQ), an oxidative-stress inducing substance, in mice. On the other hand, synthesis of metallothionein (MT), a cysteine-rich protein having radical scavenging activity, is induced by PQ, and the induction by PQ is significantly enhanced by pretreatment of mice with BSO. The purpose of present study is to examine whether generation of reactive oxygens is involved in the induction of MT synthesis by PQ under inhibition of GSH synthesis. Administration of PQ to BSO-pretreated mice increased hepatic lipid peroxidation and frequency of DNA single strand breakage followed by manifestation of the liver injury and induction of MT synthesis. Both vitamin E and deferoxamine prevented MT induction as well as lipid peroxidation in the liver of mice caused by administration of BSO and PQ. In cultured colon 26 cells, both cytotoxicity and the increase in MT mRNA level caused by PQ were significantly enhanced by pretreatment with BSO. Facilitation of PQ-induced reactive oxygen generation was also observed by BSO treatment. These results suggest that reactive oxygens generated by PQ under inhibition of GSH synthesis may stimulate MT synthesis. GSH depletion markedly increased reactive oxygen generation induced by PQ, probably due to the reduced cellular capability to remove the radical species produced. PMID:9641256

Nakagawa, I; Suzuki, M; Imura, N; Naganuma, A



A small molecule that induces reactive oxygen species via cellular glutathione depletion.  


Induction of excessive levels of reactive oxygen species (ROS) by small-molecule compounds has been considered a potentially effective therapeutic strategy against cancer cells, which are often subjected to chronic oxidative stress. However, to elucidate the mechanisms of action of bioactive compounds is generally a time-consuming process. We have recently identified NPD926, a small molecule that induces rapid cell death in cancer cells. Using a combination of two comprehensive and complementary approaches, proteomic profiling and affinity purification, together with the subsequent biochemical assays, we have elucidated the mechanism of action underlying NPD926-induced cell death: conjugation with glutathione mediated by GST, depletion of cellular glutathione and subsequent ROS generation. NPD926 preferentially induced effects in KRAS-transformed fibroblast cells, compared with their untransformed counterparts. Furthermore, NPD926 sensitized cells to inhibitors of system x(c)?, a cystine-glutamate antiporter considered to be a potential therapeutic target in cancers including cancer stem cells. These data show the effectiveness of a newly identified ROS inducer, which targets glutathione metabolism, in cancer treatment. PMID:25011393

Kawamura, Tatsuro; Kondoh, Yasumitsu; Muroi, Makoto; Kawatani, Makoto; Osada, Hiroyuki



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


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

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



Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity  

Microsoft Academic Search

The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50?g tamoxifen 24h before

Mélanie Bourque; Bin Liu; Dean E. Dluzen; Thérèse Di Paolo



Dopamine, Working Memory, and Training Induced Plasticity: Implications for Developmental Research  

ERIC Educational Resources Information Center

Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also…

Soderqvist, Stina; Bergman Nutley, Sissela; Peyrard-Janvid, Myriam; Matsson, Hans; Humphreys, Keith; Kere, Juha; Klingberg, Torkel



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

PubMed Central

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

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



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

SciTech Connect

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

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



Depletion of Tumor-Associated Macrophages Slows the Growth of Chemically Induced Mouse Lung Adenocarcinomas  

PubMed Central

Chronic inflammation is a risk factor for lung cancer, and low-dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programing changes within 2?weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ?50% of control levels after 4–6?weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of insulin-like growth factor-I, CXCL1, IL-6, and CCL2 diminished with clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and clodronate liposome-treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression. PMID:25505466

Fritz, Jason M.; Tennis, Meredith A.; Orlicky, David J.; Yin, Hao; Ju, Cynthia; Redente, Elizabeth F.; Choo, Kevin S.; Staab, Taylor A.; Bouchard, Ronald J.; Merrick, Daniel T.; Malkinson, Alvin M.; Dwyer-Nield, Lori D.



Experimental system to search for induced depletion of 108mAg  

NASA Astrophysics Data System (ADS)

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).

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



Presynaptic dopamine in schizophrenia.  


Presynaptic dopamine (DA) transmission has been measured in schizophrenia using different paradigms aimed at providing estimates of the integrity or the activity of the presynaptic dopaminergic neuron. RESEARCHERS HAVE MEASURED: (1) DA synthesis capacity with [(18) F]DOPA, a measure of the activity of dopa decarboxylase, (2) DA release with studies measuring the impact of a DA releasing stimulant challenge on the binding of a D(2) receptor radiotracer, (3) D(2) baseline occupancy by DA, a measure of baseline intrasynaptic DA, assessed by the changes in binding of D(2) radiotracer induced by DA depletion, and (4) the DA and the vesicular monoamine transporters, to assess the integrity of presynaptic terminals. The relationship between DA release and D(2) receptor occupancy at baseline by DA has also been assessed in the same patients. Overall, these different imaging modalities have converged to show a dysregulation of presynaptic dopaminergic activity in schizophrenia, leading to excessive DA release in the striatum, particularly in the projection to the associative striatum, an area of integration between cognitive and limbic cortical inputs. Excessive striatal presynaptic DA is linked to the emergence of acute psychotic symptoms and to their response to treatment in schizophrenia. Understanding the etiology of this dysregulation and its consequences on the rest of the circuitry is important for future drug development. PMID:21199451

Miyake, Nobumi; Thompson, Judy; Skinbjerg, Mette; Abi-Dargham, Anissa



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

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.

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



Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion  

PubMed Central

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2?-desoxy-9-(S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC50 ?3.9 ?M) and comparable to the antibacterial macrolide azithromycin (IC50 ?2.4 ?M). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance. PMID:23542952

Sabater, Juan R.; Clarke, Tainya C.; Tan, Chong D.; Davies, Catrin M.; Liu, Jia; Yeung, Arthur; Garland, Alaina L.; Stutts, M. Jackson; Abraham, William M.; Phillips, Gary; Baker, William R.; Wright, Clifford D.; Wilbert, Sibylle



Relationship between dopamine transporter occupancy and methylphenidate induced high in humans  

SciTech Connect

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}.

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



Uranium bioaccumulation and biological disorders induced in zebrafish (Danio rerio) after a depleted uranium waterborne exposure.  


Because of its toxicity and its ubiquity within aquatic compartments, uranium (U) represents a significant hazard to aquatic species such as fish. In a previous study, we investigated some biological responses in zebrafish either exposed to depleted or to enriched U (i.e., to different radiological activities). However, results required further experiments to better understand biological responses. Moreover, we failed to clearly demonstrate a significant relationship between biological effects and U radiological activity. We therefore chose to herein examine U bioaccumulation and induced effects in zebrafish according to a chemical dose-response approach. Results showed that U is highly bioconcentrated in fish, according to a time- and concentration-dependent model. Additionally, hepatic antioxidant defenses, red blood cells DNA integrity and brain acetylcholinesterase activity were found to be significantly altered. Generally, the higher the U concentration, the sooner and/or the greater the effect, suggesting a close relationship between accumulation and effect. PMID:21093136

Barillet, Sabrina; Adam-Guillermin, Christelle; Palluel, Olivier; Porcher, Jean-Marc; Devaux, Alain



Dropped head sign induced by transdermal application of the dopamine agonist rotigotine in parkinsonian syndrome: a case report  

PubMed Central

Introduction ‘Dropped head sign’ relates to a severe disproportionate antecollis in parkinsonism. We present the first report of a rotigotine-induced dropped head sign in a patient with suspected idiopathic Parkinson’s disease, which was later defined as multiple system atrophy. The ‘dropped head sign’ is considered a rare symptom of unknown etiology in parkinsonian disorders, though a disproportionate antecollis is frequently observed in multiple system atrophy. It has also been described as a side effect of dopamine agonist medication with cabergoline and pramipexole. Rotigotine is a transdermally applied, non-ergot dopamine agonist, resulting in a continuous stimulation of dopamine receptors, which is widely used in the treatment of patients with Parkinson’s disease. Case presentation We report a case of a 64-year-old Caucasian woman with a rapidly progressive two-and-a-half-year history of a hypokinetic Parkinson’s syndrome with asymmetric development of symptoms and an initially good response to levodopa medication. Due to side effects of other dopamimetic medications the patient was switched to rotigotine medication five weeks before clinical admission. Progressive antecollis without muscle weakness and prominent paraspinal muscle contraction developed within two weeks of treatment and resolved within a week after discontinuation of rotigotine and initiation of levodopa/cabergoline medication. Conclusion While the pathophysiology still remains unresolved, this case supports the concept of a dopaminergic imbalance as a cause of certain axial dystonias like disproportionate antecollis including the ‘dropped head sign’. We believe this case is specifically useful for neurologists and general practitioners, as the easily recognizable symptom should prompt a thorough reevaluation of diagnosis and medication in patients with Parkinson’s disease. PMID:23829877



Depletion of Kupffer cells modulates ethanol-induced hepatocyte DNA synthesis in C57Bl/6 mice.  


Kupffer cells (KCs) are important in hepatic homeostasis and responses to xenobiotics. KCs are activated on interaction with endotoxin, releasing cytokines, and reactive oxygen species normally associated with increased gene expression, cellular growth, or hepatic injury. Ethanol-induced endotoxemia is one means of KC activation. We propose that KC depletion attenuates the effect of EtOH-induced endotoxemia to impact the hepatic growth response. Hepatic DNA synthesis was examined in KC competent (KC+) or KC-depleted (KC-) C57BL/6 mice fed EtOH-containing diet in the presence or absence of polyphenol-60 antioxidant. KC depletion was assessed by F4/80 antigen, and DNA synthesis was assessed by 5-bromo-2'-deoxyuridine incorporation. Tumor necrosis factor alpha (TNF-?) messenger RNA released was quantified by RT-PCR/electrophoresis. ERK1/2 phosphorylation was evaluated by Western blotting, and Nrf2 and CYP2E1protein were also assayed. Apoptosis and hepatic injury were examined by the Tunnel assay and hepatic transaminases in serum, respectively. Hepatic transaminases in serum (AST and ALT) were within normal range. Over 90% of KC was depleted by clodronate treatment. KC depletion decreased TNF-? mRNA release, ERK1/2 phosphorylation, and hepatocyte DNA synthesis. KC depletion is associated with increased numbers of apoptotic cells bodies in KC- mice. Antioxidant treatment decreased DNA synthesis, Nrf2, and CYP2E1 protein expression in EtOH-consuming mice. Our data indicate that upon ethanol exposure, KC participates in hepatic DNA synthesis and growth responses. Collectively, these observations suggest that KC depletion attenuates the downstream effect of ethanol-induced endotoxemia by reduced cytokine and reactive oxygen species production with its concomitant effect on MAPK-signaling pathway on hepatocyte DNA synthesis. PMID:22996800

Owumi, Solomon E; Corthals, Stacy M; Uwaifo, Anthony O; Kamendulis, Lisa M; Klaunig, James E



Amphetamine potency varies with dopamine uptake rate across striatal subregions.  


Amphetamine is a central nervous system psychostimulant with a high potential for abuse. Recent literature has shown that genetic and drug-induced elevations in dopamine transporter (DAT) expression augment the neurochemical and behavioral potency of psychostimulant releasers. However, it remains to be determined if the well-documented differences in DAT levels across striatal regions drive regionally distinct amphetamine effects within individuals. DAT levels and dopamine uptake rates have been shown to follow a gradient in the striatum, with the highest levels in the dorsal regions and lowest levels in the nucleus accumbens shell; thus, we hypothesized that amphetamine potency would follow this gradient. Using fast scan cyclic voltammetry in mouse brain slices, we examined DAT inhibition and changes in exocytotic dopamine release by amphetamine across four striatal regions (dorsal and ventral caudate-putamen, nucleus accumbens core and shell). Consistent with our hypothesis, amphetamine effects at the DAT and on release decreased across regions from dorsal to ventral, and both measures of potency were highly correlated with dopamine uptake rates. Separate striatal subregions are involved in different aspects of motivated behaviors, such as goal-directed and habitual behaviors, that become dysregulated by drug abuse, making it critically important to understand regional differences in drug potencies. Amphetamine is a central nervous system psychostimulant with a high potential for abuse, which may be augmented by increased dopamine transporter (DAT) expression. We here show that the ability of amphetamine to inhibit dopamine (DA) transport and deplete dopamine vesicles increases in a graded manner across striatal subregions from ventral to dorsal with the greatest effects on DA neurotransmission in the dorsal caudate-putamen. Additionally, DA uptake rate and amphetamine potency positively correlated, suggesting that differences across regions result from disparate DA transporter levels. PMID:24988947

Siciliano, Cody A; Calipari, Erin S; Jones, Sara R



Pharmacology of Signaling Induced by Dopamine D1-Like Receptor Activation  

PubMed Central

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

Undieh, Ashiwel S.



Methamphetamine-induced hyperthermia and lethal toxicity: Role of the dopamine and serotonin transporters  

Microsoft Academic Search

We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and\\/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg\\/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+\\/? SERT?\\/? mice). Mice with no DAT copies and a single SERT gene copy (DAT?\\/? SERT+\\/? mice) showed significant but

Yohtaro Numachi; Arihisa Ohara; Motoyasu Yamashita; Setsu Fukushima; Hideaki Kobayashi; Harumi Hata; Hidekazu Watanabe; F. Scott Hall; Klaus-Peter Lesch; Dennis L. Murphy; George R. Uhl; Ichiro Sora



Involvement of dopamine D 2 receptors in apomorphine-induced facilitation of forebrain serotonin output  

Microsoft Academic Search

The effect of systemic administration of the nonselective dopamine receptor agonist apomorphine on efflux of serotonin (5-hydroxytryptamine, 5-HT) in striatum and hippocampus of freely moving rats was examined using in vivo microdialysis. 5-HT efflux was increased by a moderate dose of apomorphine sufficient for a postsynaptic dopaminergic effect (0.5 mg\\/kg, s.c.), but not by a lower dose (0.1 mg\\/kg, s.c.),

Anna Mendlin; Francisco J Mart??n; Barry L Jacobs



Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats  

NASA Technical Reports Server (NTRS)

Anti-dopamine beta-hydroxylase immunotoxin (DHIT) is an antibody-targeted noradrenergic lesioning tool comprised of a monoclonal antibody against the noradrenergic enzyme, dopamine beta-hydroxylase, conjugated to saporin, a ribosome-inactivating protein. Noradrenergic-neuron specificity and completeness and functionality of sympathectomy were assessed. Adult, male Sprague-Dawley rats were given 28.5, 85.7, 142 or 285 micrograms/kg DHIT i.v. Three days after injection, a 6% to 73% decrease in the neurons was found in the superior cervical ganglia of the animals. No loss of sensory, nodose and dorsal root ganglia, neurons was observed at the highest dose of DHIT. In contrast, the immunotoxin, 192-saporin (142 micrograms/kg), lesioned all three ganglia. To assess the sympathectomy, 2 wk after treatment (285 micrograms/kg), rats were anesthetized with urethane (1 g/kg) and cannulated in the femoral artery and vein. DHIT-treated animals' basal systolic blood pressure and heart rate were significantly lower than controls. Basal plasma norepinephrine levels were 41% lower in DHIT-treated animals than controls. Tyramine-stimulated release of norepinephrine in DHIT-treated rats was 27% of controls. Plasma epinephrine levels of DHIT animals were not reduced. DHIT-treated animals exhibited a 2-fold hypersensitivity to the alpha-adrenergic agonist phenylephrine. We conclude that DHIT selectively delivered saporin to noradrenergic neurons resulting in destruction of these neurons. Anti-dopamine beta-hydroxylase immunotoxin administration produces a rapid, irreversible sympathectomy.

Picklo, M. J.; Wiley, R. G.; Lonce, S.; Lappi, D. A.; Robertson, D.



Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast-twitch skeletal muscles.  


The physiological role of epinephrine in the regulation of skeletal muscle protein metabolism under fasting is unknown. We examined the effects of plasma epinephrine depletion, induced by adrenodemedullation (ADMX), on muscle protein metabolism in fed and 2-day-fasted rats. In fed rats, ADMX for 10 days reduced muscle mass, the cross-sectional area of extensor digitorum longus (EDL) muscle fibers, and the phosphorylation levels of Akt. In addition, ADMX led to a compensatory increase in muscle sympathetic activity, as estimated by the rate of norepinephrine turnover; this increase was accompanied by high rates of muscle protein synthesis. In fasted rats, ADMX exacerbated fasting-induced proteolysis in EDL but did not affect the low rates of protein synthesis. Accordingly, ADMX activated lysosomal proteolysis and further increased the activity of the ubiquitin (Ub)-proteasome system (UPS). Moreover, expression of the atrophy-related Ub ligases atrogin-1 and MuRF1 and the autophagy-related genes LC3b and GABARAPl1 were upregulated in EDL muscles from ADMX-fasted rats compared with sham-fasted rats, and ADMX reduced cAMP levels and increased fasting-induced Akt dephosphorylation. Unlike that observed for EDL muscles, soleus muscle proteolysis and Akt phosphorylation levels were not affected by ADMX. In isolated EDL, epinephrine reduced the basal UPS activity and suppressed overall proteolysis and atrogin-1 and MuRF1 induction following fasting. These data suggest that epinephrine released from the adrenal medulla inhibits fasting-induced protein breakdown in fast-twitch skeletal muscles, and these antiproteolytic effects on the UPS and lysosomal system are apparently mediated through a cAMP-Akt-dependent pathway, which suppresses ubiquitination and autophagy. PMID:24169047

Graça, Flávia A; Gonçalves, Dawit A P; Silveira, Wilian A; Lira, Eduardo C; Chaves, Valéria Ernestânia; Zanon, Neusa M; Garófalo, Maria Antonieta R; Kettelhut, Isis C; Navegantes, Luiz C C



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


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

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



Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression  

PubMed Central

Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d–/– mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion–induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependence–mediated PCD during NB regression. PMID:23778138

Zhu, Yuyan; Li, Yuanyuan; Haraguchi, Seiki; Yu, Meng; Ohira, Miki; Ozaki, Toshinori; Nakagawa, Atsuko; Ushijima, Toshikazu; Isogai, Eriko; Koseki, Haruhiko; Nakamura, Yohko; Kong, Cuize; Mehlen, Patrick; Arakawa, Hirofumi; Nakagawara, Akira



Exercise-induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling.  


The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-?-cyclodextrin, a well-known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-?-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise. PMID:23733522

Ziolkowski, Wieslaw; Vadhana M S, Dhivya; Kaczor, Jan Jacek; Olek, Robert Antoni; Flis, Damian Jozef; Halon, Malgorzata; Wozniak, Michal; Fedeli, Donatella; Carloni, Manuel; Antosiewicz, Jedrzej; Gabbianelli, Rosita



Effects of Acute Dopamine Precusor Depletion on Immediate Reward Selection Bias and Working Memory Depend on Catechol-O-methyltransferase Genotype  

PubMed Central

Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O-methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18–21) as adults. Moreover, many studies have included female subjects without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that among healthy adult males (ages 22–40), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[?]), and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance, but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA’s role in immediate reward bias in humans. PMID:23937688

Kelm, Mary Katherine; Boettiger, Charlotte A.



Human neural stem cells survive long term in the midbrain of dopamine-depleted monkeys after GDNF overexpression and project neurites toward an appropriate target.  


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

Wakeman, Dustin R; Redmond, D Eugene; Dodiya, Hemraj B; Sladek, John R; Leranth, Csaba; Teng, Yang D; Samulski, R Jude; Snyder, Evan Y



Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine.  


Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins. PMID:20547199

Santiago, Ronise M; Barbieiro, Janaína; Lima, Marcelo M S; Dombrowski, Patrícia A; Andreatini, Roberto; Vital, Maria A B F



Vitamin D attenuates nucleoside reverse transcriptase inhibitor induced human skeletal muscle mitochondria DNA depletion  

PubMed Central

Objective To evaluate the impact of the active metabolite of vitamin D, 1?,25-dihydroxycholecalciferol (1,25D3), on nucleoside reverse transcriptase inhibitor (NRTI) induced mitochondrial DNA (mtDNA) depletion in human skeletal muscle myoblasts and myotubes. Design mtDNA was quantified in human skeletal muscle myoblasts and myotubes following 1,25D3 and NRTI treatment using real-time PCR. Methods Human skeletal muscle myoblasts and myotubes were treated with didanosine (ddI), stavudine (d4T), zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) alone or in combination either in the presence or absence of 1,25D3 for 5 days. Cells were harvested, DNA extracted and mtDNA quantified. Results ddI and ddI-d4T significantly decreased both myoblast and myotube mtDNA in the absence of 1,25D3 compared with untreated controls (P ? 0.029). In addition, the ZDV-3TC combination resulted in a 47% decrease in myotube mtDNA (P = 0.005). 1,25D3 increased myotube mtDNA levels in ddI, ZDV, 3TC, ABC, ddI-d4T, d4T-3TC, ZDV-3TC, ZDV-ABC and ZDV-3TC-ABC-containing regimens and myoblast mtDNA levels in ddI, d4T, ZDV, 3TC, ddI-d4T, ZDV-3TC and ZDV-ABC-containing regimens. Of note, 1,25D3 protected against myotube mtDNA depletion following ZDV-3TC treatment, rendering them similar to 1,25D3 untreated controls (P = 0.62), and increased both myotube and myoblast mtDNA two to three-fold in ddI-containing regimens (P < 0.05). Conclusion 1,25D3 confers a protective effect against NRTI-induced mitochondrial toxicity in skeletal muscle myoblasts and myotubes. These findings support a protective role for vitamin D in preventing mitochondrial toxicity and suggest that supplemental vitamin D may protect against NRTI-associated mitochondrial toxicity. PMID:23435299

Campbell, Grant R.; Pallack, Zachary T.; Spector, Stephen A.



Optogenetics reveals a role for accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization  

PubMed Central

Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse. PMID:25352792

Song, Shelly Sooyun; Kang, Byeong Jun; Wen, Lei; Lee, Hyo Jin; Sim, Hye-ri; Kim, Tae Hyong; Yoon, Sehyoun; Yoon, Bong-June; Augustine, George J.; Baik, Ja-Hyun



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

PubMed Central

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



Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens.  


Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response. PMID:24971603

Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles



/sup 3/H-imipramine uptake into rat striatal slices and imipramine-induced /sup 3/H-dopamine efflux  

SciTech Connect

The effect of imipramine on spontaneous efflux of radiolabelled dopamine (DA) from slices of rat striatum was examined by a superfusion method. Imipramine at concentrations of 10 - 100 microM enhanced the efflux of DA accumulated in a high-affinity uptake system in a concentration-dependent manner. This efflux of /sup 3/H-DA was not affected by conditions (Ca/sup 2 +/-free medium, 100 microM bretylium and 30 microM tetrodotoxin) which inhibited the release of /sup 3/H-DA by electrical stimulation. Furthermore, this imipramine-induced /sup 3/H-DA efflux was temperature-dependent. The uptake of /sup 3/H-imipramine into striatal slices was determined. This uptake was concentration- and temperature-dependent and increased linearly. These results are discussed in relation to the hypothesis that /sup 3/H-DA efflux by imipramine is connected with uptake of imipramine.

Saito, R.; Kawasaki, K.; Ono, N.; Kamiya, H.



Music and Methamphetamine: Conditioned Cue-induced Increases in Locomotor Activity and Dopamine Release in Rats  

PubMed Central

Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection (“Four” by Miles Davis) played repeatedly for ninety minutes. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drug while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation. PMID:21145911

Polston, J.E.; Rubbinaccio, H.Y.; Morra, J.T.; Sell, E.M.; Glick, S.D.



Protein kinase D1-dependent phosphorylation of dopamine D1 receptor regulates cocaine-induced behavioral responses.  


The dopamine (DA) D1 receptor (D1R) is critically involved in reward and drug addiction. Phosphorylation-mediated desensitization or internalization of D1R has been extensively investigated. However, the potential for upregulation of D1R function through phosphorylation remains to be determined. Here we report that acute cocaine exposure induces protein kinase D1 (PKD1) activation in the rat striatum, and knockdown of PKD1 in the rat dorsal striatum attenuates cocaine-induced locomotor hyperactivity. Moreover, PKD1-mediated phosphorylation of serine 421 (S421) of D1R promotes surface localization of D1R and enhances downstream extracellular signal-regulated kinase signaling in D1R-transfected HEK 293 cells. Importantly, injection of the peptide Tat-S421, an engineered Tat fusion-peptide targeting S421 (Tat-S421), into the rat dorsal striatum inhibits cocaine-induced locomotor hyperactivity and injection of Tat-S421 into the rat hippocampus or the shell of the nucleus accumbens (NAc) also inhibits cocaine-induced conditioned place preference (CPP). However, injection of Tat-S421 into the rat NAc shell does not establish CPP by itself and injection of Tat-S421 into the hippocampus does not influence spatial learning and memory. Thus, targeting S421 of D1R represents a promising strategy for the development of pharmacotherapeutic treatments for drug addiction and other disorders that result from DA imbalances. PMID:24362306

Wang, Ning; Su, Ping; Zhang, Ying; Lu, Jie; Xing, Baoming; Kang, Kai; Li, Wenqi; Wang, Yun



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


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

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



Methamphetamine and dopamine neurotoxicity: differential effects of agents interfering with glutamatergic transmission  

Microsoft Academic Search

The effects of riluzole and lamotrigine, two agents which interfere with the release of glutamate (GLU), and MK-801, a blocker of N-methyl-d-aspartate (NMDA) receptors, were compared in the model of methamphetamine-induced depletion of dopamine (DA) levels in mice. Repeated injections with methamphetamine (4 × 5 mg\\/kg i.p.) markedly decreased levels of DA, 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) levels.

Alain Boireau; Frangoise Bordier; Pierre Dubédat; Adam Doble



Dopamine-induced tyrosine phosphorylation of NR2B (Tyr1472) is essential for ERK1/2 activation and processing of novel taste information  

PubMed Central

Understanding the heterosynaptic interaction between glutamatergic and neuromodulatory synapses is highly important for revealing brain function in health and disease. For instance, the interaction between dopamine and glutamate neurotransmission is vital for memory and synaptic plasticity consolidation, and it is known to converge on extracellular signal-regulated kinase (ERK)-MAPK signaling in neurons. Previous studies suggest that dopamine induces N-methyl-D-aspartate (NMDA) receptor phosphorylation at the NR2B Y1472 subunit, influencing receptor internalization at the synaptic plasma membrane. However, it is unclear whether this phosphorylation is upstream to and/or necessary for ERK1/2 activation, which is known to be crucial for synaptic plasticity and memory consolidation. Here, we tested the hypothesis that tyrosine phosphorylation of NR2B at Y1472 is correlated with ERK1/2 activation by dopamine and necessary for it as well. We find that dopamine receptor D1, but not D2, activates ERK1/2 and leads to NR2BY1472 phosphorylation in the mature hippocampus and cortex. Moreover, our results indicate that NR2B Y1472 phosphorylation is necessary for ERK1/2 activation. Importantly, application of dopamine or the D1 receptor agonist SKF38393 to hippocampal slices from NR2B F1472 mutant mice did not result in ERK1/2 activation, suggesting this site is not only correlated with ERK1/2 activation by dopamine stimulation, but also necessary for it. In addition, NR2B F1472 mice show impairment in learning of attenuation of taste neophobia but not associative taste learning. Our study shows that the dopaminergic and glutamatergic transmission converge on the NMDA receptor itself, at the Y1472 site of the NR2B subunit, and that this convergence is essential for ERK1/2 activation in the mature brain and for processing new sensory information in the cortex. PMID:25100942

David, Orit; Barrera, Iliana; Chinnakkaruppan, Adaikkan; Kaphzan, Hanoch; Nakazawa, Takanobu; Yamamoto, Tadashi; Rosenblum, Kobi



Renal dysfunction induced by long-term exposure to depleted uranium in rats.  


Depleted uranium (DU) is a kind of radioactive heavy metal which can enter into the body via inhalation (aerosols), ingestion (drinking and eating) and wounds (embedded), and causes chemical and/or radiation-induced toxicities. In this study, male Sprague Dawley rats were surgically implanted in gastrocnemius muscle with DU fragments at three dose levels (low-dose, medium-dose and high-dose), with biologically inert tantalum (Ta) fragments served as controls. At 1 day, 7 days, and 3, 6, and 12 months after implantation, the rats were euthanized and tissue samples were collected, and uranium levels were measured in a variety of tissues by inductively coupled plasma-mass spectrometry (ICP-MS) to analyze the dynamic changes and distribution of uranium in rats. Thereafter, at 3, 6 and 12 months after implantation, the rats were euthanized after the collection of 24 h urine, blood and kidney samples were collected for analysis of DU-induced renal histopathologic changes and renal dysfunction. It was observed that DU concentrations in all the DU implanted groups were higher than that in Ta control group, and DU concentrations in the kidney increased with the implanted times, peaked at the 90 days after implantation, with a high correlation to the implanted DU doses, and then began to decrease gradually and slowly, and the DU concentrations in kidney still maintained at a relatively high level even at the 360 days after implantation. Otherwise, chronic DU contamination could induce the pathological changes of renal glomeruli, tubules and mesenchyme, such as interstitial fibrosis, enlarged interstice of renal tubular epithelial cells, tumefactions and necrosis of epithelial cells, shrinkage and disappearance of cavity of Bowman's capsule. By TEM, it was shown that the basement membrane of glomerulus was incrassated, mitochondrial of kidney proximal tubule had visible tumefaction and became bigger, and the mitochondrial cristae became shorter and disorderly in alignment. Compared to the control group, it was found that there was significant increase in the DU implantation group in terms of their blood urea nitrogen (BUN) and serum creatinine, urinary beta2-microglobulin (beta2-MG) and albumin, with a high correlation to the implanted DU dosage and periods. It was concluded that DU could accumulate in kidneys for a long period, and causes kidney injury by the toxic chemical/radioactive action such as renal dysfunction and structural damage. PMID:18594794

Zhu, Guoying; Xiang, Xiqiao; Chen, Xiao; Wang, Lihua; Hu, Heping; Weng, Shifang



Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders.  


Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease. PMID:15130772

Ben-Shachar, D; Zuk, R; Gazawi, H; Ljubuncic, P



Dopaminergic drug-induced modulation of the expression of the dopamine transporter in peripheral blood lymphocytes in Parkinson's disease.  


The modulation of expression of the dopamine transporter by dopaminergic drugs was investigated by flow cytometry in peripheral blood lymphocytes from patients suffering Parkinson's disease. An 8-week in vivo exposure to pramipexole (0.7 mg free base, 3 times a day) or ropinirole (12 mg, once daily), but not levodopa/carbidopa (100/25 mg, 3 times a day), significantly reduced the mean fluorescence intensity of the dopamine transporter in peripheral blood lymphocytes. These results demonstrate that levodopa differs from dopamine agonists in its regulation of dopamine transporter expression in peripheral blood lymphocytes. PMID:22001994

Fanciulli, Alessandra; Misasi, Roberta; Campanelli, Dario; Buttarelli, Francesca R; Pontieri, Francesco R



Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion.  


Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin. PMID:19376154

Jones, Jermaine D; Hall, F Scott; Uhl, George R; Rice, Kenner; Riley, Anthony L



Amphetamine induced dopamine release increases anxiety in individuals recovered from anorexia nervosa  

PubMed Central

Objective Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. Method We used an amphetamine challenge and positron emission tomography [11C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared to 9 control women (CW). Results REC AN and CW were similar for baseline, post-amphetamine [11C]raclopride binding potential (BPND) and change (?) in BPND for all regions. In CW, ventral striatum ? BPND was associated with euphoria (r = ? .76; p = .03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and ? BPND in the pre-commissural dorsal caudate (r = ?.62, p = .05). Discussion REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants. PMID:21541980

Bailer, Ursula F.; Narendran, Rajesh; Frankle, W. Gordon; Himes, Michael L; Duvvuri, Vikas; Mathis, Chester A; Kaye, W.H.



ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene.  


The human D(1A) dopamine receptor is transcribed from a tissue-specific regulated gene under the control of two promoters. An activator region (AR1) located between nucleotides -1154 and -1136 (relative to the first ATG) enhances transcription from the upstream promoter that is active in the brain. In this investigation, we sought to identify the nuclear factors that regulate the D(1A) gene through their binding to AR1 using yeast one-hybrid screening. Sp3 and Zic2 were among the positive clones isolated. Although Sp1 was not isolated from this screening and purified Sp1 alone does not bind to AR1 in gel shift experiments, this general transcription factor binds to AR1 in the presence of D(1A) expressing NS20Y nuclear extract and activates the D(1A) promoter. Thus, Sp1 appears to require an unknown factor(s) or post-translational modification to interact with AR1. On the other hand, Zic2 and Sp3 inhibit Sp1-induced activation of the D(1A) gene in an AR1-dependent manner. Zic2 and D(1A) genes have reciprocal brain regional distributions; Zic2 is expressed primarily in the cerebellum, and D(1A) is highly expressed in corpus striatum. These observations collectively suggest that one of the physiologic functions of Zic2 is repression of D(1A) gene transcription and that the intracellular balance among Sp1, Sp3 and Zic2 is important for regulating the tissue-specific expression of this dopamine receptor. PMID:10984499

Yang, Y; Hwang, C K; Junn, E; Lee, G; Mouradian, M M



Reversal effect of DM9384 on scopolamine-induced acetylcholine depletion in certain regions of the mouse brain  

Microsoft Academic Search

The effect of a new cognition enhancer, DM-9384, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, on regional acetylcholine (ACh) levels and against scopolamine-induced ACh depletion was examined in mouse brain. In addition, the effects of DM-9384 were compared with those of oxiracetam, physostigmine and tacrine. Independent administration of DM-9384 (1, 3, 10 or 30 mg\\/kg, PO) or oxiracetam (10 or 50 mg\\/kg, PO) to mice

Eiichi Abe



Propionyl l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model  

Microsoft Academic Search

This study has been initiated to investigate whether endogenous carnitine depletion and\\/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-l-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six

Abdulhakeem A. Al-Majed; Mohamed M. Sayed-Ahmed; Abdulaziz A. Al-Yahya; Abdulaziz M. Aleisa; Salim S. Al-Rejaie; Othman A. Al-Shabanah



Serotonin reuptake inhibitors do not prevent 5,7-dihydroxytryptamine-induced depletion of serotonin in rat brain.  


Although the selective toxicity of 5,7-dihydroxytryptamine (5,7-DHT) is thought to depend on the drug's transport into serotonin (5HT) neurons via the 5HT transporter, few studies have critically examined this postulation. We therefore evaluated if 5,7-DHT-induced reductions in 5HT concentrations and synthesis rate in rat brain are blocked by pretreatment with 5HT-selective reuptake inhibitors. Rats pretreated with desipramine (DMI) (to prevent norepinephrine depletion) received intracerebroventricular injections of 5,7-DHT (5, 50, 100, 200 microg/rat) 30 min after fluoxetine (20 mg/kg ip). Forty-eight hours later, they received m-hydroxybenzylhydrazine 30 min before sacrifice. The concentrations of 5HT and 5-hydroxytryptophan (5HTP, an index of 5HT synthesis) were measured in hypothalamus, cortex and brainstem. Each 5,7-DHT dose produced significant reductions in 5HT and 5HTP concentrations in all regions examined (5 microg reduced 5HT but not 5HTP), effects that were not blocked by fluoxetine. Two other 5HT reuptake blockers (chlorimipramine, alaproclate) also failed to block the 5HT and 5HTP depleting actions of 5,7-DHT. Desipramine blocked 5,7-DHT-induced norepinephrine (NE) depletion. Pretreatment with the 5HT receptor antagonist metergoline, or the 5HT(1A) agonist 8-hydroxy-(di-n-propylamino)tetralin (to slow 5HT neuronal firing rate) also failed to antagonize the 5HT depleting action of 5,7-DHT. Together, the data strongly suggest that the mechanism by which 5,7-DHT depletes the brain of serotonin does not involve 5HT-transporter-mediated concentration of neurotoxin in 5HT neurons, may not involve 5HT receptor interaction, and does not depend on the firing rate of the 5HT neuron. PMID:15064132

Choi, SuJean; Jonak, Elizabeth; Fernstrom, John D



Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.  


We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity. PMID:25698528

Rangel-Barajas, Claudia; Malik, Maninder; Mach, Robert H; Luedtke, Robert R



Neuroprotective Effects of Jitai Tablet, a Traditional Chinese Medicine, on the MPTP-Induced Acute Model of Parkinson's Disease: Involvement of the Dopamine System  

PubMed Central

Jitai tablet (JTT) is a traditional Chinese medicine used to treat neuropsychiatric disorders. We previously demonstrated that JTT treatment led to increased level of dopamine transporter (DAT) in the striatum, thus indicating that JTT might have therapeutic potential for Parkinson's disease (PD), which is characterized by dysregulated dopamine (DA) transmission and decreased striatal DAT expression. The aim of this study was to investigate the neuroprotective effect of JTT on MPTP-induced PD mice. Using locomotor activity test and rotarod test, we evaluated the effects of JTT (0.50, 0.15, or 0.05?g/kg) on MPTP-induced behavioral impairments. Tyrosine hydroxylase TH-positive neurons in the substantia nigra and DAT and dopamine D2 receptor (D2R) levels in the striatum were detected by immunohistochemical staining and/or autoradiography. Levels of DA and its metabolites were determined by HPLC. In MPTP-treated mice, behavioral impairments were alleviated by JTT treatment. Moreover, JTT protected against impairment of TH-positive neurons and attenuated the MPTP-induced decreases in DAT and D2R. Finally, high dose of JTT (0.50?g/kg) inhibited the MPTP-induced increase in DA metabolism rate. Taken together, results from our present study provide evidence that JTT offers neuroprotective effects against the neurotoxicity of MPTP and thus might be a potential treatment for PD. PMID:24799940

Liu, Jia; Gao, Jinlong; Xu, Shasha; Liu, Ying; Shang, Weihu; Gu, Chenxin; Huang, Yiyun; Han, Mei



Octopamine and Dopamine differentially modulate the nicotine-induced calcium response in Drosophila Mushroom Body Kenyon Cells.  


In Drosophila associative olfactory learning, an odor, the conditioned stimulus (CS), is paired to an unconditioned stimulus (US). The CS and US information arrive at the Mushroom Bodies (MB), a Drosophila brain region that processes the information to generate new memories. It has been shown that olfactory information is conveyed through cholinergic inputs that activate nicotinic acetylcholine receptors (nAChRs) in the MB, while the US is coded by biogenic amine (BA) systems that innervate the MB. In this regard, the MB acts as a coincidence detector. A better understanding of the properties of the responses gated by nicotinic and BA receptors is required to get insights on the cellular and molecular mechanisms responsible for memory formation. In recent years, information has become available on the properties of the responses induced by nAChR activation in Kenyon Cells (KCs), the main neuronal MB population. However, very little information exists on the responses induced by aminergic systems in fly MB. Here we have evaluated some of the properties of the calcium responses gated by Dopamine (DA) and Octopamine (Oct) in identified KCs in culture. We report that exposure to BAs induces a fast but rather modest increase in intracellular calcium levels in cultured KCs. The responses to Oct and DA are fully blocked by a VGCC blocker, while they are differentially modulated by cAMP. Moreover, co-application of BAs and nicotine has different effects on intracellular calcium levels: while DA and nicotine effects are additive, Oct and nicotine induce a synergistic increase in calcium levels. These results suggest that a differential modulation of nicotine-induced calcium increase by DA and Oct could contribute to the events leading to learning and memory in flies. PMID:24334164

Leyton, V; Goles, N I; Fuenzalida-Uribe, N; Campusano, J M



Dopamine D3 receptors in the basolateral amygdala and the lateral habenula modulate cue-induced reinstatement of nicotine seeking.  


Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 ?g/0.5 ?l/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 ?g/0.5 ?l/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [(125)I]7-OH-PIPAT to D3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D2 and D3 receptors in modulating this behavior. The current study supports an important role for D3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement. PMID:24998621

Khaled, Maram A T M; Pushparaj, Abhiram; Di Ciano, Patricia; Diaz, Jorge; Le Foll, Bernard



Salsolinol modulation of dopamine neurons  

PubMed Central

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

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



Prefrontal and striatal dopamine metabolism during enhanced rebound hyperphagia induced by space restriction—a rat model of binge eating  

Microsoft Academic Search

Background: Several lines of evidence indicate that abnormalities in brain dopamine and serotonin metabolism may play an important role in bulimia nervosa. However, the regional neurochemical mechanism of the binge eating is poorly understood. Our purpose was to elucidate brain neurochemical mechanisms of binge eating using a rat model.Methods: The dopamine release and metabolism in the prefrontal cortex (PFC) and

Koki Inoue; Nobuo Kiriike; Masakage Okuno; Yasutoshi Fujisaki; Masanori Kurioka; Shinichi Iwasaki; Sakae Yamagami



Mechanisms of protection induced by attenuated simian immunodeficiency virus. II. Lymphocyte depletion does not abrogate protection.  


To determine the role that cellular immune responses play in the protection conferred by vaccination with attenuated SIVmac32H (pC8), we have attempted to deplete macaques of their CD8+ cells prior to challenge with wild-type SIVmac32H (pJ5). In two of four pC8-infected macaques, N109 and N112, a transient partial depletion of CD8+ cells by antibody treatment was achieved. On the day of challenge peripheral CD2+CD4-CD8+ cell counts were reduced by 92 and 95%, respectively, in animals N109 and N112 and their lymph nodes revealed a 46 and 58% reduction, respectively, in CD2+CD4-CD8+ cells. Two other pC8-immunized macaques, N110 and N111, treated in the same way, did not show significant depletion of CD8+ cells. None of these four pC8-immunized animals became infected when challenged with 50 MID50 of pJ5. Treatment of a further four pC8-infected and protected macaques and two naive control animals with Campath-1H antibody successfully depleted peripheral CD3+ cell counts by >99% in all treated animals. Campath-1H depletion resulted in enhanced, longer lasting lymphoid depletion. Yet subsequent challenge with 20 MID50 of pJ5 still failed to infect the pC8-immunized animals. All eight of the naive controls, including two Campath-1H-treated animals, became infected following challenge. In summary, partial depletion of circulating CD8+ cells or total lymphocytes prior to challenge failed to abrogate the protection conferred by vaccination with pC8. PMID:9737590

Stebbings, R; Stott, J; Almond, N; Hull, R; Lines, J; Silvera, P; Sangster, R; Corcoran, T; Rose, J; Cobbold, S; Gotch, F; McMichael, A; Walker, B



Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice.  


l-3,4-Dihydroxyphenylalanine (l-Dopa)-induced dyskinesia (LID) in Parkinson's disease (PD) is a major clinical problem. The prevailing view is that in PD patients and animal PD models dyskinesia develops after repeated l-dopa use or priming, independent of l-dopa's anti-PD therapeutic effect that occurs immediately. Here we show that in mice with severe and consistent dopamine (DA) loss in the dorsal striatum, rendered by transcription factor Pitx3 null mutation, the very first injection of l-dopa or D1-like agonist SKF81297 induced both normal ambulatory and dyskinetic movements. Furthermore, the robust stimulating effects on normal and dyskinetic movements had an identical time course and parallel dose-response curves. In contrast, D2-like agonist ropinirole stimulated normal and dyskinetic movements relatively modestly. These results demonstrate that severe DA loss in the dorsal striatum sets the stage for dyskinesia to occur on the first exposure to l-dopa or a D1 agonist without any priming. These results also indicate that l-dopa stimulated both normal and dyskinetic movements primarily via D1 receptor activation and that proper D1 agonism is potentially an efficacious therapy for PD motor deficits. PMID:23357114

Li, L; Zhou, F-M



GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons.  


Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA(A) receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non-benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5-c]pyridine-3-ol (THIP) (also known as gaboxadol) that acts preferentially via high-affinity extrasynaptic GABA(A) receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABA(A) receptor ?(-/-) mice, which have a loss of extrasynaptic GABA(A) receptors. In behavioral experiments, we found neither acute reinforcement in intravenous self-administration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic ?-subunit-containing GABA(A) receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion. PMID:22496576

Vashchinkina, Elena; Panhelainen, Anne; Vekovischeva, Olga Yu; Aitta-aho, Teemu; Ebert, Bjarke; Ator, Nancy A; Korpi, Esa R



Proteome of Rhipicephalus sanguineus tick saliva induced by the secretagogues pilocarpine and dopamine  

PubMed Central

One dimensional gel electrophoresis was used to separate proteins from the saliva of Rhipicephalus sanguineus female ticks fed on rabbits. Gel slices were subjected to tryptic digestion and analyzed by reversed-phase HPLC followed by MS/MS analysis. The data were compared to a database of salivary proteins of the same tick and to the predicted proteins of the host. Saliva was obtained by either pilocarpine or dopamine stimulation of partially-fed ticks. Electrophoretic separations of both yielded products that were identified by mass spectrometry, although the pilocarpine-derived sample was of much better quality. The majority of identified proteins were of rabbit origin, indicating the recycling of the host proteins in the tick saliva, including hemoglobin, albumin, haptoglobin, transferring, and a plasma serpin. The few proteins found that were previously associated with parasitism and blood feeding include 2 glycine-rich, cement-like proteins, 2 lipocalins, and a thyropin protease inhibitor. Among other of the 19 tick proteins identified, albeit with undefined roles, were SPARC and cyclophilin A. This catalog provides a resource that can be mined for secreted molecules that play a role in tick-host interactions. PMID:24029695

Oliveira, C.J.; Anatriello, E.; de Miranda-Santos, I.K.; Francischetti, I.M.; Sá-Nunes, A.; Ferreira, B.R.; Ribeiro, J.M.C.



Anti-Asialo GM1 NK Cell Depleting Antibody Does Not Alter the Development of Bleomycin Induced Pulmonary Fibrosis  

PubMed Central

Despite circumstantial evidence postulating a protective role for NK cells in many fibrotic conditions, their contribution to the development of pulmonary fibrosis has yet to be tested. Lung-migrating NK cells are thought to attenuate the development of bleomycin induced pulmonary fibrosis (BIPF) by providing anti-fibrotic mediators and cytokines, such as IFN-?. If true, we reasoned that depletion of NK cells during experimentally-induced fibrotic disease would lead to exacerbated fibrosis. To test this, we treated mice with NK cell-depleting antisera (anti-asialo GM1) and evaluated lung inflammation and fibrosis in the BIPF model. While NK cell infiltration into the airways was maximal at day 10 after bleomycin injection, NK cells represented a minor portion (1–3%) of the total leukocytes in BAL fluid. Anti-asialo GM1 significantly abrogated NK cell numbers over the course of the disease. Depletion of NK cells with anti-asialo GM1 before and throughout the BIPF model, or during just the fibrotic phase did not alter fibrosis development or affect the levels of any of the pro-inflammatory/pro-fibrotic cytokines measured (IL-1?, IL-17, IFN-?, TGF-? and TNF-?). In addition, adoptively transferred NK cells, which were detectable systemically and in the airways throughout BIPF, failed to impact lung fibrosis. These findings indicate that NK cells likely do not play an essential protective role in controlling pulmonary fibrosis development. PMID:24922516

Monnier, Justin; Zabel, Brian A.



Thiourea-induced thyroid hormone depletion impairs testicular recrudescence in the air-breathing catfish, Clarias gariepinus.  


We used thiourea-induced thyroid hormone depletion as a strategy to understand the influence of thyroid hormones on testicular recrudescence of the air-breathing catfish, Clarias gariepinus. Treatment with 0.03% thiourea via immersion for 21 days induced hypothyroidism (thyroid hormone depletion) as evidenced by significantly reduced serum T(3) levels. Thiourea-treated males had narrowed seminiferous lobules with fewer spermatozoa in testis, very little or no secretory fluid, reduced protein and sialic acid levels in seminal vesicles when compared to controls. The histological changes were accompanied by reduction in serum and tissue levels of testosterone (T) and 11-ketotestosterone (11-KT), a potent male specific androgen in fish. Qualitative changes in the localization of catfish gonadotropin-releasing hormone (cfGnRH) and luteinizing hormone (LH, heterologous system) revealed a reduction in the distribution of immunoreactive neuronal cells and fibers in thyroid depleted fish. Interestingly, thiourea-withdrawal group showed physiological and histological signs of recovery after 21 days such as reappearance of spermatozoa and partial restoration of 11-KT and T levels. These data demonstrate that thyroid hormones play a significant role in testicular function of catfish. The mechanism of action includes modulating sex steroids either directly or through the hypothalamo (GnRH)-hypophyseal (LH) axis. PMID:16564715

Swapna, I; Rajasekhar, M; Supriya, A; Raghuveer, K; Sreenivasulu, G; Rasheeda, M K; Majumdar, K C; Kagawa, H; Tanaka, H; Dutta-Gupta, A; Senthilkumaran, B



Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis  

PubMed Central

Background and objectives Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. Design, setting, participants, & measurements A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. Results In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase–ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS]=0) was achieved in all patients. Major relapse (BVAS?3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. Conclusion This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted. PMID:24626432

Pendergraft, William F.; Cortazar, Frank B.; Wenger, Julia; Murphy, Andrew P.; Rhee, Eugene P.; Laliberte, Karen A.; Niles, John L.



Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects protein Kinase M zeta (PKM?), dopamine, and glutamate receptors  

PubMed Central

Methamphetamine (MA) is a toxic, addictive drug shown to modulate learning and memory, yet the neural mechanisms are not fully understood. We investigated the effects of 2 weekly injections of MA (30 mg/kg) on working memory using the radial 8-arm maze (RAM) across 5 weeks in adolescent-age mice. MA-treated mice show a significant improvement in working memory performance 1 week following the first MA injection compared to saline-injected controls. Following 5 weeks of MA abstinence mice were re-trained on a reference and working memory version of the RAM to assess cognitive flexibility. MA-treated mice show significantly more working memory errors without effects on reference memory performance. The hippocampus and dorsal striatum were assessed for expression of glutamate receptors subunits, GluA2 and GluN2B; dopamine markers, dopamine 1 receptor (D1), dopamine transporter (DAT) and tyrosine hydroxylase (TH); and memory markers, protein kinase M zeta (PKM?) and protein kinase C zeta (PKC?). Within the hippocampus, PKM? and GluA2 are both significantly reduced after MA supporting the poor memory performance. Additionally, a significant increase in GluN2B and decrease in D1 identifies dysregulated synaptic function. In the striatum, MA treatment increased cytosolic DAT and TH levels associated with dopamine hyperfunction. MA treatment significantly reduced GluN2B while increasing both PKM? and PKC? within the striatum. We discuss the potential role of PKM?/PKC? in modulating dopamine and glutamate receptors after MA treatment. These results identify potential underlying mechanisms for working memory deficits induced by MA. PMID:25566006

Braren, Stephen H.; Drapala, Damian; Tulloch, Ingrid K.; Serrano, Peter A.



FTT:Power : A global model of the power sector with induced technological change and natural resource depletion  

E-print Network

This work introduces a model of Future Technology Transformations for the power sector (FTT:Power), a representation of global power systems based on market competition, induced technological change (ITC) and natural resource use and depletion. It is the first component of a family of sectoral bottom-up models of technology, designed for integration into the global macroeconometric model E3MG. ITC occurs as a result of technological learning produced by cumulative investment and leads to highly nonlinear, irreversible and path dependent technological transitions. The model uses a dynamic coupled set of logistic differential equations. As opposed to traditional bottom-up energy models based on systems optimisation, such differential equations offer an appropriate treatment of the times and structure of change involved in sectoral technology transformations, as well as a much reduced computational load. Resource use and depletion are represented by local cost-supply curves, which give rise to different regional...

Mercure, J -F



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


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

Yun, Jaesuk



GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine.  


Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation. PMID:8987758

Tseng, J L; Baetge, E E; Zurn, A D; Aebischer, P



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


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 2.9Å 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

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



Activation of D1/D5 Dopamine Receptors Protects Neurons from Synapse Dysfunction Induced by Amyloid-? Oligomers*  

PubMed Central

Soluble oligomers of the amyloid-? peptide (A?Os) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. A?Os have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of A?Os. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by A?Os in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser845, which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of A?Os, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by A?Os in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD. PMID:21115476

Jürgensen, Sofia; Antonio, Leandro L.; Mussi, Gabriela E. A.; Brito-Moreira, Jordano; Bomfim, Theresa R.; De Felice, Fernanda G.; Garrido-Sanabria, Emilio R.; Cavalheiro, Ésper A.; Ferreira, Sergio T.



Dopamine Activity in the Lateral Anterior Hypothalamus Modulates Aas-Induced Aggression through D2 but not D5 Receptors  

PubMed Central

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, in order to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD67 (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD67 neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression. PMID:20939664

Schwartzer, Jared J.; Melloni, Richard H.



On the possible fault activation induced by UGS in depleted reservoirs  

NASA Astrophysics Data System (ADS)

Underground gas storage (UGS) represents an increasingly used approach to cope with the growing energy demand and occurs in many countries worldwide. Gas is injected in previously depleted deep reservoirs during summer when consumption is limited and removed in cold season mainly for heating. As a major consequence the pore pressure p within a UGS reservoir fluctuates yearly between a maximum close to the value pi prior to the field development and a minimum usually larger than the lowest pressure experienced by the reservoir at the end of its production life. The high frequency pressure fluctuations generally confine the pressure change volume to the reservoir volume without significantly involving the aquifers hydraulically connected to the hydrocarbon field (lateral and/or bottom waterdrive). The risk of UGS-induced seismicity is therefore restricted to those cases where existing faults cross or bound the reservoir. The possible risk of anthropogenic seismicity due to UGS operations is preliminary investigated by an advanced Finite Element (FE) - Interface Element (IE) 3-D elasto-plastic geomechanical model in a representative 1500 m deep reservoir bounded by a regional sealing fault and compartimentalized by an internal non-sealing thrust. Gas storage/production is ongoing with p ranging between pi in October/November and 60%pi in April/May. The yearly pressure fluctuation is assumed to be on the order of 50 bar. The overall geomechanical response of the porous medium has been calibrated by reproducing the vertical and horizontal cyclic displacements measured above the reservoir by advanced persistent scatterer interferometry. The FE-IE model shows that the stress variations remain basically confined within the gas field and negligibly propagate within the caprock and the waterdrive. Based on the Mohr-Coulomb failure criterion, IEs allow for the prediction of the fault activated area A, located at the reservoir depth as expected, and slip displacement d. A number of parametric scenarios are investigated to address the major uncertainties on the geomechanical fault properties, i.e., cohesion c and friction angle ? of the fault materials, and the initial stress regime (passive or compressive basin). The magnitude M of potential seismic events induced by the fault reactivation is evaluated by an empirical relation derived from seismological theories. M turns out to be correlated to the activated volume A × d and the shear modulus G of the host rock. With G = 3.9 × 104 bar, as provided by the calibration of the geomechanical model, the results point out that M may peak up to around 1 in the most conservative scenario, i.e. c = 0 bar, ? = 30°, entirely instantaneous slip and a passive stress basin. With c = 10 bar, a plausible value for the investigated reservoir, the fault does not activate. Under the above conditions fault activation by UGS does not appear to be a matter of concern.

Feronato, Massimiliano; Gambolati, Giuseppe; Janna, Carlo; Teatini, Pietro; Tosattto, Omar



Punishment induced behavioural and neurophysiological variability reveals dopamine-dependent selection of kinematic movement parameters  

PubMed Central

Action selection describes the high-level process which selects between competing movements. In animals, behavioural variability is critical for the motor exploration required to select the action which optimizes reward and minimizes cost/punishment, and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioural and neurophysiological variability on DA, and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant’s behaviour but pre-determined. Blocks highly-biased towards punishment were associated with increased MA variability relative to blocks with either reward or without feedback. This increase in behavioural variability was positively correlated with neurophysiological variability, as measured by changes in cortico-spinal excitability with transcranial magnetic stimulation over the primary motor cortex. Following the administration of a DA-antagonist, the variability associated with punishment diminished and the correlation between behavioural and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a pre-determined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioural variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcomes. PMID:23447607

Galea, Joseph M.; Ruge, Diane; Buijink, Arthur; Bestmann, Sven; Rothwell, John C.



Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder.  


Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n = 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n = 31) and wild-type (n = 28) mice) and acute (C57BL/6J mice (n = 89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by high-reward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies. PMID:25005251

van Enkhuizen, Jordy; Henry, Brook L; Minassian, Arpi; Perry, William; Milienne-Petiot, Morgane; Higa, Kerin K; Geyer, Mark A; Young, Jared W



Modelling of Depletion-Induced Microseismic Events by Coupled Reservoir Simulation: Application to Valhall Field  

E-print Network

to compute the change in reservoir effective stress and associated propagation of fractures and reactivation not necessarily reflect any position of the Society of Petroleum Engineers, its officers, or members. Electronic of SPE copyright. Abstract Reservoir depletion/injection results in changes in effective stress, which


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

Microsoft Academic Search

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

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



Oxytocin Reverses Amphetamine-Induced Deficits in Social Bonding: Evidence for an Interaction with Nucleus Accumbens Dopamine  

PubMed Central

Drug addiction has devastating consequences on social behaviors and can lead to the impairment of social bonding. Accumulating evidence indicates that alterations in oxytocin (OT) and dopamine (DA) neurotransmission within brain reward circuitry may be involved. We investigated this possibility, as well as the therapeutic potential of OT for drug-induced social deficits, using the prairie vole (Microtus ochrogaster)—a socially monogamous rodent that forms enduring pair bonds between adult mates. We demonstrate that repeated exposure to the commonly abused psychostimulant amphetamine (AMPH) inhibits the formation of partner preferences (an index of pair bonding) in female prairie voles. AMPH exposure also altered OT and DA neurotransmission in regions that mediate partner preference formation: it decreased OT and DA D2 receptor immunoreactivity in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), respectively, and increased NAcc DA levels. Administration of OT directly into the mPFC of AMPH-exposed voles restored partner preferences, and altered NAcc DA levels, and this effect was dependent on OT receptor activation. Together, these data suggest that repeated AMPH exposure impairs pair bonding through an OT-mediated mechanism, and that OT and DA systems within brain reward circuitry may interact to mediate the complex relationship between drug abuse and social bonding. Further, these results provide empirical support for the idea that the central OT system may represent an important target for the treatment of social deficits in addiction. PMID:24948805

Liu, Yan; Gobrogge, Kyle L.; Wang, Hui



Forward Genetic Analysis to Identify Determinants of Dopamine Signaling in Caenorhabditis elegans Using Swimming-Induced Paralysis  

PubMed Central

Disrupted dopamine (DA) signaling is believed to contribute to the core features of multiple neuropsychiatric and neurodegenerative disorders. Essential features of DA neurotransmission are conserved in the nematode Caenorhabditis elegans, providing us with an opportunity to implement forward genetic approaches that may reveal novel, in vivo regulators of DA signaling. Previously, we identified a robust phenotype, termed Swimming-induced paralysis (Swip), that emerges in animals deficient in the plasma membrane DA transporter. Here, we report the use and quantitative analysis of Swip in the identification of mutant genes that control DA signaling. Two lines captured in our screen (vt21 and vt22) bear novel dat-1 alleles that disrupt expression and surface trafficking of transporter proteins in vitro and in vivo. Two additional lines, vt25 and vt29, lack transporter mutations but exhibit genetic, biochemical, and behavioral phenotypes consistent with distinct perturbations of DA signaling. Our studies validate the utility of the Swip screen, demonstrate the functional relevance of DA transporter structural elements, and reveal novel genomic loci that encode regulators of DA signaling. PMID:22908044

Hardaway, J. Andrew; Hardie, Shannon L.; Whitaker, Sarah M.; Baas, Sarah R.; Zhang, Bing; Bermingham, Daniel P.; Lichtenstein, Ariana J.; Blakely, Randy D.



Radiation-enhanced gate-induced-drain-leakage current in the 130 nm partially-depleted SOI pMOSFET  

NASA Astrophysics Data System (ADS)

The total ionizing dose (TID) effect of the pMOSFET from 130 nm partially-depleted silicon-on-insulator (PDSOI) is investigated. The data obtained from 60Co ?-ray irradiation experiments indicate that input/output (I/O) device is more susceptible to TID effect than the core device. An anomalous off-state leakage increase is observed for I/O pMOSFET when drain is biased at a high voltage after irradiation. It is proved that this radiation-induced leakage relates to the enhanced gate-induce-drain-leakage (GIDL). Both the radiation-induced interface traps at the gate-oxide/body interface and the oxide trapped charges in the buried oxide (BOX) are responsible for the growth of the leakage current. These conclusions are also verified by the TCAD simulations. The isothermal annealing can recover the leakage current to the pre-irradiation level.

Peng, Chao; Hu, Zhiyuan; Ning, Bingxu; Dai, Lihua; Bi, Dawei; Zhang, Zhengxuan



Examining the Complex Regulation and Drug-Induced Plasticity of Dopamine Release and Uptake Using Voltammetry in Brain Slices  

PubMed Central

Fast scan cyclic voltammetry in brain slices (slice voltammetry) has been used over the last several decades to increase substantially our understanding of the complex local regulation of dopamine release and uptake in the striatum. This technique is routinely used for the study of changes that occur in the dopamine system associated with various disease states and pharmacological treatments, and to study mechanisms of local circuitry regulation of dopamine terminal function. In the context of this Review, we compare the relative advantages of voltammetry using striatal slice preparations versus in vivo preparations, and highlight recent advances in our understanding of dopamine release and uptake in the striatum specifically from studies that use slice voltammetry in drug-naïve animals and animals with a history of psychostimulant self-administration. PMID:23581570



Potential involvement of oxygen intermediates and glutathione depletion in UV-induced epidermal cell injury in vitro  

SciTech Connect

Generation of reactive oxygen species (ROS) and depletion of glutathione (GSH) are suggested as the cytotoxic mechanisms for UVB-induced cellular damage. Primary monolayer cultures of epidermal keratinocytes (KCs) prepared from the skin of neonatal rats were irradiated with UVB at levels of 0.25-3.0 J/cm{sup 2}. Cytotoxicity was measured at 3, 6, and 12 hr after UVB radiation. Exposure of KCs to UVB resulted in time- and dose-related toxic responses as determined by plasma membrane integrity, lysosomal function and mitochondrial metabolic activity. Irradiated KCs generated superoxide in a dose-dependent manner when compared to sham-irradiated cells. Superoxide formation, which occurred before and concomitant with cell injury, was decreased by superoxide dismutase (SOD). Cell injury was also significantly prevented by ROS scavengers, SOD and catalase. Pretreatment of cells with endocytosis inhibitors, cytochalasin B and methylamine, suppressed the ability of SOD and catalase to protect keratinocytes from UVB-induced toxicity. Irradiation of cells with UVB caused rapid depletion of GSH to about 30% of unirradiated levels within 15 min. UVB-irradiation led to a rapid transient increase in GSH peroxidase activity, concomitant with a marked decrease in the GSH/GSSG ratio. After 1 hr., while the GSH/GSSG ratio remained low, the GSH peroxidase activity declined below the control levels in UVB-treated epidermal cells. Following extensive GSH depletion in cells preincubated with 0.1 mM buthiomine sulfoximine, KCs became strongly sensitized to the cytotoxic action of UVB. These results indicate that UVB-induced cell injury in cultured KCs may be mediated by ROs and that endogenous GSH may play an important protective role against the cytotoxic action of UVB.

Hsieh, G.C.; Acosta, D. (Univ. of Texas, Austin (United States))



Recovery of striatal dopamine function after acute amphetamine- and methamphetamine-induced neurotoxicity in the vervet monkey  

Microsoft Academic Search

In six vervet monkeys, presynaptic striatal dopamine function was assessed longitudinally by [18F]fluoro-l-DOPA (FDOPA)–positron emission tomography (PET) after administration (2×2 mg\\/kg, i.m., 4 h apart) of either amphetamine (Amp), n=3, or methamphetamine (MeAmp), n=3. At 1–2 weeks postdrug, both Amp and MeAmp exposure effected similar decreases (60–70%) in the FDOPA influx rate constant (FDOPA Ki), an index of striatal dopamine

William P Melega; Michael J Raleigh; David B Stout; Goran Lacan; Sung-Cheng Huang; Michael E Phelps



Antifolate-Induced Depletion of Intracellular Glycine and Purines Inhibits Thymineless Death in E. coli  

PubMed Central

Despite the therapeutic importance of antifolates, the links between their direct antimetabolite activity and downstream consequences remain incompletely understood. Here we employ metabolomics to examine the complete metabolic effects of the antibiotic trimethoprim in E. coli. In rich media, trimethoprim treatment causes thymineless death. In minimal media, in contrast, trimethoprim addition results in rapid stoppage of cell growth and stable cell stasis. We show that initial impairment of cell growth is due to rapid depletion of glycine and associated activation of the stringent response. Long-term stasis is due to purine insufficiency. Thus, E. coli has dual systems for surviving folate depletion and avoiding thymineless death: a short-term response based on sensing of amino acids and a long-term response based on sensing of nucleotides. PMID:20553049

Kwon, Yun Kyung; Higgins, Meytal B.; Rabinowitz, Joshua D.



Effects of Lithium on Dopamine Behavioural Supersensitivity Induced by Rapid Eye Movement Sleep Deprivation  

Microsoft Academic Search

The effects of lithium on the potentiation of d-amphetamine-induced hyperlocomotion were evaluated in rapid eye movement (REM) sleep deprived rats. Under control conditions, pretreatment with lithium during 7 days did not modify the hyperlocomotion produced by d-amphetamine. REM sleep deprivation induced a pronounced potentiation of the locomotor response to d-amphetamine. In a stress control group this potentiation also occurred, but

Filipe Arriaga; Christine Dugovic; Albert Wauquier



Evidence of depleted uranium?induced hormesis and differential plant response in three grasses  

Microsoft Academic Search

General plant response to depleted uranium (DU) was tested using three widespread range?grass species, Aristida purpurea Nutt. (purple threeawn), Buchloe dactyloides (Nutt.) Engelm. (buffalograss), and Schizachyrium scoparium (Michx.) Nash (little bluestem). Aboveground, belowground, and total biomass measures of these grasses were analyzed over the five different DU soil concentrations of 0, 50, 500, 5,000, and 25,000 mg kg. Differential plant

Michael C. Meyer; Terry McLendon; David Price



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

PubMed Central

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

Hassan, J O; Curtiss, R



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

Microsoft Academic Search

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

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



Activation of D1-like dopamine receptors increases the NMDA-induced gain modulation through a PKA-dependent pathway in the premotor nucleus of adult zebra finches.  


Interaction between dopamine (DA) and N-methyl-d-aspartate (NMDA) in the brain plays an important role in learning and memory. In the songbirds, the premotor robust nucleus of the arcopallium (RA) receives excitatory glutamatergic inputs from the high vocal center (HVC) and lateral magnocellular nucleus of the anterior nidopallium (LMAN), as well as dopaminergic inputs mostly from the periaqueductal gray (PAG) and ventral tegmental area (VTA). In zebra finch, DA potentiates the excitability of projection neurons in the RA through activation of D1-like dopamine receptors (D1 receptors). The relationship between D1 receptors and NMDA in the RA projection neurons is essentially unknown. Our previous work showed that NMDA can induce gain modulation in the RA projection neurons. Here, using the whole-cell current-clamp recording from brain slices of male zebra finches, we observed whether D1 receptors regulate the NMDA-induced gain modulation in the RA projection neurons. Our results showed that activation of D1 receptors further increased the slope (gain) of the firing frequency-injected current (f-I) relationship induced by NMDA in the RA projection neurons. Blocking D1 receptors had no effect on the NMDA-induced gain modulation in the RA projection neurons. The enhanced effects of D1 receptors agonists were blocked by protein kinase A (PKA) inhibitors. Our results suggest that activation of D1 receptors can increase the NMDA-induced gain modulation through a PKA-dependent pathway. PMID:25596438

Wang, Songhua; Liao, Congshu; Meng, Wei; Huang, Qingyao; Li, Dongfeng



Impact of prefrontal cortex in nicotine-induced excitation of VTA dopamine neurons in anesthetized rats  

PubMed Central

Systemic administration of nicotine increases dopaminergic (DA) neuron firing in the ventral tegmental area (VTA), which is thought to underlie nicotine reward. Here, we report that the medial prefrontal cortex (mPFC) plays a critical role in nicotine-induced excitation of VTA DA neurons. In chloral hydrate-anesthetized rats, extracellular single-unit recordings showed that VTA DA neurons exhibited two types of firing responses to systemic nicotine. After nicotine injection, the neurons with type-I response showed a biphasic early inhibition and later excitation, whereas the neurons with type-II response showed a monophasic excitation. The neurons with type-I, but not type-II, response exhibited pronounced slow oscillations (SO) in firing. Pharmacological or structural mPFC inactivation abolished SO and prevented systemic nicotine-induced excitation in the neurons with type-I, but not type-II, response, suggesting that these VTA DA neurons are functionally coupled to the mPFC and nicotine increases firing rate in these neurons in part through the mPFC. Systemic nicotine also increased the firing rate and SO in mPFC pyramidal neurons. mPFC infusion of a non-?7 nAChR antagonist mecamylamine blocked the excitatory effect of systemic nicotine on the VTA DA neurons with type-I response, but mPFC infusion of nicotine failed to excite these neurons. These results suggest that nAChR activation in the mPFC is necessary, but not sufficient, for systemic nicotine-induced excitation of VTA neurons. Finally, systemic injection of bicuculline prevented nicotine-induced firing alterations in the neurons with type-I response. We propose that the mPFC plays a critical role in systemic nicotine-induced excitation of VTA DA neurons. PMID:22956827

Zhang, Die; Gao, Ming; Xu, Dan; Shi, Wei-Xing; Gutkin, Boris S.; Steffensen, Scott C.; Lukas, Ronald J.; Wu, Jie



Suppression of dopamine-related side effects of morphine by aripiprazole, a dopamine system stabilizer.  


Dopamine receptor antagonists are commonly used to counter the adverse effects of opioids such as hallucinations, delusions and emesis. However, most of these agents themselves have side effects, including extrapyramidal symptoms. Here, we investigated the effect of the dopamine system stabilizer aripiprazole on morphine-induced dopamine-related actions in mice. Morphine-induced hyperlocomotion and reward were significantly suppressed by either the dopamine receptor antagonist prochlorperazine or aripiprazole. Catalepsy was observed with a high dose of prochlorperazine, but not with an even higher dose of aripiprazole. The increased level of dialysate dopamine in the nucleus accumbens stimulated by morphine was significantly decreased by pretreatment with aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced dopamine-related side effects. PMID:18955042

Narita, Minoru; Takei, Daisuke; Shiokawa, Mitsuru; Tsurukawa, Yuri; Matsushima, Yuki; Nakamura, Atsushi; Takagi, Shigemi; Asato, Megumi; Ikegami, Daigo; Narita, Michiko; Amano, Taku; Niikura, Keiichi; Hashimoto, Keisuke; Kuzumaki, Naoko; Suzuki, Tsutomu



Evidence for the Involvement of Dopamine in Stress-Induced Suppression of Reproduction in the Cichlid Fish Oreochromis mossambicus.  


In the present study, we examined whether stress-induced suppression of reproduction is mediated through the catecholaminergic neurotransmitter dopamine (DA) in the female cichlid fish Oreochromis mossambicus. In the first experiment, application of antibody against tyrosine hydroxylase (TH; a marker for DA) in brain sections revealed the presence of intensely stained TH immunoreactive cells in the preoptic area (POA) and nucleus preopticus (NPO) during the previtellogenic phase. These cells showed weak immunoreactivity during the vitellogenic and prespawning phases concomitant with darkly stained luteinising hormone (LH) immunoreactive content in the proximal pars distalis (PPD) of the pituitary gland and fully ripened follicles (stage V) in the ovary of control fish. However, in fish exposed to aquacultural stressors, TH secreting cells remained intensely stained in POA and NPO regions during the prespawning phase, indicating increased synthetic and secretory activity, which was reflected by a significantly higher DA content compared to controls. Increased DA activity as a result of stress was associated with a decrease in the LH immunoreactive content in the PPD and an absence of stage V follicles in the ovary. In the second experiment, administration of DA caused effects similar to those in stressed fish, whereas DA receptor antagonist domperidone (DOM) treatment significantly increased the LH content in the PPD and the number of stage V follicles in unstressed fish. On the other hand, treatment of stressed fish with DOM resulted in dark accumulations of LH immunoreactive content in the PPD accompanied by the presence of stage V follicles in the ovary. Taken together, these results suggest an additional pathway for the inhibitory effects of stress through dopaminergic neurones along the reproductive axis. PMID:25712855

Chabbi, A; Ganesh, C B



Stress-induced dopamine response in subjects at clinical high risk for schizophrenia with and without concurrent cannabis use.  


Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [(11)C]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BPND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BPND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BPND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BPND in the CHR group, CHR-CU group exhibited an increase in BPND. Stress-induced changes in regional BPND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction. PMID:24385130

Mizrahi, Romina; Kenk, Miran; Suridjan, Ivonne; Boileau, Isabelle; George, Tony P; McKenzie, Kwame; Wilson, Alan A; Houle, Sylvain; Rusjan, Pablo



Glial–glial and glial–neuronal interfaces in radiation-induced, glia-depleted spinal cord  

PubMed Central

This review summarises some of the major findings derived from studies using the model of a glia-depleted environment developed and characterised in this laboratory. Glial depletion is achieved by exposure of the immature rodent spinal cord to x-radiation which markedly reduces both astrocyte and oligodendrocyte populations and severely impairs myelination. This glia-depleted, hypomyelinated state presents a unique opportunity to examine aspects of spinal cord maturation in the absence of a normal glial population. An associated sequela within 2–3 wk following irradiation is the appearance of Schwann cells in the dorsal portion of the spinal cord. Characteristics of these intraspinal Schwann cells, their patterns of myelination or ensheathment, and their interrelations with the few remaining central glia have been examined. A later sequela is the development of Schwann cells in the ventral aspect of the spinal cord where they occur predominantly in the grey matter. Characteristics of these ventrally situated intraspinal Schwann cells are compared with those of Schwann cells located dorsally. Recently, injury responses have been defined in the glia-depleted spinal cord subsequent to the lesioning of dorsal spinal nerve roots. In otherwise normal animals, dorsal nerve root injury induces an astrocytic reaction within the spinal segments with which the root(s) is/are associated. Lesioning of the 4th lumbar dorsal root on the right side in irradiated or nonirradiated animals results in markedly different glial responses with little astrocytic scarring in the irradiated animals. Tracing studies reveal that these lesioned dorsal root axons regrow rather robustly into the spinal cord in irradiated but not in nonirradiated animals. To examine role(s) of glial cells in preventing this axonal regrowth, glial cells are now being added back to this glia-depleted environment through transplantation of cultured glia into the irradiated area. Transplanted astrocytes establish barrier-like arrangements within the irradiated cords and prevent axonal regrowth into the cord. Studies using other types of glial cultures (oligodendrocyte or mixed) are ongoing. PMID:9034878




Pneumococcal Polysaccharide Abrogates Conjugate-Induced Germinal Center Reaction and Depletes Antibody Secreting Cell Pool, Causing Hyporesponsiveness  

PubMed Central

Background Plain pneumococcal polysaccharide (PPS) booster administered during second year of life has been shown to cause hyporesponsiveness. We assessed the effects of PPS booster on splenic memory B cell responses and persistence of PPS-specific long-lived plasma cells in the bone marrow (BM). Methods Neonatal mice were primed subcutanously (s.c.) or intranasally (i.n.) with pneumococcal conjugate (Pnc1-TT) and the adjuvant LT-K63, and boosted with PPS+LT-K63 or saline 1, 2 or 3 times with 16 day intervals. Seven days after each booster, spleens were removed, germinal centers (GC), IgM+, IgG+ follicles and PPS-specific antibody secreting cells (AbSC) in spleen and BM enumerated. Results PPS booster s.c., but not i.n., compromised the Pnc1-TT-induced PPS-specific Abs by abrogating the Pnc1-TT-induced GC reaction and depleting PPS-specific AbSCs in spleen and limiting their homing to the BM. There was no difference in the frequency of PPS-specific AbSCs in spleen and BM between mice that received 1, 2 or 3 PPS boosters s.c.. Repeated PPS+LT-K63 booster i.n. reduced the frequency of PPS-specific IgG+ AbSCs in BM. Conclusions PPS booster-induced hyporesponsiveness is caused by abrogation of conjugate-induced GC reaction and depletion of PPS-specific IgG+ AbSCs resulting in no homing of new PPS-specific long-lived plasma cells to the BM or survival. These results should be taken into account in design of vaccination schedules where polysaccharides are being considered. PMID:24069152

Bjarnarson, Stefania P.; Benonisson, Hreinn; Del Giudice, Giuseppe; Jonsdottir, Ingileif



p-Dichlorobenzene-induced hepatotoxicity in mice depleted of glutathione by treatment with buthionine sulfoximine.  


p-Dichlorobenzene (p-DCB) is widely used as a moth repellent and a space deodorant. In mice pretreated with DL-buthionine sulfoximine (BSO; 2 mmol/kg or higher doses, i.p.), an inhibitor of glutathione (GSH) synthesis, administration of p-DCB (100-400 mg/kg, p.o.) resulted in dose-dependent hepatotoxicity as judged by increased serum alanine aminotransferase (ALT) activities and liver calcium concentrations and by histological examination of the liver, p-DCB alone (up to 1200 mg/kg) resulted in no hepatotoxicity. Administration of GSH monoethyl ester, which is known as a useful means for increasing organ GSH levels, protected against the hepatotoxicity caused by p-DCB in combination with BSO. Treatment with inhibitors of hepatic cytochrome P-450-dependent monooxygenases, carbon disulfide, metyrapone and piperonyl butoxide also prevented the hepatotoxicity. These results suggest that p-DCB is activated by a cytochrome P-450-dependent metabolic reaction and that the hepatotoxicity is caused by inadequate rates of detoxification of the resulting metabolite in mice depleted of hepatic GSH by BSO treatment. The liver injury was preceded by an extensive depletion of hepatic GSH but not accompanied by significant changes in hepatic contents of lipid peroxides and protein thiols. PMID:7801330

Mizutani, T; Nakahori, Y; Yamamoto, K



Grape seed and skin extract alleviates high-fat diet-induced renal lipotoxicity and prevents copper depletion in rat.  


Obesity is a public health problem that contributes to morbidity and mortality from diabetes, heart disease, stroke, and cancers. The purpose of this investigation was to analyse the link between obesity-induced oxidative stress, renal steatosis, and kidney dysfunction, as well as the protective effect of grape seed and skin extract. Rats were fed a standard diet or a high-fat diet for 6 weeks and were either treated or not treated with grape seed and skin extract. Fat-induced oxidative stress was evaluated in the kidney with a special emphasis on transition metals. High-fat diet induced triglyceride deposition and disturbances in kidney function parameters, which are linked to an oxidative stress status and depletion of copper from the kidney. Grape seed and skin extract abrogated almost all fat-induced kidney disturbances. Grape seed and skin extract exerted potential protection against fat-induced kidney lipotoxicity and should find potential application in other kidney-related diseases. PMID:23537016

Charradi, Kamel; Elkahoui, Salem; Karkouch, Ines; Limam, Ferid; Hamdaoui, Ghaith; Hassine, Fethy Ben; El May, Michèle Veronique; El May, Ahmed; Aouani, Ezzedine



Glucose concentrations in brain and blood: regulation by dopamine receptor subtypes.  


The stimulation of D1 and D2 dopamine (DA) receptors by selective agonists produced large increases in brain glucose concentrations. D2 receptor stimulation also produced large increases in blood glucose. The D1-induced increases were somewhat variable in normal animals, but were more reliably observed and greatly increased in animals with brain DA depletions. Blockade of D1 receptors prevented these increases. Likewise, centrally acting D2 antagonists, but not the peripheral D2 antagonist domperidone, prevented D2 agonist-induced increases in brain and blood glucose. These observations point to an important role for DA in the regulation of glucose homeostasis. PMID:1829974

Saller, C F; Kreamer, L D



Dopamine released from nerve terminals activates prejunctional dopamine receptors in dog mesenteric arterial vessels.  

PubMed Central

The fractional release of dopamine and noradrenaline (NA) from the main trunk of the dog mesenteric artery and its proximal branches, when elicited by K+ (52 mM), was measured by high pressure liquid chromatography with electrochemical detection. K+-induced depolarization released both dopamine and NA. For the main trunk of the mesenteric artery, the fractional release of dopamine and NA were of the same order of magnitude, whereas for the proximal branches dopamine fractional release was significantly lower than that of NA. Phentolamine (0.2 microM) significantly increased dopamine and NA release in both segments of the mesenteric artery. However, for the proximal branches the effect of phentolamine on dopamine and NA release was greater than that observed in the main trunk. Sulpiride (1 microM) significantly increased dopamine and NA release in the proximal branches of the mesenteric artery, whereas in the main trunk sulpiride did not increase amine release. In the proximal branches of the mesenteric artery, sulpiride significantly enhanced dopamine and NA fractional release even after it had been augmented by phentolamine. Apomorphine (0.3 microM) significantly reduced dopamine and NA release in both segments of the mesenteric artery under study; this effect was abolished by sulpiride but not by phentolamine. These results suggest that dopamine and NA released during depolarization by K+ activate prejunctional dopamine and alpha-adrenoceptors, respectively, thereby playing a role in the control of transmitter release. PMID:3607368

Soares-da-Silva, P.



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

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

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



Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism  

Microsoft Academic Search

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

Yotam Sagi; Silvia Mandel; Tamar Amit; Moussa B. H. Youdim



Considerations for evaluating ultraviolet radiation-induced genetic damage relative to Antarctic ozone depletion.  

PubMed Central

Springtime ozone depletion over the Antarctic results in increased UVB in local marine environments. It has been established that decreases in primary productivity occur with decreases in ozone concentrations, but the impact of increased UVB on the functioning and stability of the ecosystem has not yet been determined. Very little has been done to evaluate the potential for genetic damage caused by the increase in UVB, and this type of damage is most significant relative to the fitness and maintenance of populations. An essential problem in evaluating genotoxic effects is the lack of appropriate techniques to sample and quantify genetic damage in field populations under ambient UVB levels. In addition, it is currently not feasible to estimate exposure levels for organisms in their natural habitats. PMID:7713036

Karentz, D



Temperature dependence of the radiation induced change of depletion voltage in silicon PIN detectors  

SciTech Connect

The silicon microstrip detectors that will be used in the SDC experiment at the Superconducting Super Collider (SSC) will be exposed to very large fluences of charged particles, neutrons, and gammas. The authors present a study of how temperature affects the change in the depletion voltage of silicon PIN detectors damaged by radiation. They study the initial radiation damage and the short-term and long-term annealing of that damage as a function of temperature in the range from {minus}10{degrees}C to +50{degrees}C, and as a function of 800 MeV proton fluence up to 1.5 {times} 10{sup 14} p/cm{sup 2}. They express the pronounced temperature dependencies in a simple model in terms of two annealing time constants which depend exponentially on the temperature.

Ziock, H.J.; Holzscheiter, K.; Morgan, A.; Palounek, A.P.T. [Los Alamos National Lab., NM (United States); Ellison, J.; Heinson, A.P.; Mason, M.; Wimpenny, S.J. [Univ. of California, Riverside, CA (United States); Barberis, E.; Cartiglia, N.; Grillo, A.; O`Shaughnessy, K.; Rahn, J.; Rinaldi, P.; Rowe, W.A.; Sadrozinski, H.F.W.; Seiden, A.; Spencer, E.; Webster, A.; Wichmann, R.; Wilder, M. [Univ. of California, Santa Cruz, CA (United States). Santa Cruz Inst. for Particle Physics; Frautschi, M.A.; Matthews, J.A.J.; McDonald, D.; Skinner, D. [Univ. of New Mexico, Albuquerque, NM (United States); Coupal, D.; Pal, T. [Superconducting Super Collider Lab., Dallas, TX (United States)



Depletion of Liver Kupffer Cells Prevents the Development of Diet-Induced Hepatic Steatosis and Insulin Resistance  

PubMed Central

OBJECTIVE Increased activity of the innate immune system has been implicated in the pathogenesis of the dyslipidemia and insulin resistance associated with obesity and type 2 diabetes. In this study, we addressed the potential role of Kupffer cells (liver-specific macrophages, KCs) in these metabolic abnormalities. RESEARCH DESIGN AND METHODS Rats were depleted of KCs by administration of gadolinium chloride, after which all animals were exposed to a 2-week high-fat or high-sucrose diet. Subsequently, the effects of these interventions on the development of hepatic insulin resistance and steatosis were assessed. In further studies, the effects of M1-polarized KCs on hepatocyte lipid metabolism and insulin sensitivity were addressed. RESULTS As expected, a high-fat or high-sucrose diet induced steatosis and hepatic insulin resistance. However, these metabolic abnormalities were prevented when liver was depleted of KCs. In vitro, KCs recapitulated the in vivo effects of diet by increasing hepatocyte triglyceride accumulation and fatty acid esterification, and decreasing fatty acid oxidation and insulin responsiveness. To address the mechanisms(s) of KC action, we inhibited a panel of cytokines using neutralizing antibodies. Only neutralizing antibodies against tumor necrosis factor-? (TNF?) attenuated KC-induced alterations in hepatocyte fatty acid oxidation, triglyceride accumulation, and insulin responsiveness. Importantly, KC TNF? levels were increased by diet in vivo and in isolated M1-polarized KCs in vitro. CONCLUSIONS These data demonstrate a role for liver macrophages in diet-induced alterations in hepatic lipid metabolism and insulin sensitivity, and suggest a role for these cells in the etiology of the metabolic abnormalities of obesity/type 2 diabetes. PMID:19934001

Huang, Wan; Metlakunta, Anantha; Dedousis, Nikolaos; Zhang, Pili; Sipula, Ian; Dube, John J.; Scott, Donald K.; O'Doherty, Robert M.



Serotonin depletion induces 'waiting impulsivity' on the human four-choice serial reaction time task: cross-species translational significance.  


Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behavior. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analog of a rodent 5-choice serial reaction time task (5-CSRTT)-- the human 4-CSRTT--and a reward delay-discounting questionnaire to measure effects on these different forms of 'waiting impulsivity'. There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire. However, TD significantly increased 4-CSRTT premature responses (or impulsive action), which is remarkably similar to the previous findings of effect of serotonin depletion on rodent 5-CSRTT performance. Moreover, the increased premature responding in TD correlated significantly with individual differences on the motor impulsivity subscale of the Barratt Impulsivity Scale. TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing. The results suggest: (i) the 4-CSRTT will be a valuable addition to the tests already available to measure impulsivity in humans in a direct translational analog of a test extensively used in rodents; (ii) TD in humans produces a qualitatively similar profile of effects to those in rodents (ie, enhancing premature responding), hence supporting the conclusion that TD in humans exerts at least some of its effects on central serotonin; and (iii) this manipulation of serotonin produces dissociable effects on different measures of impulsivity, suggesting considerable specificity in its modulatory role. PMID:24385133

Worbe, Yulia; Savulich, George; Voon, Valerie; Fernandez-Egea, Emilio; Robbins, Trevor W



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


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

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



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

SciTech Connect

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.

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: [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan (China)



Hypoxia-inducible factor-1? upregulates tyrosine hydroxylase and dopamine transporter by nuclear receptor ERR? in SH-SY5Y cells.  


Hypoxia-inducible factor-1? (HIF-1?) is a transcription factor relevant to the development of many mammalian organs including the brain. However, the molecular mechanisms by which signaling events mediate neuronal differentiation have not been fully elucidated. In the present study, we show for the first time that the orphan nuclear receptor estrogen-related receptor ? (ERR?) is upregulated by HIF-1? and plays essential roles in HIF-1?-induced upregulation of dopaminergic marker molecules such as tyrosine hydroxylase and dopamine transporter. We found that deferoxamine upregulated HIF-1? and enhanced the dopaminergic phenotype and neurite outgrowth of SH-SY5Y cells. Deferoxamine activated transcription and protein expression of ERR?, and deferoxamine-induced upregulation of tyrosine hydroxylase and dopamine transporter was attenuated by using the ERR? inverse agonist or silencing ERR?. Altogether, these results suggest that HIF-1? can positively regulate the dopaminergic phenotype through ERR?. This study could provide new perspectives for understanding the mechanisms underlying the promotion of dopaminergic neuronal differentiation by hypoxia. PMID:25807177

Lim, Juhee; Kim, Hyo-In; Bang, Yeojin; Seol, Wongi; Choi, Hueng-Sik; Choi, Hyun Jin



The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuropathic rat.  


We studied in rats with a spinal nerve ligation-induced neuropathy whether dopamine D2 receptors (D2Rs) play a role in descending control of pain induced by stimulation of the primary motor cortex (M1). Noxious heat-evoked responses were determined in spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons, with and without electrical M1 stimulation. A D2R antagonist, raclopride, was administered into the dorsal striatum or spinally in attempts to reverse spinal antinociception induced by M1 stimulation. Moreover, influence of M1 stimulation on the noxious heat-induced limb withdrawal reflex was determined following block of spinal D2Rs with raclopride or a lidocaine-induced block of the hypothalamic A11 cell group, the main source of spinal dopamine. Striatal administration of raclopride enhanced the heat-evoked baseline responses of WDR but not NS neurons and reversed the M1 stimulation-induced suppression of the heat response in WDR neurons. Following spinal administration of raclopride, M1 stimulation failed to suppress the heat response of WDR neurons, whereas the heat response of NS neurons was enhanced by M1-stimulation. After blocking the A11 with lidocaine or spinal D2Rs with raclopride, M1 stimulation failed to suppress the noxious heat-evoked withdrawal reflex. The results indicate that descending pain control induced by stimulation of the M1 cortex in neuropathic animals involves supraspinal (presumably striatal) and, through A11, spinal D2Rs. Supraspinal and spinal D2Rs have partly dissociative effects on spinal dorsal horn WDR and NS neurons, possibly reflecting differential roles and wirings that these sensory neurons have in pain-processing circuitries. PMID:22902996

Viisanen, Hanna; Ansah, Osei Bonsu; Pertovaara, Antti



Clonal evolution following chemotherapy-induced stem cell depletion in cats heterozygous for glucose-6-phosphate dehydrogenase  

SciTech Connect

The number of hematopoietic stem cells necessary to support normal hematopoiesis is not known but may be small. If so, the depletion or damage of such cells could result in apparent clonal dominance. To test this hypothesis, dimethylbusulfan (2 to 4 mg/kg intravenously (IV) x 3) was given to cats heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD). These cats were the daughters of domestic X Geoffroy parents. After the initial drug-induced cytopenias (2 to 4 weeks), peripheral blood counts and the numbers of marrow progenitors detected in culture remained normal, although the percentages of erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony-forming cells (CFU-GM) in DNA synthesis increased, as determined by the tritiated thymidine suicide technique. In three of six cats treated, a dominance of Geoffroy-type G-6-PD emerged among the progenitor cells, granulocytes, and RBCs. These skewed ratios of domestic to Geoffroy-type G-6-PD have persisted greater than 3 years. No changes in cell cycle kinetics or G-6-PD phenotypes were noted in similar studies in six control cats. These data suggest that clonal evolution may reflect the depletion or damage of normal stem cells and not only the preferential growth and dominance of neoplastic cells.

Abkowitz, J.L.; Ott, R.M.; Holly, R.D.; Adamson, J.W.



Drug-Induced Activation of Dopamine D1 Receptor Signaling and Inhibition of Class I\\/II Histone Deacetylase Induce Chromatin Remodeling in Reward Circuitry and Modulate Cocaine-Related Behaviors  

Microsoft Academic Search

Chromatin remodeling, including histone modification, is involved in stimulant-induced gene expression and addiction behavior. To further explore the role of dopamine D1 receptor signaling, we measured cocaine-related locomotor activity and place preference in mice pretreated for up to 10 days with the D1 agonist SKF82958 and\\/or the histone deacetylase inhibitor (HDACi), sodium butyrate. Cotreatment with D1 agonist and HDACi significantly

Frederick A Schroeder; Krista L Penta; Anouch Matevossian; Sara R Jones; Christine Konradi; Andrew R Tapper; Schahram Akbarian



Stress-induced depression of motor activity correlates with regional changes in brain norepinephrine but not in dopamine  

Microsoft Academic Search

This experiment examined how inescapable tail shock alters the level of dopamine and norepinephrine within various brain regions of the rat and the relationship of these changes to the depression of motor activity produced by the shock. Following exposure to tail shock that is known to interfere with acquisition of active behavioral tasks, animals were briefly tested for spontaneous motor

J. M. Weiss; W. H. Bailey; L. A. Pohorecky; D. Korzeniowski; G. Grillione



NMDA and Dopamine Converge on the NMDA-Receptor to Induce ERK Activation and Synaptic Depression in Mature Hippocampus  

Microsoft Academic Search

The formation of enduring internal representation of sensory information demands, in many cases, convergence in time and space of two different stimuli. The first conveys the sensory input, mediated via fast neurotransmission. The second conveys the meaning of the input, hypothesized to be mediated via slow neurotransmission. We tested the biochemical conditions and feasibility for fast (NMDA) and slow (dopamine)

Hanoch Kaphzan; Kenneth J. O'Riordan; Kile P. Mangan; Jonathan M. Levenson; Kobi Rosenblum; Rachel Wong



Electroacupuncture-Induced Neuroprotection against Cerebral Ischemia in Rats: Role of the Dopamine D2 Receptor  

PubMed Central

Background. Cerebral ischemia is known to produce brain damage and related behavioural deficits, including memory deficits and motor disorders. Evidence shows that EA significantly promotes recovery of neurological function and thus improves quality of life. Objective. Evidence exists for the involvement of catecholamines in human neuroplasticity. A better understanding of dopaminergic (DAergic) modulation in this process will be important. Methods. A total of 72 adult male Sprague-Dawley (SD) rats were divided into 6 groups: normal, model, EA, spiperone group, EA + spiperone group, and pergolide. The middle cerebral artery occlusion (MCAO) model was used in all 6 groups except the normal group. A behavioural assessment was conducted at 1, 3, 5, and 7 days after MCAO. The percent of brain infarct area was also determined 7 days after MCAO. Tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP-43) fluorescence double labeling was performed in the striatum. Results. In this study, we found that EA at Fengchi (GB20) acupoints resulted in marked improvements based on a behavioural assessment. Both TTC staining and GAP-43 immunofluorescence labeling results showed that EA treatment reduced ischemia injury and promoted neuroplasticity compared with the model group. The D2R-selective agonist, pergolide, showed similar results, but these results were reversed by the D2R-selective antagonist, spiperone. We also found that there were more colocalization and expression of GAP-43 and TH in the EA and pergolide groups than those in the other groups. Conclusion. These results suggest that the neuroplasticity induced by EA was mediated by D2 autoreceptors in DAergic neurons. PMID:24348687

Xu, Ming-Shu; Zhang, Shu-Jing; Zhao, Dan; Liu, Cheng-Yong; Li, Chang-Zhi; Chen, Chun-Yan; Li, Li-Hui; Li, Ming-Zhe; Xu, Jia; Ge, Lin-Bao



Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats  

Microsoft Academic Search

Rationale.  \\u000a A growing literature indicates that increased dopamine transmission in the nucleus accumbens contributes to priming-induced\\u000a reinstatement of cocaine-seeking behavior.\\u000a \\u000a \\u000a \\u000a Objectives.  \\u000a The present experiments were designed to assess the role of D1-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug\\u000a seeking.\\u000a \\u000a \\u000a \\u000a Methods.  \\u000a Rats were trained to lever press for cocaine using a

Sharon M. Anderson; Ausaf A. Bari; R. Christopher Pierce



Nucleostemin Depletion Induces Post-G1 Arrest Apoptosis in Chronic Myelogenous Leukemia K562 Cells  

PubMed Central

Purpose: Despite significant improvements in treatment of chronic myelogenous leukemia (CML), the emergence of leukemic stem cell (LSC) concept questioned efficacy of current therapeutical protocols. Remaining issue on CML includes finding and targeting of the key genes responsible for self-renewal and proliferation of LSCs. Nucleostemin (NS) is a new protein localized in the nucleolus of most stem cells and tumor cells which regulates their self-renewal and cell cycle progression. The aim of this study was to investigate effects of NS knocking down in K562 cell line as an in vitro model of CML. Methods: NS gene silencing was performed using a specific small interfering RNA (NS-siRNA). The gene expression level of NS was evaluated by RT-PCR. The viability and growth rate of K562 cells were determined by trypan blue exclusion test. Cell cycle distribution of the cells was analyzed by flow cytometry. Results: Our results showed that NS knocking down inhibited proliferation and viability of K562 cells in a time-dependent manner. Cell cycle studies revealed that NS depletion resulted in G1 cell cycle arrest at short times of transfection (24 h) followed with apoptosis at longer times (48 and 72 h), suggest that post-G1 arrest apoptosis is occurred in K562 cells. Conclusion: Overall, these results point to essential role of NS in K562 cells, thus, this gene might be considered as a promising target for treatment of CML. PMID:24409410

Seyed-Gogani, Negin; Rahmati, Marveh; Zarghami, Nosratollah; Asvadi-Kermani, Iraj; Hoseinpour-Feyzi, Mohammad Ali; Moosavi, Mohammad Amin



Thin liquid film structure and stability: The role of depletion and surface-induced structural forces  

SciTech Connect

Film stability and structure formation inside a liquid film containing colloidal particles are investigated by Monte Carlo (MC) numerical simulations and by analytical methods. The effective pair interaction between particles is calculated from the Ornstein--Zernike theory with Percus--Yevick closure. Consistent with the recent experimental observations and theoretical studies, these MC simulations reveal the phenomena of internal particle layering as well as inlayer structure formation. In particular, an ordered two-dimensional hexagonal structure is observed at a particle concentration of 37 vol% (instead of 43 vol% for the hard-sphere potential) when the effective pair interaction between particles is taken into account. Furthermore, the particles inside a layer ``condense`` due to the attractive depletion force which leads to the formation of voids. The formation of such void structures results in the formation of ``dark spots`` which have been observed in film thinning experiments. The calculated film structural disjoining pressure, created by the particles inside the film, is found to be in agreement with the experimentally measured force-distance curves using the surface force apparatus. {copyright} {ital 1995} {ital American} {ital Institute} {ital of} {ital Physics}.

Chu, X.L.; Nikolov, A.D.; Wasan, D.T. [Department of Chemical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616 (United States)] [Department of Chemical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616 (United States)



Maillard reaction products in purified diets induce taurine depletion in cats which is reversed by antibiotics.  


The effects of heat processing (Maillard reaction) and addition of antibiotics to diets on the metabolism of taurine in adult cats were studied. Groups of four cats were given daily 22 g/kg body weight one of four purified diets based on casein and starch. All diets contained the same major ingredients as the control (diet 1), except for starch substitutions. Diet 2 was autoclaved; in diet 3, 50 g glucose replaced 50 g starch before autoclaving; in diet 4, only the casein component was autoclaved with 50 g glucose before addition to the diet. Diets were fed for 5 wk, then a mixture of antibiotics was added to all diets and they were fed for a further 5 wk. In the first (no antibiotics) period, cats given the Maillard reaction products (diets 3 and 4) had a significant depletion of plasma and whole blood taurine and had twice the fecal, but less than half the urinary total taurine excretion of control cats. The addition of antibiotics to the diets restored plasma and whole blood concentration in cats given diets 3 and 4, reduced fecal and increased urinary taurine excretion, and decreased fecal cholyltaurine hydrolase activity. These results suggest that Maillard reaction products promote an enteric flora that favors degradation of taurine and decreases recycling of taurine by the enterohepatic route. PMID:8558301

Kim, S W; Rogers, Q R; Morris, J G



Nitric oxide-mediated depletion of Langerhans cells from the epidermis may be involved in UVA radiation-induced immunosuppression.  


Ultraviolet A (UVA) irradiation of the dorsal skin of mice reduced the contact hypersensitivity (CHS) response and the density of epidermal Langerhans cells (LC). The roles of nitric oxide (NO) and reactive oxygen species (ROS) in these biological effects of UVA were investigated. Topical application of N(G)-monomethyl-L-arginine acetate, an inhibitor of NO production, 2,2'-dipyridyl, an iron chelater, or 4-hydroxy-tempo, a superoxide dismutase mimicking agent, inhibited UVA-induced suppression of the CHS response. N(G)-monomethyl-L-arginine acetate but not the ROS inhibitors prevented UVA from reducing LC numbers in the epidermis. This suggests that NO but not ROS produced in response to UVA mediates a depletion of LC from the epidermis, probably by signaling these cells to migrate from the skin. This could be responsible for UVA-induced immunosuppression. UVA-induced ROS can also cause immunosuppression, but by a different mechanism. Agents that inhibit or modulate NO or ROS production may be useful for preventing damage caused by the UVA component of sunlight to the skin immune system. PMID:12009849

Yuen, Kylie S; Nearn, Malcolm R; Halliday, Gary M



Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein ? pathway  

PubMed Central

Although uncontrolled inflammatory response plays a central role in the pathogenesis of acute lung injury (ALI), the precise molecular mechanisms underlying the development of this disorder remain poorly understood. SOCS3 is an important negative regulator of IL-6-type cytokine signaling. SOCS3 is induced in lung during LPS-induced lung injury, suggesting that generation of SOCS3 may represent a regulatory product during ALI. In the current study, we created mice lacking SOCS3 expression in macrophages and neutrophils (LysM-cre SOCS3fl/fl). We evaluated the lung inflammatory response to LPS in both LysM-cre SOCS3fl/fl mice and the wild-type (WT) mice (SOCS3fl/fl). LysM-cre SOCS3fl/fl mice displayed significant increase of the lung permeability index (lung vascular leak of albumin), neutrophils, lung neutrophil accumulation (myeloperoxidase activity), and proinflammatory cytokines/chemokines in bronchial alveolar lavage fluids compared to WT mice. These phenotypes were consistent with morphological evaluation of lung, which showed enhanced inflammatory cell influx and intra-alveolar hemorrhage. We further identify the transcription factor, CCAAT/enhancer-binding protein (C/EBP) ? as a critical downstream target of SOCS3 in LPS-induced ALI. These results indicate that SOCS3 has a protective role in LPS-induced ALI by suppressing C/EBP? activity in the lung. Elucidating the function of SOCS3 would represent prospective targets for a new generation of drugs needed to treat ALI.—Yan, C., Ward, P. A., Wang, X., Gao, H. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein ? pathway. PMID:23585399

Yan, Chunguang; Ward, Peter A.; Wang, Ximo; Gao, Hongwei



Acetic Acid Induces pH-Independent Cellular Energy Depletion in Salmonella enterica.  


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

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



Nutr Cancer . Author manuscript Freeze-dried ham promotes azoxymethane-induced mucin-depleted foci  

E-print Network

Nutr Cancer . Author manuscript Page /1 9 Freeze-dried ham promotes azoxymethane-induced mucin and red meat consumption is associated with the risk of colorectal cancer. Meta-analyses have suggested. The promoting effect of a freeze-dried, cooked, cured ham diet was looked for in a 100-day study. Colon

Paris-Sud XI, Université de


Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson's disease: a review.  


The spatiotemporal progression of dopamine depletion in Parkinson's disease (PD) provides a special model for assessing dopaminergic effects on neural systems with differential baseline dopamine levels. This study aims at reviewing cognitive effects of dopaminergic stimulation in PD. While considering dopaminergic drugs (levodopa or dopamine agonists), temporal intervals (acute or chronic) and cognitive domains, we found that empirical evidence was almost focused on acute effects of levodopa on executive functions. The paucity of empirical evidence suggests that no meaningful conclusions can be actually drawn and further research is needed in relation to: (1) other cognitive domains; (2) the acute cognitive effects of dopamine agonists, as compared with levodopa; (3) possible differences between cognitive effects of different dopamine agonists; (4) the cognitive effects of chronic dopaminergic therapies. The latter issue is of particular clinical interest considering that many PD patients present a mild cognitive impairment: is this cognitive feature worsened or improved by the prolonged dopaminergic therapy? In addition to the potential risk of inducing dyskinesia and behavioral side effects such as impulse control disorders, also cognitive effects of prolonged dopaminergic treatments should be taken in account by clinicians in order to anticipate or to delay their prescription to PD patients. PMID:24167681

Poletti, Michele; Bonuccelli, Ubaldo



Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission  

Microsoft Academic Search

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2\\/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in

Monica M Marcus; Kent Jardemark; Anna Malmerfelt; Carl Björkholm; Torgny H Svensson



Effects of selective D-1 and D-2 dopamine antagonists on development of methamphetamine-induced behavioral sensitization  

Microsoft Academic Search

The present study examined effects of selective antagonists of D-1 and D-2 dopamine receptors on the development of behavioral sensitization produced by repeated methamphetamine (MAP) administration. Male Sprague-Dawley rats were divided into four groups. Each group received a daily injection of saline (control group), 4 mg\\/kg MAP (MAP group), 1 mg\\/kg YM-09151-2 plus 4 mg\\/kg MAP (YM+MAP group) or 0.5

Hiroshi Ujike; Taichi Onoue; Kazufumi Akiyama; Takashi Hamamura; Saburo Otsuki



Methylenedioxymethamphetamine-induced inhibition of neuronal firing in the nucleus accumbens is mediated by both serotonin and dopamine  

Microsoft Academic Search

Methylenedioxymethamphetamine (MDMA) is a mood-altering, legally-restricted drug that has been reported to inhibit glutamate-evoked firing of cells in the nucleus accumbens. This study used extracellular recording combined with microiontophoresis to examine whether the inhibitory effect of MDMA on neuronal firing in the nucleus accumbens is mediated by serotonin and\\/or dopamine. Serotonin and serotonin agonists with relative selectivity for the receptor

T Obradovic; K. M Imel; S. R White



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

Microsoft Academic Search

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

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



l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells.  


Enzymatic depletion of the nonessential amino acid l-Arginine (l-Arg) in patients with cancer by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, l-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T cells. Strikingly, we found that peg-Arg I blocked proliferation and cell-cycle progression in normal activated T cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T cells exposed to peg-Arg I. Further mechanistic investigations showed that the addition of citrulline, a metabolic precursor for l-Arg, rescued the antiproliferative effects of peg-Arg I on T cells in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control nonrepressed-2 eIF2? kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the l-Arg-depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings. PMID:25406192

Fletcher, Matthew; Ramirez, Maria E; Sierra, Rosa A; Raber, Patrick; Thevenot, Paul; Al-Khami, Amir A; Sanchez-Pino, Dulfary; Hernandez, Claudia; Wyczechowska, Dorota D; Ochoa, Augusto C; Rodriguez, Paulo C



Serum depletion of holo-ceruloplasmin induced by silver ions in vivo reduces uptake of cisplatin.  


There is an emerging link between extracellular copper concentration and the uptake of cisplatin mediated by copper transporter CTR1 in cell cultures and unicellular eukaryotes. To test the link between extracellular copper level and cisplatin uptake by organs in vivo we used mice with low copper status parameters induced by AgCl-containing diet (Ag-mice). In Ag-mice, serum copper status and liver copper metabolism were characterized. It was shown that the expression level of copper transporter genes and activity of ubiquitous intracellular cuproenzymes were not affected but the level of serum holo-ceruloplasmin was not detectable. Silver was selectively absorbed by liver and accumulated in the mitochondrial matrix. Silver was present in an exchangeable form and was excreted through bile. Ag-mice model is characterized by high reproducibility, reversibility, synchronicity, and definiteness of ceruloplasmin-associated copper deficiency. After cisplatin treatment Ag-mice, as compared to control mice, demonstrated the delay in platinum uptake by organs during first 30 min. This effect was not observed at later time points probably due to cisplatin induced copper release to blood, which resulted in the recovery of copper status. These data allowed us to conclude that cisplatin uptake was coupled to copper transport in vivo. PMID:23018271

Zatulovskiy, Evgeny A; Skvortsov, Alexey N; Rusconi, Paolo; Ilyechova, Ekaterina Yu; Babich, Polina S; Tsymbalenko, Nadezhda V; Broggini, Massimo; Puchkova, Ludmila V



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

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.

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



Suppression of Induced microRNA-15b Prevents Rapid Loss of Cardiac Function in a Dicer Depleted Model of Cardiac Dysfunction  

PubMed Central

Background Dicer endonuclease, critical for maturation of miRNAs, is depleted in certain forms of cardiomyopathy which results in differential expression of certain microRNAs. We sought to elucidate the mechanisms underlying the rapid loss of cardiac function following cardiac-specific Dicer depletion in adult mice. Results Conditional Dicer deletion in the adult murine myocardium demonstrated compromised heart function, mitochondrial dysfunction and oxidant stress. Elevated miR-15b was observed as an early response to Dicer depletion and was found to silence Pim-1 kinase, a protein responsible for maintaining mitochondrial integrity and function. Anti-miRNA based suppression of induced miRNA-15b rescued the function of Dicer-depleted adult heart and attenuated hypertrophy. Conclusions Anti-miRNA based suppression of inducible miRNA-15b can prevent rapid loss of cardiac function in a Dicer-depleted adult heart and can be a key approach worthy of therapeutic consideration. PMID:23840532

Gnyawali, Surya C.; Khanna, Savita; He, Guanglong; Pfeiffer, Douglas; Zweier, Jay L.; Sen, Chandan K.



Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest  

PubMed Central

The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this impacts the mechanisms that maintain genomic stability is unclear. Here, we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal ?-H2AX focus formation but a higher frequency of cells with delayed ?-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea-induced replication stress, lamin A/C-deficient cells had an increased frequency of cells with delayed disappearance of ?-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data can be interpreted to suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair. PMID:23319047

Singh, Mayank; Hunt, Clayton R.; Pandita, Raj K.; Kumar, Rakesh; Yang, Chin-Rang; Horikoshi, Nobuo; Bachoo, Robert; Serag, Sara; Story, Michael D.; Shay, Jerry W.; Powell, Simon N.; Gupta, Arun; Jeffery, Jessie; Pandita, Shruti; Chen, Benjamin P. C.; Deckbar, Dorothee; Löbrich, Markus; Yang, Qin; Khanna, Kum Kum; Worman, Howard J.



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


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

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



Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity  

SciTech Connect

This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. -- Highlights: ? AAI-induced acute renal failure in rats and the proximal tubule was the target. ? Tubular mitochondria were morphologically aberrant in ultrastructural examination. ? AAI impair mitochondrial bioenergetic function and mtDNA replication.

Jiang, Zhenzhou, E-mail:; Bao, Qingli, E-mail:; Sun, Lixin, E-mail:; Huang, Xin, E-mail:; Wang, Tao, E-mail:; Zhang, Shuang, E-mail:; Li, Han, E-mail:; Zhang, Luyong, E-mail:



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

PubMed Central

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

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



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


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

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



Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland  

SciTech Connect

Research highlights: {yields} We focused on the rat pituitary intermediate lobe (IL) under continuous stress (CS). {yields} CS induced PAP-I and PAP-II expression in melanotrophs of the IL. {yields} This gene induction was triggered by CS-related dopamine dysregulation. {yields} PAP-I and PAP-II may sustain homeostasis of the IL under CS. -- Abstract: Under continuous stress (CS) in rats, melanotrophs, the predominant cell-type in the intermediate lobe (IL) of the pituitary, are hyperactivated to secrete {alpha}-melanocyte-stimulating hormone and thereafter degenerate. Although these phenomena are drastic, the molecular mechanisms underlying the cellular changes are mostly unknown. In this study, we focused on the pancreatitis-associated protein (PAP) family members of the secretory lectins and characterized their expression in the IL of CS model rats because we had identified two members of this family as up-regulated genes in our previous microarray analysis. RT-PCR and histological studies demonstrated that prominent PAP-I and PAP-II expression was induced in melanotrophs in the early stages of CS, while another family member, PAP-III, was not expressed. We further examined the regulatory mechanisms of PAP-I and PAP-II expression and revealed that both were induced by the decreased dopamine levels in the IL under CS. Because the PAP family members are implicated in cell survival and proliferation, PAP-I and PAP-II secreted from melanotrophs may function to sustain homeostasis of the IL under CS conditions in an autocrine or a paracrine manner.

Konishi, Hiroyuki, E-mail: [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan) [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program 'Base to Overcome Fatigue', Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan); Ogawa, Tokiko, E-mail: [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan) [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program 'Base to Overcome Fatigue', Osaka City University Graduate School of Medicine, Osaka (Japan); Kawahara, Shinichi, E-mail: [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan)] [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); Matsumoto, Sakiko, E-mail: [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan) [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan); Kiyama, Hiroshi, E-mail: [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan) [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program 'Base to Overcome Fatigue', Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan)



Synapsins Differentially Control Dopamine and Serotonin Release  

PubMed Central

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

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



Synapsins differentially control dopamine and serotonin release.  


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

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



Extracellular sodium and chloride depletion enhances nonexocytotic noradrenaline release induced by energy deficiency in rat heart.  


The effect of either extracellular sodium or extracellular chloride reduction on the release of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylglycol (DOPEG) has been studied in the isolated perfused rat heart under conditions of ischaemia and cyanide intoxication. The overflow of noradrenaline and DOPEG was determined by high pressure liquid chromatography. The efflux of DOPEG, the predominant neuronal noradrenaline adrenaline metabolite, served as indicator of the free axoplasmic plasmic amine concentration. A calcium-free perfusion buffer was used to avoid exocytotic noradrenaline release. Sodium and chloride in the perfusion buffer were replaced by lithium and isethionate, respectively. (1) Reduction of extracellular sodium or chloride increased noradrenaline overflow in ischaemia. The release was suppressed by the uptake1 blocker cocaine indicating carrier-mediated outward transport of noradrenaline. (2) In cyanide intoxication sodium or chloride reduction accelerated the onset of DOPEG efflux reflecting increased axoplasmic noradrenaline concentrations. This was accompanied by increased noradrenaline release. The ratio of noradrenaline/DOPEG overflow was increased by reduced sodium or chloride, indicating facilitation of carrier-mediated noradrenaline net outward transport. (3) In the presence of unaltered energy metabolism overflow of both, noradrenaline and DOPEG, was not enhanced by sodium or chloride reduction. The results demonstrate that reduction of extracellular sodium or chloride has two effects on noradrenaline release from the sympathetic neuron with reduced energy supply. First, reduced sodium or chloride induces increased axoplasmic noradrenaline concentrations by interference with vesicular storage function. Second, both interventions enhance carrier-mediated noradrenaline release. PMID:2812038

Kurz, T; Schömig, A



Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine  

PubMed Central

Purpose: Methimazole is the most convenient drug used in the management of hyperthyroid patients. However, associated with its clinical use is hepatotoxicity as a life threatening adverse effect. The exact mechanism of methimazole-induced hepatotoxicity is still far from clear and no protective agent has been developed for this toxicity. Methods: This study attempts to evaluate the hepatotoxicity induced by methimazole at different experimental conditions in a mice model. Methimazole-induced hepatotoxicity was investigated in different situations such as enzyme induced and/or glutathione depleted animals. Results: Methimazole (100 mg/kg, i.p) administration caused hepatotoxicity as revealed by increase in serum alanine aminotransferase (ALT) activity as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in methimazole-treated mice. Combined administration of L-buthionine sulfoximine (BSO), as a glutathione depletory agent, caused a dramatic change in methimazole-induced hepatotoxicity characterized by hepatic necrosis and a severe elevation of serum ALT activity. Enzyme induction using phenobarbital and/or ?-naphtoflavone beforehand, deteriorated methimazole-induced hepatotoxicity in mice. N-acetyl cysteine (300 mg/kg, i.p) administration effectively alleviated hepatotoxic effects of methimazole in both glutathione-depleted and/or enzyme induced animals. Conclusion: The severe hepatotoxic effects of methimazole in glutathione-depleted animals, reveals the crucial role of glutathione as a cellular defense mechanism against methimazole-induced hepatotoxicity. Furthermore, the more hepatotoxic properties of methimazole in enzyme-induced mice, indicates the role of reactive intermediates in the hepatotoxicity induced by this drug. The protective effects of N-acetylcysteine could be attributed to its radical/reactive metabolite scavenging, and/or antioxidant properties as well as glutathione replenishment activities. PMID:24409405

Heidari, Reza; Babaei, Hossein; Roshangar, Leila; Eghbal, Mohammad Ali



Freeze-dried ham promotes azoxymethane-induced mucin-depleted foci and aberrant crypt foci in rat colon  

PubMed Central

Processed and red meat consumption is associated with the risk of colorectal cancer. Meta-analyses have suggested that the risk associated with processed meat is higher. Most processed meats are cured and cooked, which leads to formation of free nitrosyl heme. We speculated that free nitrosyl heme is more toxic than native myoglobin. The promoting effect of a freeze-dried, cooked, cured ham diet was looked for in a 100-day study. Colon carcinogenesis endpoints were aberrant crypt foci and mucin depleted foci (MDF). A second study (14 days) was designed 1) to compare the effect of ham, hemoglobin, and hemin; and 2) to test the effect of sodium chloride, nitrite, and phosphate in diet on early biomarkers associated with heme-induced promotion. In the 100-day study, control and ham-fed rats had 3.5 and 8.5 MDF/colon, respectively (P < 0.0001). Promotion was associated with cytotoxicity and lipid peroxidation. In the short-term study, cytotoxicity and lipid peroxidation of fecal water, and the urinary marker of lipid peroxidation, increased dramatically in ham- and hemin-fed rat. In contrast, the hemoglobin diet, sodium chloride, nitrite, phosphate diet had no effect. Freeze-dried cooked ham can promote colon carcinogenesis in a rodent model. Hemin, but not hemoglobin, mimicked ham effect on early biochemical markers associated with carcinogenesis. PMID:20574917

Pierre, Fabrice; Santarelli, Raphaëlle L; Chartron, Mickael; Allam, Ossama; Taché, Sylviane; Naud, Nathalie; Guéraud, Francoise; Corpet, Denis E



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

SciTech Connect

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.

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:



Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms  

Microsoft Academic Search

Background  Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms\\u000a (EPS) during treatment with antipsychotic drugs.\\u000a \\u000a \\u000a \\u000a Methods  Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism,\\u000a tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight

Cüneyt Güzey; Maria Gabriella Scordo; Edoardo Spina; Veslemøy Malm Landsem; Olav Spigset



Cutting edge: Experimentally induced immune activation in natural hosts of simian immunodeficiency virus induces significant increases in viral replication and CD4+ T cell depletion.  


Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable nonpathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and with stable viral loads for long periods of time. In vivo administration of 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(+) 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 proliferation are key factors in AIDS pathogenesis. PMID:18981083

Pandrea, Ivona; Gaufin, Thaidra; Brenchley, Jason M; Gautam, Rajeev; Monjure, Christopher; Gautam, Aarti; Coleman, Clint; Lackner, Andrew A; Ribeiro, Ruy M; Douek, Daniel C; Apetrei, Cristian



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

SciTech Connect

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.

Ribeiro, Ruy M [Los Alamos National Laboratory



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


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

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



Na+ appetite induced by depleting extracellular fluid volume activates the enkephalin/mu-opioid receptor system in the rat forebrain.  


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

Grondin, M-E; Gobeil-Simard, A; Drolet, G; Mouginot, D



Feedback inhibition by thiols outranks glutathione depletion: a luciferase-based screen reveals glutathione-deficient ?-ECS and glutathione synthetase mutants impaired in cadmium-induced sulfate assimilation.  


Plants exposed to heavy metals rapidly induce changes in gene expression that activate and enhance detoxification mechanisms, including toxic-metal chelation and the scavenging of reactive oxygen species. However, the mechanisms mediating toxic heavy metal-induced gene expression remain largely unknown. To genetically elucidate cadmium-specific transcriptional responses in Arabidopsis, we designed a genetic screen based on the activation of a cadmium-inducible reporter gene. Microarray studies identified a high-affinity sulfate transporter (SULTR1;2) among the most robust and rapid cadmium-inducible transcripts. The SULTR1;2 promoter (2.2?kb) was fused with the firefly luciferase reporter gene to quantitatively report the transcriptional response of plants exposed to cadmium. Stably transformed luciferase reporter lines were ethyl methanesulfonate (EMS) mutagenized, and stable M(2) seedlings were screened for an abnormal luciferase response during exposure to cadmium. The screen identified non-allelic mutant lines that fell into one of three categories: (i) super response to cadmium (SRC) mutants; (ii) constitutive response to cadmium (CRC) mutants; or (iii) non-response and reduced response to cadmium (NRC) mutants. Two nrc mutants, nrc1 and nrc2, were mapped, cloned and further characterized. The nrc1 mutation was mapped to the ?-glutamylcysteine synthetase gene and the nrc2 mutation was identified as the first viable recessive mutant allele in the glutathione synthetase gene. Moreover, genetic, HPLC mass spectrometry, and gene expression analysis of the nrc1 and nrc2 mutants, revealed that intracellular glutathione depletion alone would be insufficient to induce gene expression of sulfate uptake and assimilation mechanisms. Our results modify the glutathione-depletion driven model for sulfate assimilation gene induction during cadmium stress, and suggest that an enhanced oxidative state and depletion of upstream thiols, in addition to glutathione depletion, are necessary to induce the transcription of sulfate assimilation genes during early cadmium stress. PMID:22283708

Jobe, Timothy O; Sung, Dong-Yul; Akmakjian, Garo; Pham, Allis; Komives, Elizabeth A; Mendoza-Cózatl, David G; Schroeder, Julian I



Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT-1.  


Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for > 90% of cortical glutamate uptake. The effect of dopamine depletion on glutamate transporters in the prefrontal cortex (PFC) remains unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters. PFC dopamine denervation elicited a marked increase in GLT-1 protein levels, but had no effect on levels of other glutamate transporters; high-affinity glutamate transport was positively correlated with the extent of dopamine depletion. GLT-1 gene expression was not altered. Our data suggest that dopamine depletion may lead to post-translational modifications that result in increased expression and activity of GLT-1 in PFC astrocytes. The glutamate transporter GLT-1 is expressed by astrocytes, which also express dopamine receptors. Regulation of prefrontal cortical (PFC) GLT-1 potentially offers a novel treatment approach to the cognitive deficits of schizophrenia. Partial PFC dopamine deafferentation increased membrane expression of GLT-1 protein and glutamate uptake, but did not alter levels of the other two neocortical glutamate transporters, GLAST and EAAC1. PMID:24611756

Vollbrecht, Peter J; Simmler, Linda D; Blakely, Randy D; Deutch, Ariel Y



Deep brain stimulation of the nucleus accumbens shell induces anti-obesity effects in obese rats with alteration of dopamine neurotransmission.  


The aim of this study was to assess the anti-obesity effects of nucleus accumbens shell (NAc-sh) deep brain stimulation (DBS) in diet-induced obese (DIO) and chow-fed (chow) rats. The influence of DBS on dopamine (DA) signaling in the NAc-sh was also evaluated. DIO and chow rats were subjected to DBS for 14 consecutive days. Food intake and weight gain were measured daily. The gene expression of the dopamine D1 and D2 receptors was evaluated by qPCR. In addition, the extracellular levels of DA and its metabolite, dihydroxyphenylacetic acid (DOPAC), were determined by microdialysis. We observed that chronic DBS induced significant reductions in total energy intake (596.0±65.0kcal vs. 1161.6±22.2kcal, p<0.001) and weight gain (1.45±0.57% vs. 9.64±0.38%, p<0.001) in DIO rats compared to sham-DIO rats. Up-regulated D2 receptor gene expression (2.43±0.12 vs. 0.64±0.04, p<0.001) and increased DA levels (2.73±0.15pmol/mL vs. 0.62±0.05pmol/mL, p<0.001) were observed in DIO rats compared to sham-DIO rats. DBS had no influence on food intake, weight gain, or DA neurotransmission in chow rats. Our results support an association of the anorexigenic effects of NAc-sh DBS with mesolimbic DA signaling and indicate that the positive alteration of DA function in DIO rats may be responsible for the different effects of DBS in DIO and chow rats. PMID:25578952

Zhang, Chao; Wei, Nai-Li; Wang, Yao; Wang, Xiu; Zhang, Jian-Guo; Zhang, Kai



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.


Ozone Depletion  

NSDL National Science Digital Library

The ozone layer forms a thin shield in the upper atmosphere, protecting life onEarth from the suns ultraviolet (UV) rays. In the 1980s, scientists began accumulating evidence that the ozone layer was being depleted. Depletion of the ozone layer results in increased UV radiation reaching the Earths surface, which in turn can lead to a greater chance of overexposure to UV radiation and the related health effects of skin cancer, cataracts, and immune suppression.

U.S. Environmental Protection Agency (EPA; Office of Air and Radiation)



After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance  

PubMed Central

Bingeing on sugar may activate neural pathways in a manner similar to taking drugs of abuse, resulting in related signs of dependence. The present experiments test whether rats that have been bingeing on sucrose and then fasted demonstrate signs of opiate-like withdrawal. Rats were maintained on 12-h deprivation followed by 12-h access to a 10% sucrose solution and chow for 28 days, then fasted for 36 h. These animals spent less time on the exposed arm of an elevated plus-maze compared with a similarly deprived ad libitum chow group, suggesting anxiety. Microdialysis revealed a concomitant increase in extracellular acetylcholine and decrease in dopamine release in the nucleus accumbens shell. These results did not appear to be due to hypoglycemia. The findings suggest that a diet of bingeing on sucrose and chow followed by fasting creates a state that involves anxiety and altered accumbens dopamine and acetylcholine balance. This is similar to the effects of naloxone, suggesting opiate-like withdrawal. This may be a factor in some eating disorders. PMID:18325546

Avena, Nicole M.; Bocarsly, Miriam E.; Rada, Pedro; Kim, Agnes; Hoebel, Bartley G.



After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance.  


Bingeing on sugar may activate neural pathways in a manner similar to taking drugs of abuse, resulting in related signs of dependence. The present experiments test whether rats that have been bingeing on sucrose and then fasted demonstrate signs of opiate-like withdrawal. Rats were maintained on 12-h deprivation followed by 12-h access to a 10% sucrose solution and chow for 28 days, then fasted for 36 h. These animals spent less time on the exposed arm of an elevated plus-maze compared with a similarly deprived ad libitum chow group, suggesting anxiety. Microdialysis revealed a concomitant increase in extracellular acetylcholine and decrease in dopamine release in the nucleus accumbens shell. These results did not appear to be due to hypoglycemia. The findings suggest that a diet of bingeing on sucrose and chow followed by fasting creates a state that involves anxiety and altered accumbens dopamine and acetylcholine balance. This is similar to the effects of naloxone, suggesting opiate-like withdrawal. This may be a factor in some eating disorders. PMID:18325546

Avena, Nicole M; Bocarsly, Miriam E; Rada, Pedro; Kim, Agnes; Hoebel, Bartley G



Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice.  


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

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



Kinetics of carotenoid distribution in human skin in vivo after exogenous stress: disinfectant and wIRA-induced carotenoid depletion recovers from outside to inside  

NASA Astrophysics Data System (ADS)

The human organism has developed a protection system against the destructive effect of free radicals. The aim of the present study was to investigate the extent of exogenous stress factors such as disinfectant and IR-A radiation on the skin, and their influence on the kinetics of carotenoids distribution during the recovery process. Ten healthy volunteers were assessed with resonance spectroscopy using an Argon-laser at 488 nm to excite the carotenoids in vivo. Additionally, Raman-confocal-micro-spectroscopy measurements were performed using a model 3510 Skin Composition Analyzer with spatially resolved measurements down to 30 ?m. The measurements were performed at a baseline of 20, 40, 60, and 120 min after an external stressor consisting either of water-filtered infrared A (wIRA) with 150 mW/cm2 or 1 ml/cm2 of an alcoholic disinfectant. Both Raman methods were capable to detect the infrared-induced depletion of carotenoids. Only Raman-microspectroscopy could reveal the carotenoids decrease after topical disinfectant application. The carotenoid-depletion started at the surface. After 60 min, recovery starts at the surface while deeper parts were still depleted. The disinfectant- and wIRA-induced carotenoid depletion in the epidermis recovers from outside to inside and probably delivered by sweat and sebaceous glands. We could show that the Raman microscopic spectroscopy is suited to analyze the carotenoid kinetic of stress effects and recovery.

Fluhr, Joachim W.; Caspers, Peter; van der Pol, J. Andre; Richter, Heike; Sterry, Wolfram; Lademann, Juergen; Darvin, Maxim E.



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


The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease. PMID:25447236

Masoud, S T; Vecchio, L M; Bergeron, Y; Hossain, M M; Nguyen, L T; Bermejo, M K; Kile, B; Sotnikova, T D; Siesser, W B; Gainetdinov, R R; Wightman, R M; Caron, M G; Richardson, J R; Miller, G W; Ramsey, A J; Cyr, M; Salahpour, A



Farnesol-Induced Apoptosis in Candida albicans Is Mediated by Cdr1-p Extrusion and Depletion of Intracellular Glutathione  

PubMed Central

Farnesol is a key derivative in the sterol biosynthesis pathway in eukaryotic cells previously identified as a quorum sensing molecule in the human fungal pathogen Candida albicans. Recently, we demonstrated that above threshold concentrations, farnesol is capable of triggering apoptosis in C. albicans. However, the exact mechanism of farnesol cytotoxicity is not fully elucidated. Lipophilic compounds such as farnesol are known to conjugate with glutathione, an antioxidant crucial for cellular detoxification against damaging compounds. Glutathione conjugates act as substrates for ATP-dependent ABC transporters and are extruded from the cell. To that end, this current study was undertaken to validate the hypothesis that farnesol conjugation with intracellular glutathione coupled with Cdr1p-mediated extrusion of glutathione conjugates, results in total glutathione depletion, oxidative stress and ultimately fungal cell death. The combined findings demonstrated a significant decrease in intracellular glutathione levels concomitant with up-regulation of CDR1 and decreased cell viability. However, addition of exogenous reduced glutathione maintained intracellular glutathione levels and enhanced viability. In contrast, farnesol toxicity was decreased in a mutant lacking CDR1, whereas it was increased in a CDR1-overexpressing strain. Further, gene expression studies demonstrated significant up-regulation of the SOD genes, primary enzymes responsible for defense against oxidative stress, with no changes in expression in CDR1. This is the first study describing the involvement of Cdr1p-mediated glutathione efflux as a mechanism preceding the farnesol-induced apoptotic process in C. albicans. Understanding of the mechanisms underlying farnesol-cytotoxicity in C. albicans may lead to the development of this redox-cycling agent as an alternative antifungal agent. PMID:22205973

Zhu, Jingsong; Krom, Bastiaan P.; Sanglard, Dominique; Intapa, Chaidan; Dawson, Clinton C.; Peters, Brian M.; Shirtliff, Mark E.; Jabra-Rizk, Mary Ann



Dopamine D2 Receptors Act Upstream of AVP in the Latero-Anterior Hypothalamus to Modulate Adolescent Anabolic/Androgenic Steroid-Induced Aggression in Syrian Hamsters  

PubMed Central

In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), i.e., a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the co-infusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. PMID:25798632

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.



Dopamine D2 receptors act upstream of AVP in the latero-anterior hypothalamus to modulate adolescent anabolic/androgenic steroid-induced aggression in Syrian hamsters.  


In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), that is, a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the coinfusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. (PsycINFO Database Record PMID:25798632

Morrison, Thomas R; Ricci, Lesley A; Melloni, Richard H



Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release.  


Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

Pehek, E A; Hernan, A E



Ephedrine induced thioredoxin-1 expression through ?-adrenergic receptor/cyclic AMP/protein kinase A/dopamine- and cyclic AMP-regulated phosphoprotein signaling pathway.  


Ephedrine (Eph) is one of alkaloids that has been isolated from the ancient herb ephedra (ma huang) and is used as the treatment of asthma, hypotension and fatigue. However, its molecular mechanism remains unknown. Thioredoxin-1 (Trx-1) is a redox regulating protein, which has various biological activities, including regulating transcription factor DNA binding activity and neuroprotection. In this study, we found that Eph induced Trx-1 expression, which was inhibited by propranolol (?-adrenergic receptor inhibitor), but not by phenoxybenzamine (?-adrenergic receptor inhibitor) in rat pheochromocytoma PC12 cells. Moreover, the increase of Trx-1 expression was inhibited by SQ22536 (adenylyl cyclase inhibitor) and H-89 (protein kinase A inhibitor). Interestingly, the effect of Eph on dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) was similar to Trx-1. Thus, the relationship between Trx-1 and DARPP-32 was further studied. The DARPP-32 siRNA significantly reduced Trx-1 expression, but Trx-1 siRNA did not exchange DARPP-32. These results suggested that Eph induced the Trx-1 expression through ?-adrenergic receptor/cyclic AMP/PKA/DARPP-32 signaling pathway. Furthermore, Eph induced PKA-mediated cyclic AMP response element-binding protein (CREB) phosphorylation. Down-regulation of DARPP-32 expression decreased phosphorylated CREB. In addition, Eph had a significant effect on the viability of the rat pheochromocytoma PC12 cells through ?-adrenergic receptors. Trx-1 may play an important role in the actions of Eph. PMID:23416460

Jia, Jin-Jing; Zeng, Xian-Si; Li, Ye; Ma, Sha; Bai, Jie



Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic deficits caused by methylenedioxymethamphetamine in mice.  


Methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that MDMA-induced neurotoxicity is mediated by oxidative stress probably due to the inhibition of mitochondrial complex I activity. In this study we investigated the contribution of dopamine (DA) to such effects. For this, we modulated the dopaminergic system of mice at the synthesis, uptake or metabolism levels. Striatal mitochondrial complex I activity was decreased 1 h after MDMA; an effect not observed in the striatum of DA depleted mice or in the hippocampus, a dopamine spare region. The DA precursor, L-dopa, caused a significant reduction of mitochondrial complex I activity by itself and exacerbated the dopaminergic deficits when combined with systemic MDMA. By contrast, no damage was observed when L-dopa was combined with intrastriatal injections of MDMA. On the other hand, dopamine uptake blockade using GBR 12909, inhibited both, the acute inhibition of complex I activity and the long-term dopaminergic toxicity caused by MDMA. Moreover, the inhibition of DA metabolism with the monoamine oxidase (MAO) inhibitor, pargyline, afforded a significant protection against MDMA-induced complex I inhibition and neurotoxicity. Taken together, these findings point to the formation of hydrogen peroxide subsequent to DA metabolism by MAO, rather than a direct DA-mediated mitochondrial complex I inhibition, and the contribution of a peripheral metabolite of MDMA, as the key steps in the chain of biochemical events leading to DA neurotoxicity caused by MDMA in mice. PMID:25666033

Barros-Miñones, L; Goñi-Allo, B; Suquia, V; Beitia, G; Aguirre, N; Puerta, E



p53-independent induction of p21waf1\\/cip1 contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells  

Microsoft Academic Search

We investigated the role of some key regulators of cell cycle in the activation of caspases during apoptosis of insulin-secreting cells after sustained depletion of GTP by a specific inosine 5?-monophosphate dehydrogenase inhibitor, mycophenolic acid (MPA). p21Waf1\\/Cip1 was significantly increased following MPA treatment, an event closely correlated with the time course of caspase activation under the same conditions. MPA-induced p21Waf1\\/Cip1

J X Huo; S A Metz; G D Li



Dopamine receptor dysregulation in hippocampus of aged rats underlies chronic pulsatile L-Dopa treatment induced cognitive and emotional alterations.  


L-Dopa is the major symptomatic therapy for Parkinson's disease, which commonly occurs in elderly patients. However, the effects of chronic use on mood and cognition in old subjects remain elusive. In order to compare the effects of a chronic pulsatile L-Dopa treatment on emotional and cognitive functions in young (3 months) and old (18 months) intact rats, an L-Dopa/carbidopa treatment was administered every 12 h over 4 weeks. Rats were assessed for behavioural despair (repeated forced swimming test, RFST), anhedonia (sucrose preference test, SPT) and spatial learning (Morris water maze, MWM) in the late phase of treatment (T). Neuronal expression of Fos in the hippocampus at the early and late phases of T, as well as after MWM was studied. The density and ratio of dopamine D5r, D3r and D2r receptors were also evaluated in the hippocampus using immunohistochemistry and confocal microscopy. Young rats showed similar patterns during behavioural tests, whereas aged treated rats showed increased immobility counts in RFST, diminished sucrose liquid intake in SPT, and spatial learning impairment during MWM. Fos expression was significantly blunted in the aged treated group after MWM. The density of D5r, D3r and D2r was increased in both aged groups. The treatment reduced the ratio of D5r/D3r and D5r/D2r in both groups. Moreover, aged treated subjects had significant lower values of D5r/D3r and higher values of D5r/D2r when compared with young treated subjects. These results indicate that chronic L-Dopa treatment in itself could trigger emotional and cognitive dysfunctions in elderly subjects through dopamine receptor dysregulation. PMID:24291463

Hernández, Vito S; Luquín, Sonia; Jáuregui-Huerta, Fernando; Corona-Morales, Aleph A; Medina, Mauricio P; Ruíz-Velasco, Silvia; Zhang, Limei



Dopamine-induced Exocytosis of Na,K-ATPase Is Dependent on Activation of Protein Kinase C-? and -?  

PubMed Central

The purpose of this study was to define mechanisms by which dopamine (DA) regulates the Na,K-ATPase in alveolar epithelial type 2 (AT2) cells. The Na,K-ATPase activity increased by twofold in cells incubated with either 1 ?M DA or a dopaminergic D1 agonist, fenoldopam, but not with the dopaminergic D2 agonist quinpirole. The increase in activity paralleled an increase in Na,K-ATPase ?1 and ?1 protein abundance in the basolateral membrane (BLM) of AT2 cells. This increase in protein abundance was mediated by the exocytosis of Na,K-pumps from late endosomal compartments into the BLM. Down-regulation of diacylglycerol-sensitive types of protein kinase C (PKC) by pretreatment with phorbol 12-myristate 13-acetate or inhibition with bisindolylmaleimide prevented the DA-mediated increase in Na,K-ATPase activity and exocytosis of Na,K-pumps to the BLM. Preincubation of AT2 cells with either 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide (Gö6983), a selective inhibitor of PKC-?, or isozyme-specific inhibitor peptides for PKC-? or PKC-? inhibited the DA-mediated increase in Na,K-ATPase. PKC-? and PKC-?, but not PKC-? or -?, translocated from the cytosol to the membrane fraction after exposure to DA. PKC-?– and PKC-?–specific peptide agonists increased Na,K-ATPase protein abundance in the BLM. Accordingly, dopamine increased Na,K-ATPase activity in alveolar epithelial cells through the exocytosis of Na,K-pumps from late endosomes into the basolateral membrane in a mechanism-dependent activation of the novel protein kinase C isozymes PKC-? and PKC-?. PMID:11950946

Ridge, Karen M.; Dada, Laura; Lecuona, Emilia; Bertorello, Alejandro M.; Katz, Adrian I.; Mochly-Rosen, Daria; Sznajder, Jacob I.



Protective roles of ascorbic acid in oxidative stress induced by depletion of superoxide dismutase in vertebrate cells.  


Superoxide dismutases (SODs) are antioxidant proteins that convert superoxide to hydrogen peroxide. In vertebrate cells, SOD1 is mainly present in the cytoplasm, with small levels also found in the nucleus and mitochondrial intermembrane space, and SOD2 is present in the mitochondrial matrix. Previously, the authors conditionally disrupted the SOD1 or SOD2 gene in DT40 cells and found that depletion of SOD1 caused lethality, while depletion of SOD2 led to growth retardation. The observations from previous work showed that the lethality observed in SOD1-depleted cells was completely rescued by ascorbic acid. Ascorbic acid is a water-soluble antioxidant present in biological fluids; however, the exact target for its antioxidant effects is not known. In this study, the authors demonstrated that ascorbic acid offset growth defects observed in SOD2-depleted cells and also lowered mitochondrial superoxide to physiological levels in both SOD1- or SOD2-depleted cells. Moreover, depletion of SOD1 or SOD2 resulted in the accumulation of intracellular oxidative stress, and this increased oxidative stress was reduced by ascorbic acid. Taken together, this study suggests that ascorbic acid can be applied as a nontoxic antioxidant that mimics the functions of cytoplasmic and mitochondrial SODs. PMID:23016763

Tamari, Yuki; Nawata, Hisakatsu; Inoue, Eri; Yoshimura, Akari; Yoshii, Hanako; Kashino, Genro; Seki, Masayuki; Enomoto, Takemi; Watanabe, Masami; Tano, Keizo



Physical activity and environmental enrichment regulate the generation of neural precursors in the adult mouse substantia nigra in a dopamine-dependent manner  

PubMed Central

Background Parkinson’s disease is characterized by a continuous loss of neurons within the substantia nigra (SN) leading to a depletion of dopamine. Within the adult SN as a non-neurogenic region, cells with mainly oligodendrocytic precursor characteristics, expressing the neuro-glial antigen-2 (NG2) are continuously generated. Proliferation of these cells is altered in animal models of Parkinson’s disease (PD). Exercise and environmental enrichment re-increase proliferation of NG2+ cells in PD models, however, a possible mechanistic role of dopamine for this increase is not completely understood. NG2+ cells can differentiate into oligodendrocytes but also into microglia and neurons as observed in vitro suggesting a possible hint for endogenous regenerative capacity of the SN. We investigated the role of dopamine in NG2-generation and differentiation in the adult SN stimulated by physical activity and environmental enrichment. Results We used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model for dopamine depletion and analysed newborn cells in the SN at different maturation stages and time points depending on voluntary physical activity, enriched environment and levodopa-treatment. We describe an activity- induced increase of new NG2-positive cells and also mature oligodendrocytes in the SN of healthy mice. Running and enriched environment refused to stimulate NG2-generation and oligodendrogenesis in MPTP-mice, an effect which could be reversed by pharmacological levodopa-induced rescue. Conclusion We suggest dopamine being a key regulator for activity-induced generation of NG2-cells and oliogodendrocytes in the SN as a potentially relevant mechanism in endogenous nigral cellular plasticity. PMID:23110504



Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels.  


Glutathione (GSH) and N-acetylcysteine (NAC) are thiol-containing antioxidants, and also act through a direct reaction with free radicals. Transient receptor potential vanilloid 1 (TRPV1) is the principal transduction channel serving as a polymodal detector. Despite the importance of oxidative stress in pain sensitivity, its role in TRPV1 modulation is poorly understood. NAC may also have a regulator role on TRPV1 channel activity in the dorsal root ganglion (DRG) neuron. Therefore, we tested the effects of GSH and NAC on TRPV1 channel current, Ca(2+) influx, oxidative stress and caspase activity in the DRG of mice. DRG neurons were freshly isolated from mice and the neurons were incubated for 6 and 24h with buthionine sulfoximine (BSO). Pretreatment of cultured DRG neurons with NAC, results in a protection against oxidative damages. This neuroprotection is associated with the attenuation of a Ca(2+) influx triggered by oxidative agents such as H2O2, 5,5'-dithiobis-(2-nitrobenzoic acid) and GSH depletion via BSO. Here, we demonstrate the contribution of cytosolic factors (related to thiol group depletion) on the activation of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin (CAP), the pungent component of hot chili peppers, and are blocked by capsazepine. An oxidative environment also increased CAP-evoked TRPV1 currents in the neurons. When NAC and GSH were included in the patch pipette as well as extracellularly in the chamber, TRPV1 channels were not activated by CAP and H2O2. TRPV1 inhibitors, 2-aminoethyl diphenylborinate and N-(p-amylcinnamoyl)anthranilic acid strongly reduced BSO-induced oxidative toxicity and Ca(2+) influx, in a manner similar to pretreatment with NAC and GSH. Caspase-3 and -9 activities of all groups were not changed by the agonists or antagonists. In conclusion, in our experimental model, TRPV1 channels are involved in the oxidative stress-induced neuronal death, and negative modu